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Sample records for degradable liposomal drug

  1. Drug delivery by phospholipase A(2) degradable liposomes

    DEFF Research Database (Denmark)

    Davidsen, Jesper; Vermehren, C.; Frøkjær, S.

    2001-01-01

    The effect of poly(ethylene glycol)-phospholipid (PE-PEG) lipopolymers on phospholipase A(2) (PLA(2)) hydrolysis of liposomes composed of stearoyl-oleoylphosphatidylcholine (SOPC) was investigated. The PLA(2) lag-time, which is inversely related to the enzymatic activity, was determined by fluore...

  2. Enzymatic degradation of polymer covered SOPC-liposomes in relation to drug delivery

    DEFF Research Database (Denmark)

    Davidsen, Jesper; Vermehren, C.; Frøkjær, S.

    2001-01-01

    Polyethylenoxide (PEG) covered liposomes are used as lipid-based drug-delivery systems. In comparison to conventional liposomes the polymer-covered liposomes display a long circulation half-life in the blood stream. We investigate the influence of polyethyleneoxide-distearoylphosphatidylethanolam......Polyethylenoxide (PEG) covered liposomes are used as lipid-based drug-delivery systems. In comparison to conventional liposomes the polymer-covered liposomes display a long circulation half-life in the blood stream. We investigate the influence of polyethyleneoxide...

  3. Plasmon resonant liposomes for controlled drug delivery

    Science.gov (United States)

    Knights-Mitchell, Shellie S.; Romanowski, Marek

    2015-03-01

    Nanotechnology use in drug delivery promotes a reduction in systemic toxicity, improved pharmacokinetics, and better drug bioavailability. Liposomes continue to be extensively researched as drug delivery systems (DDS) with formulations such as Doxil® and Ambisome® approved by FDA and successfully marketed in the United States. However, the limited ability to precisely control release of active ingredients from these vesicles continues to challenge the broad implementation of this technology. Moreover, the full potential of the carrier to sequester drugs until it can reach its intended target has yet to be realized. Here, we describe a liposomal DDS that releases therapeutic doses of an anticancer drug in response to external stimulus. Earlier, we introduced degradable plasmon resonant liposomes. These constructs, obtained by reducing gold on the liposome surface, facilitate spatial and temporal release of drugs upon laser light illumination that ultimately induces an increase in temperature. In this work, plasmon resonant liposomes have been developed to stably encapsulate and retain doxorubicin at physiological conditions represented by isotonic saline at 37o C and pH 7.4. Subsequently, they are stimulated to release contents either by a 5o C increase in temperature or by laser illumination (760 nm and 88 mW/cm2 power density). Successful development of degradable plasmon resonant liposomes responsive to near-infrared light or moderate hyperthermia can provide a new delivery method for multiple lipophilic and hydrophilic drugs with pharmacokinetic profiles that limit clinical utility.

  4. Synthesis and membrane behavior of a new class of unnatural phospholipid analogs useful as phospholipase A2 degradable liposomal drug carriers

    DEFF Research Database (Denmark)

    Andresen, Thomas Lars; Jørgensen, Kent

    2005-01-01

    A new and unnatural type of lipid analogs with the phosphocholine and phosphoglycerol head groups linked to the C-2 position of the glycerol moiety have been synthesized and the thermodynamic lipid membrane behavior has been investigated using differential scanning calorimetry. From the heat capa...... results also suggest new approaches to rationally design liposomal drug carries that can undergo a triggered activation in diseased tissue by overexpressed PLA2....

  5. Targeted drug delivery using temperature-sensitive liposomes

    International Nuclear Information System (INIS)

    Magin, R.L.; Niesman, M.R.

    1984-01-01

    Liposomes are receiving considerable attention as vehicles for selective drug delivery. One method of targeting liposomal contents involves the combination of local hyperthermia with temperature-sensitive liposomes. Such liposomes have been used to increase the uptake of methotrexate and cis-platinum into locally heated mouse tumors. However, additional information is needed on the mechanism of liposome drug release and the physiologic deposition of liposomes in vivo before clinical trails are begun. Current research is directed at studying the encapsulation and release of water soluble drugs from temperature-sensitive liposomes. The influence of liposome size, structure, and composition on the rapid release in plasma of cytosine arabinoside, cis-platinum, and the radiation sensitizer SR-2508 are described. These results demonstrate potential applications for temperature-sensitive liposomes in selective drug delivery

  6. Allometric scaling of pegylated liposomal anticancer drugs.

    Science.gov (United States)

    Caron, Whitney P; Clewell, Harvey; Dedrick, Robert; Ramanathan, Ramesh K; Davis, Whitney L; Yu, Ning; Tonda, Margaret; Schellens, Jan H; Beijnen, Jos H; Zamboni, William C

    2011-10-01

    Pegylated liposomal formulations contain lipid conjugated to polyethylene glycol. The disposition of encapsulated drug is dictated by the composition of the liposome, thus altering the pharmacokinetic (PK) profile of the drug. Allometric scaling is based on a power-log relationship between body weight (W) and drug clearance (CL) among mammals and has been used to compare the disposition of nonliposomal drugs across species. The objectives of this study were to use allometric scaling to: (1) compare the disposition of pegylated liposomal drugs across speciesand determine the best scaling model and (2) predict PK parameters of pegylated liposomal drugs in humans. The PK of pegylated liposomal CKD-602 (S-CKD602), doxorubicin (Doxil®), and cisplatin (SPI-077) were compared. PK studies ofS-CKD602, Doxil®, and SPI-077 were performed at the maximum tolerated dose (MTD) in male and female mice, rats, dogs and patients with refractory solid tumors. The allometric equation used to evaluate the relationship between W and CL in each species was CL = a(W)(m) (a = empirical coefficient; m = allometric exponent). Substitution of physiological variables other than body weight, such as factors representative of the mononuclear phagocyte system (MPS) were evaluated. Dedrick Plots and Maximum Life-Span Potential (MLP) were used to determine scaling feasibility. Standard allometry demonstrated a relationship between clearance of S-CKD602, Doxil®, and SPI-077 and body, spleen, liver, and kidney weights, total monocyte count, and spleen and liver blood flow. However, using scaling to predict CL of these agents in humans often resulted in differences >30%. Despite a strong correlation between body weight and MPS-associated variables with CL among preclinical species, the use of the equations did not predict CL. Thus, new methods of allometric scaling and measures of MPS function need to be developed.

  7. Interaction of cationic drugs with liposomes.

    Science.gov (United States)

    Howell, Brett A; Chauhan, Anuj

    2009-10-20

    Interactions between cationic drugs and anionic liposomes were studied by measuring binding of drugs and the effect of binding on liposome permeability. The measurements were analyzed in the context of a continuum model based on electrostatic interactions and a Langmuir isotherm. Experiments and modeling indicate that, although electrostatic interactions are important, the fraction of drug sequestered in the double-layer is negligible. The majority of drug enters the bilayer with the charged regions interacting with the charged lipid head groups and the lipophilic regions associated with the bilayer. The partitioning of the drug can be described by a Langmuir isotherm with the electrostatic interactions increasing the sublayer concentration of the drug. The binding isotherms are similar for all tricyclic antidepressants (TCA). Bupivacaine (BUP) binds significantly less compared to TCA because its structure is such that the charged region has minimal interactions with the lipid heads once the BUP molecule partitions inside the bilayer. Conversely, the TCAs are linear with distinct hydrophilic and lipophilic regions, allowing the lipophilic regions to lie inside the bilayer and the hydrophilic regions to protrude out. This conformation maximizes the permeability of the bilayer, leading to an increased release of a hydrophilic fluorescent dye from liposomes.

  8. Delivery of aerosolized drugs encapsulated in liposomes

    Energy Technology Data Exchange (ETDEWEB)

    Cheng, Yung-Sung; Lyons, C.R. [Univ. of New Mexico, Albuquerque, NM (United States); Schmid, M.H.

    1995-12-01

    Mycobacterium tuberculosis (Mtb) is an infectious disease that resides in the human lung. Due to the difficulty in completely killing off the disease in infected individuals, Mtb has developed drug-resistant forms and is on the rise in the human population. Therefore, ITRI and the University of New Mexico are collaborating to explore the treatment of Mtb by an aerosolized drug delivered directly to the lungs. In conclusion, it is feasible to obtain an appropriate size and concentration of the liposomes before and after aerosolization.

  9. Liposomal Drug Delivery of Anticancer Agents

    DEFF Research Database (Denmark)

    Pedersen, Palle Jacob

    In the first part of the thesis the work towards a new generation of liposomal drug delivery systems for anticancer agents is described. The drug delivery system takes advantage of the elevated level of secretory phospholipase A2 (sPLA2) IIA in many tumors and the enhanced permeability......-trans retinoic acid, α-tocopheryl succinate and calcitriol were examined for their ability to be incorporated into the investigated drug delivery system and syntheses of the phospholipid prodrugs are described. The majority of the phospholipid prodrugs were able to form particles with diameters close to 100 nm...... that upon sPLA2 triggering the formulated phospholipid prodrugs displayed IC50 values in range from 3–36 μM and complete cell death was observed when higher drug concentrations were applied. Promising for the drug delivery system the majority of the phospholipid prodrugs remain non-toxic in the absence...

  10. Advances and Challenges of Liposome Assisted Drug Delivery

    Directory of Open Access Journals (Sweden)

    Lisa eSercombe

    2015-12-01

    Full Text Available The application of liposomes to assist drug delivery has already had a major impact on many biomedical areas. They have been shown to be beneficial for stabilizing therapeutic compounds, overcoming obstacles to cellular and tissue uptake, and improving biodistribution of compounds to target sites in vivo. This enables effective delivery of encapsulated compounds to target sites while minimizing systemic toxicity. Liposomes present as an attractive delivery system due to their flexible physicochemical and biophysical properties, which allow easy manipulation to address different delivery considerations. Despite considerable research in the last 50 years and the plethora of positive results in preclinical studies, the clinical translation of liposome assisted drug delivery platforms has progressed incrementally. In this review, we will discuss the advances in liposome assisted drug delivery, biological challenges that still remain, and current clinical and experimental use of liposomes for biomedical applications. The translational obstacles of liposomal technology will also be presented.

  11. Liposome-based drug delivery in breast cancer treatment

    International Nuclear Information System (INIS)

    Park, John W

    2002-01-01

    Drug delivery systems can in principle provide enhanced efficacy and/or reduced toxicity for anticancer agents. Long circulating macromolecular carriers such as liposomes can exploit the 'enhanced permeability and retention' effect for preferential extravasation from tumor vessels. Liposomal anthracyclines have achieved highly efficient drug encapsulation, resulting in significant anticancer activity with reduced cardiotoxicity, and include versions with greatly prolonged circulation such as liposomal daunorubicin and pegylated liposomal doxorubicin. Pegylated liposomal doxorubucin has shown substantial efficacy in breast cancer treatment both as monotherapy and in combination with other chemotherapeutics. Additional liposome constructs are being developed for the delivery of other drugs. The next generation of delivery systems will include true molecular targeting; immunoliposomes and other ligand-directed constructs represent an integration of biological components capable of tumor recognition with delivery technologies

  12. Stimuli-Responsive Liposomes for Controlled Drug Delivery

    KAUST Repository

    Li, Wengang

    2014-09-01

    Liposomes are promising drug delivery vesicles due to their biodegradibility, large volume and biocompatibility towards both hydrophilic and hydrophobic drugs. They suffer, however, from poor stability which limits their use in controlled delivery applications. Herein, a novel method was devised for modification of liposomes with small molecules, polymers or nanoparticles to afford stimuli responsive systems that release on demand and stay relatively stable in the absence of the trigger.. This dissertation discusses thermosensitive, pH sensitive, light sensitive and magnetically triggered liposomes that have been prepared for controlled drug delivery application. RAFT polymerization was utilized for the preparation of thermosensitive liposomes (Cholesterol-PNIPAm) and acid-labile liposomes (DOPE-PAA). With low Mw Cholesterol-PNIPAm, the thermosensitive liposomes proved to be effective for controlled release and decreased the cytotoxicity of PNIPAm by eliciting the polymer doses. By crosslinking the DOPE-PAA on liposome surface with acid-labile diamine linkers, DOPE-PAA liposomes were verified to be sensitive at low pH. The effects of polymer structures (linear or hyperbranched) have also been studied for the stability and release properties of liposomes. Finally, a dual-responsive Au@SPIO embedded liposome hybrid (ALHs) was prepared with light-induced “on-and-off” function by photo-thermal process (visible light) and instant release properties triggered by alternating magnetic field, respectively. The ALH system would be further applied into the cellular imaging field as MRI contrast agent.

  13. Liposomal Conjugates for Drug Delivery to the Central Nervous System

    Directory of Open Access Journals (Sweden)

    Frieder Helm

    2015-04-01

    Full Text Available Treatments of central nervous system (CNS diseases often fail due to the blood–brain barrier. Circumvention of this obstacle is crucial for any systemic treatment of such diseases to be effective. One approach to transfer drugs into the brain is the use of colloidal carrier systems—amongst others, liposomes. A prerequisite for successful drug delivery by colloidal carriers to the brain is the modification of their surface, making them invisible to the reticuloendothelial system (RES and to target them to specific surface epitopes at the blood–brain barrier. This study characterizes liposomes conjugated with cationized bovine serum albumin (cBSA as transport vectors in vitro in porcine brain capillary endothelial cells (PBCEC and in vivo in rats using fluorescently labelled liposomes. Experiments with PBCEC showed that sterically stabilized (PEGylated liposomes without protein as well as liposomes conjugated to native bovine serum albumin (BSA were not taken up. In contrast, cBSA-liposomes were taken up and appeared to be concentrated in intracellular vesicles. Uptake occurred in a concentration and time dependent manner. Free BSA and free cBSA inhibited uptake. After intravenous application of cBSA-liposomes, confocal fluorescence microscopy of brain cryosections from male Wistar rats showed fluorescence associated with liposomes in brain capillary surrounding tissue after 3, 6 and 24 h, for liposomes with a diameter between 120 and 150 nm, suggesting successful brain delivery of cationized-albumin coupled liposomes.

  14. Formulation and Evaluation of Rifampicin Liposomes for Buccal Drug Delivery.

    Science.gov (United States)

    Lankalapalli, Srinivas; Tenneti, V S Vinai Kumar

    2016-01-01

    Drug delivery through liposomes offers several advantages, but still challenging to the researchers for the use of liposomes as carriers in drug delivery due to their poor physical stability, unpredictable drug encapsulation and systemic availability of the loaded drug. The present investigation was planned with an objective to prepare Rifampicin loaded liposomes by using response surface methodology of statistical 32 factorial design and further to formulate them into pastilles for deliver through buccal route thereby to enhance systemic absorption. Rifampicin liposomes were prepared by using different ratios of soya lecithin and cholesterol by solvent Injection method. These liposomes were characterized by using optical microscopy, Scanning Electron Microscopy (SEM) and evaluated for particle size, entrapment efficiency (EE), in vitro and ex vivo drug release. Main effects and interaction terms of the formulation variables were evaluated quantitatively using a mathematical statistical model approach showing that both independent variables have significant (P value value: 0.0273), percentage entrapment efficiency (P value: 0.0096), percentage drug release through dialysis membrane (P value: 0.0047) and percentage drug release through porcine buccal membrane (P value: 0.0019). The statistical factorial design of liposomal formulations fulfilled all the requirements of the target set and exhibited suitable values for the selected test parameters. Pastilles were prepared for liposomes using glycerol gelatin base and were found to be soft, smooth with uniform drug content and drug release.

  15. Electromagnetic field triggered drug and chemical delivery via liposomes

    Science.gov (United States)

    Liburdy, Robert P.

    1993-01-01

    The present invention relates to a system and to a method of delivering a drug to a preselected target body site of a patient, comprising the steps of encapsulating the chemical agent within liposomes, essentially temperature insensitive, i.e. not having a specific predetermined phase transition temperature within the specific temperature range of drug administration; administering the liposomes to the target body site; and subjecting the target body site to nonionizing electromagnetic fields in an area of the preselected target body in order to release said chemical agent from the liposomes at a temperature of between about +10 and 65.degree. C. The invention further relates to the use of said liposomes to bind to the surface of or to enter target tissue or an organ in a living system, and, when subjected to a nonionizing field, to release a drug from the liposomes into the target site.

  16. Physico-chemical characterization of liposomes and drug substance-liposome interactions in pharmaceutics using capillary electrophoresis and electrokinetic chromatography

    DEFF Research Database (Denmark)

    Franzen, Ulrik; Østergaard, Jesper

    2012-01-01

    electrophoresis and liposome electrokinetic chromatography for the characterization of liposomes in a pharmaceutical context. Capillary electrophoretic techniques have been used for the measurement of electrophoretic mobility, which provides information on liposome surface charge, size and membrane permeability...... of liposomes. The use of liposome electrokinetic chromatography and capillary electrophoresis for determination of liposome/water partitioning and characterization of drug-liposome interactions is reviewed. A number of studies indicate that capillary electrophoresis may have a role in the characterization......Liposomes are self-assembled phospholipid vesicles and have numerous research and therapeutic applications. In the pharmaceutical and biomedical sciences liposomes find use as models of biological membranes, partitioning medium and as drug carriers. The present review addresses the use of capillary...

  17. Encapsulation of antitumor drug methotrexate in liposome vesicles

    International Nuclear Information System (INIS)

    Xu Bo; Sun Qixun; Zhang Nianbao; Xie Binghua; Zhang Jiong

    1990-01-01

    Liposome vesicles containing antitumor drug methotrexate (MTX) were prepared. MTX was labelled by the tritium ion beam method. After purification by TLC, the specific radioactivity of 3 H-MTX was 1.19 GBq/mmol with radiochemical purity orver 95%. Under various forming conditions of liposome vesicles, the efficiency of encapsulation was 21-53%

  18. Recent advances in liposomal nanohybrid cerasomes as promising drug nanocarriers.

    Science.gov (United States)

    Yue, Xiuli; Dai, Zhifei

    2014-05-01

    Liposomes have been extensively investigated as possible carriers for diagnostic or therapeutic agents due to their unique properties. However, liposomes still have not attained their full potential as drug and gene delivery vehicles because of their insufficient morphological stability. Recently, a super-stable and freestanding hybrid liposomal cerasome (partially ceramic- or silica-coated liposome) has drawn much attention as a novel drug delivery system because its atomic layer of polyorganosiloxane surface imparts higher morphological stability than conventional liposomes and its liposomal bilayer structure reduces the overall rigidity and density greatly compared to silica nanoparticles. Cerasomes are more biocompatible than silica nanoparticles due to the incorporation of the liposomal architecture into cerasomes. Cerasomes combine the advantages of both liposomes and silica nanoparticles but overcome their disadvantages so cerasomes are ideal drug delivery systems. The present review will first highlights some of the key advances of the past decade in the technology of cerasome production and then review current biomedical applications of cerasomes, with a view to stimulating further research in this area of study. Copyright © 2013 Elsevier B.V. All rights reserved.

  19. Designing of 'intelligent' liposomes for efficient delivery of drugs.

    Science.gov (United States)

    Voinea, Manuela; Simionescu, Maya

    2002-01-01

    The liposome- vesicles made by a double phospholipid layers which may encapsulate aqueous solutions- have been introduced as drug delivery vehicles due to their structural flexibility in size, composition and bilayer fluidity as well as their ability to incorporate a large variety of both hydrophilic and hydrophobic compounds. With time the liposome formulations have been perfected so as to serve certain purposes and this lead to the design of "intelligent" liposomes which can stand specifically induced modifications of the bilayers or can be surfaced with different ligands that guide them to the specific target sites. We present here a brief overview of the current strategies in the design of liposomes as drug delivery carriers and the medical applications of liposomes in humans.

  20. Radionuclide imaging of liposomal drug delivery

    NARCIS (Netherlands)

    van der Geest, Tessa; Laverman, Peter; Metselaar, Josbert M.|info:eu-repo/dai/nl/244207690; Storm, G|info:eu-repo/dai/nl/073356328; Boerman, Otto C.

    2016-01-01

    Introduction: Ever since their discovery, liposomes have been radiolabeled to monitor their fate in vivo. Despite extensive preclinical studies, only a limited number of radiolabeled liposomal formulations have been examined in patients. Since they can play a crucial role in patient management, it

  1. Radionuclide imaging of liposomal drug delivery

    NARCIS (Netherlands)

    Geest, T. van der; Laverman, P.; Metselaar, J.M.; Storm, G.; Boerman, O.C.

    2016-01-01

    Ever since their discovery, liposomes have been radiolabeled to monitor their fate in vivo. Despite extensive preclinical studies, only a limited number of radiolabeled liposomal formulations have been examined in patients. Since they can play a crucial role in patient management, it is of

  2. Lipophilic drug transfer between liposomal and biological membranes

    DEFF Research Database (Denmark)

    Fahr, Alfred; van Hoogevest, Peter; Kuntsche, Judith

    2006-01-01

    This review presents the current knowledge on the interaction of lipophilic, poorly water soluble drugs with liposomal and biological membranes. The center of attention will be on drugs having the potential to dissolve in a lipid membrane without perturbing them too much. The degree of interaction...... is described as solubility of a drug in phospholipid membranes and the kinetics of transfer of a lipophilic drug between membranes. Finally, the consequences of these two factors on the design of lipid-based carriers for oral, as well as parenteral use, for lipophilic drugs and lead selection of oral...... lipophilic drugs is described. Since liposomes serve as model-membranes for natural membranes, the assessment of lipid solubility and transfer kinetics of lipophilic drug using liposome formulations may additionally have predictive value for bioavailability and biodistribution and the pharmacokinetics...

  3. Avanafil Liposomes as Transdermal Drug Delivery for Erectile ...

    African Journals Online (AJOL)

    Conclusion: The developed avanafil liposomes represent a promising transdermal drug delivery system for the treatment of erectile dysfunction. ... skin, in recent years, transdermal drug delivery has been used to overcome the problems ... Drugs Technology Co., Ltd. [Hangzhou, China]. The egg phosphatidylcholine (PC), ...

  4. Thermosensitive liposomal drug delivery systems: state of the art review

    Directory of Open Access Journals (Sweden)

    Kneidl B

    2014-09-01

    Full Text Available Barbara Kneidl,1,2 Michael Peller,3 Gerhard Winter,2 Lars H Lindner,1 Martin Hossann11Department of Internal Medicine III, University Hospital Munich, 2Department of Pharmacy, Pharmaceutical Technology and Biopharmaceutics, 3Institute for Clinical Radiology, University Hospital Munich, Ludwig-Maximilians University, Munich, GermanyAbstract: Thermosensitive liposomes are a promising tool for external targeting of drugs to solid tumors when used in combination with local hyperthermia or high intensity focused ultrasound. In vivo results have demonstrated strong evidence that external targeting is superior over passive targeting achieved by highly stable long-circulating drug formulations like PEGylated liposomal doxorubicin. Up to March 2014, the Web of Science listed 371 original papers in this field, with 45 in 2013 alone. Several formulations have been developed since 1978, with lysolipid-containing, low temperature-sensitive liposomes currently under clinical investigation. This review summarizes the historical development and effects of particular phospholipids and surfactants on the biophysical properties and in vivo efficacy of thermosensitive liposome formulations. Further, treatment strategies for solid tumors are discussed. Here we focus on temperature-triggered intravascular and interstitial drug release. Drug delivery guided by magnetic resonance imaging further adds the possibility of performing online monitoring of a heating focus to calculate locally released drug concentrations and to externally control drug release by steering the heating volume and power. The combination of external targeting with thermosensitive liposomes and magnetic resonance-guided drug delivery will be the unique characteristic of this nanotechnology approach in medicine.Keywords: thermosensitive liposomes, phosphatidyloligoglycerol, hyperthermia, high intensity focused ultrasound, drug delivery, drug targeting

  5. Liposomal Drug Product Development and Quality: Current US Experience and Perspective.

    Science.gov (United States)

    Kapoor, Mamta; Lee, Sau L; Tyner, Katherine M

    2017-05-01

    Research in the area of liposomes has grown substantially in the past few decades. Liposomes are lipid bilayer structures that can incorporate drug substances to modify the drug's pharmacokinetic profile thereby improving drug delivery. The agency has received over 400 liposomal drug product submissions (excluding combination therapies), and there are currently eight approved liposomal drug products on the US market. In order to identify the pain points in development and manufacturing of liposomal drug products, a retrospective analysis was performed from a quality perspective on submissions for new and generic liposomal drug products. General analysis on liposomal drug product submissions was also performed. Results indicated that 96% of the submissions were Investigational New Drug (IND) applications, 3% were New Drug Applications (NDAs), and the remaining 1% was Abbreviated New Drug Applications (ANDAs). Doxorubicin hydrochloride was the most commonly used drug substance incorporated into the liposomes (31%). The majority of the liposomal products were administered via intravenous route (84%) with cancer (various types) being the most common indication (63%). From a quality perspective, major challenges during the development of liposomal drug products included identification and (appropriate) characterization of critical quality attributes of liposomal drug products and suitable control strategies during product development. By focusing on these areas, a faster and more efficient development of liposomal drug products may be achieved. Additionally, in this way, the drug review process for such products can be streamlined.

  6. “Smart” Drug Carriers: PEGylated TATp-Modified pH-Sensitive Liposomes

    Science.gov (United States)

    KALE, AMIT A.; TORCHILIN, VLADIMIR P.

    2012-01-01

    To engineer drug carriers capable of spontaneous accumulation in tumors and ischemic areas via the enhanced permeability and retention (EPR) effect and further penetration and drug delivery inside tumor or ischemic cells via the action of the cell-penetrating peptide (CPP), we have prepared liposomes simultaneously bearing on their surface CPP (TAT peptide, TATp) moieties and protective PEG chains. PEG chains were incorporated into the liposome membrane via the PEG-attached phosphatidylethanolamine (PE) residue with PEG and PE being conjugated with the lowered pH-degradable hydrazone bond (PEG-HZ-PE). Under normal conditions, liposome-grafted PEG “shielded” liposome-attached TATp moieties since the PEG spacer for TATp attachment (PEG1000) was shorter than protective PEG2000. PEGy-lated liposomes are expected to accumulate in targets via the EPR effect, but inside the “acidified” tumor or ischemic tissues lose their PEG coating due to the lowered pH-induced hydrolysis of HZ and penetrate inside cells via the now-exposed TATp moieties. This concept is shown here to work in cell cultures in vitro as well as in ischemic cardiac tissues in the Langendorff perfused rat heart model and in tumors in experimental mice in vivo. PMID:18027240

  7. "Smart" drug carriers: PEGylated TATp-modified pH-sensitive liposomes.

    Science.gov (United States)

    Kale, Amit A; Torchilin, Vladimir P

    2007-01-01

    To engineer drug carriers capable of spontaneous accumulation in tumors and ischemic areas via the enhanced permeability and retention (EPR) effect and further penetration and drug delivery inside tumor or ischemic cells via the action of the cell-penetrating peptide (CPP), we have prepared liposomes simultaneously bearing on their surface CPP (TAT peptide, TATp) moieties and protective PEG chains. PEG chains were incorporated into the liposome membrane via the PEG-attached phosphatidylethanolamine (PE) residue with PEG and PE being conjugated with the lowered pH-degradable hydrazone bond (PEG-HZ-PE). Under normal conditions, liposome-grafted PEG "shielded" liposome-attached TATp moieties since the PEG spacer for TATp attachment (PEG(1000)) was shorter than protective PEG(2000). PEGylated liposomes are expected to accumulate in targets via the EPR effect, but inside the "acidified" tumor or ischemic tissues lose their PEG coating due to the lowered pH-induced hydrolysis of HZ and penetrate inside cells via the now-exposed TATp moieties. This concept is shown here to work in cell cultures in vitro as well as in ischemic cardiac tissues in the Langendorff perfused rat heart model and in tumors in experimental mice in vivo.

  8. Soft Interaction in Liposome Nanocarriers for Therapeutic Drug Delivery

    Directory of Open Access Journals (Sweden)

    Domenico Lombardo

    2016-06-01

    Full Text Available The development of smart nanocarriers for the delivery of therapeutic drugs has experienced considerable expansion in recent decades, with the development of new medicines devoted to cancer treatment. In this respect a wide range of strategies can be developed by employing liposome nanocarriers with desired physico-chemical properties that, by exploiting a combination of a number of suitable soft interactions, can facilitate the transit through the biological barriers from the point of administration up to the site of drug action. As a result, the materials engineer has generated through the bottom up approach a variety of supramolecular nanocarriers for the encapsulation and controlled delivery of therapeutics which have revealed beneficial developments for stabilizing drug compounds, overcoming impediments to cellular and tissue uptake, and improving biodistribution of therapeutic compounds to target sites. Herein we present recent advances in liposome drug delivery by analyzing the main structural features of liposome nanocarriers which strongly influence their interaction in solution. More specifically, we will focus on the analysis of the relevant soft interactions involved in drug delivery processes which are responsible of main behaviour of soft nanocarriers in complex physiological fluids. Investigation of the interaction between liposomes at the molecular level can be considered an important platform for the modeling of the molecular recognition processes occurring between cells. Some relevant strategies to overcome the biological barriers during the drug delivery of the nanocarriers are presented which outline the main structure-properties relationships as well as their advantages (and drawbacks in therapeutic and biomedical applications.

  9. Liposomal drug delivery system from laboratory to clinic

    Directory of Open Access Journals (Sweden)

    Kshirsagar N

    2005-01-01

    Full Text Available The main objective of drug delivery systems is to deliver a drug effectively, specifically to the site of action and to achieve greater efficacy and minimise the toxic effects compared to conventional drugs. Amongst various carrier systems, liposomes have generated a great interest because of their versatility. Liposomes are vesicular concentric bilayered structures, which are biocompatible, biodegradable and nonimmumnogenic. They can control the delivery of drugs by targeting the drug to the site of action or by site avoidance drug delivery or by prolonged circulation of drugs. Amphotericin B (Amp B remains the drug of choice in most systemic mycoses and also as a second line treatment for Kala azar. However, its toxic effects often limit its use. Although the liposome delivery system has been tried for several drugs, only a few have been used in patients due to the slow development of necessary large-scale pharmaceutical procedures. This paper reviews the development of the technique for liposomal Amphotericin B (L-Amp-LRC-1, FungisomeTM drug delivery system in our laboratory in collaboration with the department of Biochemistry, Delhi University in India and proving the safety and efficacy of this preparation in clinical practice. It also attempts to compare the efficacy and benefits of our product for Indian patients with those of similar products and it includes facts from the publications that flowed from our work. As compared to conventional Amp B, Fungisome is infused over a much shorter period requiring a smaller volume and no premedication. It was found to be safe in patients who had developed serious unacceptable toxicity with conventional Amp B. In renal transplant patients, Fungisome did not produce any nephrotoxicity. Fungisome is effective in fungal infections resistant to fluconazole, conventional Amp B and in virgin and resistant cases of visceral leishmaniasis. The cost of any drug is of great significance, especially in India

  10. Thermosensitive liposomes entrapping iron oxide nanoparticles for controllable drug release

    International Nuclear Information System (INIS)

    Tai, L-A; Wang, Y-C; Wang, Y-J; Yang, C-S; Tsai, P-J; Lo, L-W

    2009-01-01

    Iron oxide nanoparticles can serve as a heating source upon alternative magnetic field (AMF) exposure. Iron oxide nanoparticles can be mixed with thermosensitive nanovehicles for hyperthermia-induced drug release, yet such a design and mechanism may not be suitable for controllable drug release applications in which the tissues are susceptible to environmental temperature change such as brain tissue. In the present study, iron oxide nanoparticles were entrapped inside of thermosensitive liposomes for AMF-induced drug release while the environmental temperature was maintained at a constant level. Carboxyfluorescein was co-entrapped with the iron oxide nanoparticles in the liposomes as a model compound for monitoring drug release and environmental temperature was maintained with a water circulator jacket. These experiments have been successfully performed in solution, in phantom and in anesthetized animals. Furthermore, the thermosensitive liposomes were administered into rat forearm skeletal muscle, and the release of carboxylfluorescein triggered by the external alternative magnetic field was monitored by an implanted microdialysis perfusion probe with an on-line laser-induced fluorescence detector. In the future such a device could be applied to simultaneous magnetic resonance imaging and non-invasive drug release in temperature-sensitive applications.

  11. Physicochemical properties of extruded and non-extruded liposomes containing the hydrophobic drug dexamethasone.

    Science.gov (United States)

    Bhardwaj, Upkar; Burgess, Diane J

    2010-03-30

    The physicochemical and release properties of non-extruded 'multilamellar' and small sonicated and extruded 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) liposomes containing hydrophobic drug dexamethasone were investigated. Non-extruded liposomes had similar diameter, however dexamethasone encapsulation decreased with increase in lipid chain length. Dexamethasone destabilized the liposome membranes as indicated by decrease in enthalpy and increase in the peak width of the main transition. Based on calorimetric analysis, it appeared that dexamethasone and cholesterol were heterogeneously distributed in the non-extruded liposomes. Sonication and extrusion reduced the diameter (DSPC>DPPC>DMPC) and decreased drug encapsulation (approximately 50%). Cholesterol incorporation decreased drug encapsulation in both extruded and non-extruded DMPC liposomes which appeared to be due to structural similarities between cholesterol and dexamethasone. Incorporation of dexamethasone and cholesterol in the same DMPC liposomes caused a marked perturbation in the phase transition. Dexamethasone release from extruded liposomes was fast, while non-extruded liposomes showed slower release. Release was fastest from DMPC liposomes and slowest from liposomes of high phase transition lipid DSPC. Incorporation of cholesterol did not decrease release from DMPC liposomes. These results indicated that change in the physicochemical properties and the phase transition behavior of liposomes, due to processing as well as incorporation of hydrophobic drug dexamethasone, changed their release properties. Copyright (c) 2009 Elsevier B.V. All rights reserved.

  12. Physicochemical characterization of liposomes after ultrasound exposure - mechanisms of drug release

    DEFF Research Database (Denmark)

    Evjen, Tove J; Hupfeld, Stefan; Barnert, Sabine

    2013-01-01

    -mediated drug release of liposomes (sonosensitivity) was shown to strongly depend on liposome membrane composition. In the current study the ultrasound-mediated drug release mechanism of liposomes was investigated. The results showed that differences in ultrasound drug release kinetics obtained for different......Ultrasound is investigated as a novel drug delivery tool within cancer therapy. Non-thermal ultrasound treatment of solid tumours post i.v.-injection of drug-carrying liposomes may induce local drug release from the carrier followed by enhanced intracellular drug uptake. Recently, ultrasound...... liposomal compositions were caused by distinctive release mechanisms of the carriers. Two types of liposomes composed of 1,2-dioleoyl-sn-glycero-3-phosphatidylethanolamine (DOPE) and hydrogenated soy L-α-phosphatidylcholine (HSPC) as main lipids, respectively, were recently shown to vary in sonosensitivity...

  13. Formation of drug nanocrystals under nanoconfinement afforded by liposomes

    DEFF Research Database (Denmark)

    Cipolla, D.; Wu, H.; Salentinig, Stefan

    2016-01-01

    Nanocrystals of drug substances have important therapeutic applications, but their preparation is often difficult due to size control in bottom up approaches, or energetic milling and surface activation in top down processing. In this study, confinement within liposome nanocompartments is demonst...... physical means (e.g., freeze/thaw) is an attractive possibility, especially in highly regulated industries such as pharmaceuticals where qualitative and quantitative changes of composition would require extensive safety evaluations....

  14. Tumor burden talks in cancer treatment with PEGylated liposomal drugs.

    Directory of Open Access Journals (Sweden)

    Yi-Yu Lin

    Full Text Available PURPOSE: PEGylated liposomes are important drug carriers that can passively target tumor by enhanced permeability and retention (EPR effect in neoplasm lesions. This study demonstrated that tumor burden determines the tumor uptake, and also the tumor response, in cancer treatment with PEGylated liposomal drugs in a C26/tk-luc colon carcinoma-bearing mouse model. METHODS: Empty PEGylated liposomes (NanoX and those encapsulated with VNB (NanoVNB were labeled with In-111 to obtain InNanoX and InVNBL in high labeling yield and radiochemical purity (all >90%. BALB/c mice bearing either small (58.4±8.0 mm(3 or large (102.4±22.0 mm(3 C26/tk-luc tumors in the right dorsal flank were intravenously administered with NanoVNB, InNanoX, InVNBL, or NanoX as a control, every 7 days for 3 times. The therapeutic efficacy was evaluated by body weight loss, tumor growth inhibition (using calipers and bioluminescence imaging and survival fraction. The scintigraphic imaging of tumor mouse was performed during and after treatment. RESULTS: The biodistribution study of InVNBL revealed a clear inverse correlation (r (2 = 0.9336 between the tumor uptake and the tumor mass ranged from 27.6 to 623.9 mg. All three liposomal drugs showed better therapeutic efficacy in small-tumor mice than in large-tumor mice. Tumor-bearing mice treated with InVNBL (a combination drug showed the highest tumor growth inhibition rate and survival fraction compared to those treated with NanoVNB (chemodrug only and InNanoX (radionuclide only. Specific tumor targeting and significantly increased tumor uptake after periodical treatment with InVNBL were evidenced by scintigraphic imaging, especially in mice bearing small tumors. CONCLUSION: The significant differences in the outcomes of cancer treatment and molecular imaging between animals bearing small and large tumors revealed that tumor burden is a critical and discriminative factor in cancer therapy using PEGylated liposomal drugs.

  15. Factorial design studies of antiretroviral drug-loaded stealth liposomal injectable: PEGylation, lyophilization and pharmacokinetic studies

    Science.gov (United States)

    Sudhakar, Beeravelli; Krishna, Mylangam Chaitanya; Murthy, Kolapalli Venkata Ramana

    2016-01-01

    The aim of the present study was to formulate and evaluate the ritonavir-loaded stealth liposomes by using 32 factorial design and intended to delivered by parenteral delivery. Liposomes were prepared by ethanol injection method using 32 factorial designs and characterized for various physicochemical parameters such as drug content, size, zeta potential, entrapment efficiency and in vitro drug release. The optimization process was carried out using desirability and overlay plots. The selected formulation was subjected to PEGylation using 10 % PEG-10000 solution. Stealth liposomes were characterized for the above-mentioned parameters along with surface morphology, Fourier transform infrared spectrophotometer, differential scanning calorimeter, stability and in vivo pharmacokinetic studies in rats. Stealth liposomes showed better result compared to conventional liposomes due to effect of PEG-10000. The in vivo studies revealed that stealth liposomes showed better residence time compared to conventional liposomes and pure drug solution. The conventional liposomes and pure drug showed dose-dependent pharmacokinetics, whereas stealth liposomes showed long circulation half-life compared to conventional liposomes and pure ritonavir solution. The results of statistical analysis showed significance difference as the p value is (<0.05) by one-way ANOVA. The result of the present study revealed that stealth liposomes are promising tool in antiretroviral therapy.

  16. Hydrophobic Drug-Loaded PEGylated Magnetic Liposomes for Drug-Controlled Release

    Science.gov (United States)

    Hardiansyah, Andri; Yang, Ming-Chien; Liu, Ting-Yu; Kuo, Chih-Yu; Huang, Li-Ying; Chan, Tzu-Yi

    2017-05-01

    Less targeted and limited solubility of hydrophobic-based drug are one of the serious obstacles in drug delivery system. Thus, new strategies to enhance the solubility of hydrophobic drug and controlled release behaviors would be developed. Herein, curcumin, a model of hydrophobic drug, has been loaded into PEGylated magnetic liposomes as a drug carrier platform for drug controlled release system. Inductive magnetic heating (hyperthermia)-stimulated drug release, in vitro cellular cytotoxicity assay of curcumin-loaded PEGylated magnetic liposomes and cellular internalization-induced by magnetic guidance would be investigated. The resultant of drug carriers could disperse homogeneously in aqueous solution, showing a superparamagnetic characteristic and could inductive magnetic heating with external high-frequency magnetic field (HFMF). In vitro curcumin release studies confirmed that the drug carriers exhibited no significant release at 37 °C, whereas exhibited rapid releasing at 45 °C. However, it would display enormous (three times higher) curcumin releasing under the HFMF exposure, compared with that without HFMF exposure at 45 °C. In vitro cytotoxicity test shows that curcumin-loaded PEGylated magnetic liposomes could efficiently kill MCF-7 cells in parallel with increasing curcumin concentration. Fluorescence microscopy observed that these drug carriers could internalize efficiently into the cellular compartment of MCF-7 cells. Thus, it would be anticipated that the novel hydrophobic drug-loaded PEGylated magnetic liposomes in combination with inductive magnetic heating are promising to apply in the combination of chemotherapy and thermotherapy for cancer therapy.

  17. Characterization and stability of liposome-enveloped trypsin/Fe3O4 for drug delivery and drug release behavior.

    Science.gov (United States)

    Kim, Min-Jung; Jang, Dae-Hwan; Kim, Hak-Kyong; Lee, Young-In; Lee, Gun-Jae; Yoo, Bong-Young; Choa, Yong-Ho

    2011-05-01

    Liposome encapsulating Fe3O4 (liposome complexes) has been prepared for targeting a drug to a specific organ, as well as for MRI (magnetic resonance imaging) contrast agents. The objective of the present work was to investigate the Fe3O4 properties and the effects of chitosan concentration on the characteristics of chitosan-coated liposome complexes. They were characterized by DLS, FT-IR, XRD, VSM, UV-Vis spectrometer, TEM and phase-contrast microscopy. The average liposome complex size was approximately 500 nm, with individual Fe3O4 nanoparticle sizes of 10 nm. The drug incorporation efficiency of trypsin in liposome complexes was 65-69%, the drug release was sustained and the incorporated drugs had the magnetization properties of the liposome complexes. Incorporation of chitosan into the liposome bilayer decreased trypsin release from the liposome complexes due to an increased rigidity of the liposome membrane structure. Chitosan-coated liposome complexes showed a higher stability when compared with the stability of non-coated liposome complexes.

  18. Determination of platinum drug release and liposome stability in human plasma by CE-ICP-MS

    DEFF Research Database (Denmark)

    Nguyen, Trinh Thi Nhu Tam; Ostergaard, Jesper; Stürup, Stefan

    2013-01-01

    by sonication was also demonstrated. Analysis of liposomal formulations with alternative phospholipid compositions containing oxaliplatin showed similar results. Thus, the present in vitro method is suitable for mimicking the in vivo drug release profile in human plasma after administration of liposomal...... of the encapsulation efficiency of the formulation, the physical stability of liposomes as well as cisplatin leakage in human plasma. The method was applied for studying the disintegration of liposomes and the interactions of leaked cisplatin with plasma components. Triggered release of the drug into plasma...... platinum formulations to patients. This approach may be of use in early drug development as well as in quality control....

  19. Indocyanine Green-Loaded Liposomes for Light-Triggered Drug Release.

    Science.gov (United States)

    Lajunen, Tatu; Kontturi, Leena-Stiina; Viitala, Lauri; Manna, Moutusi; Cramariuc, Oana; Róg, Tomasz; Bunker, Alex; Laaksonen, Timo; Viitala, Tapani; Murtomäki, Lasse; Urtti, Arto

    2016-06-06

    Light-triggered drug delivery systems enable site-specific and time-controlled drug release. In previous work, we have achieved this with liposomes containing gold nanoparticles in the aqueous core. Gold nanoparticles absorb near-infrared light and release the energy as heat that increases the permeability of the liposomal bilayer, thus releasing the contents of the liposome. In this work, we replaced the gold nanoparticles with the clinically approved imaging agent indocyanine green (ICG). The ICG liposomes were stable at storage conditions (4-22 °C) and at body temperature, and fast near-infrared (IR) light-triggered drug release was achieved with optimized phospholipid composition and a 1:50 ICG-to-lipid molar ratio. Encapsulated small molecular calcein and FITC-dextran (up to 20 kDa) were completely released from the liposomes after light exposure for 15 s. Location of ICG in the PEG layer of the liposomes was simulated with molecular dynamics. ICG has important benefits as a light-triggering agent in liposomes: fast content release, improved stability, improved possibility of liposomal size control, regulatory approval to use in humans, and the possibility of imaging the in vivo location of the liposomes based on the fluorescence of ICG. Near-infrared light used as a triggering mechanism has good tissue penetration and safety. Thus, ICG liposomes are an attractive option for light-controlled and efficient delivery of small and large drug molecules.

  20. Liposomal Doxorubicin Delivery Systems: Effects of Formulation and Processing Parameters on Drug Loading and Release Behavior.

    Science.gov (United States)

    Mohammadi, Zahra Ali; Aghamiri, Seyed Foad; Zarrabi, Ali; Talaie, Mohammad Reza

    2016-01-01

    Liposomes can serve as promising carriers for targeting delivery and controlled release of anti-cancer drugs. Doxorubicin-loaded liposomes have achieved enhanced efficacy in some solid tumors due to EPR effect with prolonged circulation and reduced toxicity. In this study the effects of liposomal structure have been investigated on the loading efficiency and controlled release behavior. Liposomes with various compositions were prepared through a thin film hydration method, and extruded to large unilamellar vesicles (LUVs) with mean particle size (Z ave~ 100 nm) by high-pressure extrusion technique. Then, doxorubicin was loaded into liposomes using remote active loading strategy. The loading efficiency and drug release behavior were evaluated using various parameters such as medium pH, liposome compositions and cholesterol concentrations. Liposomes prepared with different compositions showed high levels of drug encapsulation. Drug loading efficiencies (>90%) achieved with high final drug/lipid ratio (0.18-0.2). Faster release was observed at pH 5.5 when compared to pH 7.4 for all formulations. The fastest release rate was observed for unsaturated lipid (<48hr) and the slowest release rate was observed for saturated lipids with high phase transition temperature such as 1, 2-distearoylphosphatidylcholine (DSPC) and hydrogenated soy phosphatidylcholine (HSPC) (10-18 days). The sustained release was observed for liposomal formulations containing cholesterol. In conclusion, we have demonstrated that drug release rate could be controlled by manipulating the composition of liposomal structures.

  1. Development of a cell-based bioassay for phospholipase A2-triggered liposomal drug release

    DEFF Research Database (Denmark)

    Arouri, Ahmad; Trojnar, Jakub; Schmidt, Steffen

    2015-01-01

    models, the pattern of sPLA2-assisted drug release is unknown due to the lack of a suitable bio-relevant model. We report here on the development of a novel bioluminescence living-cell-based luciferase assay for the monitoring of sPLA2-triggered release of luciferin from liposomes. To this end, we...... engineered breast cancer cells to produce both luciferase and sPLA2 enzymes, where the latter is secreted to the extracellular medium. We report on setting up a robust and reproducible bioassay for testing sPLA2-sensitive, luciferin remote-loaded liposomal formulations, using 1,2-distearoyl-sn-glycero-3......-phosphatidylcholine/1,2-distearoyl-sn-glycero-3-phosphatidylglycerol (DSPC/DSPG) 7:3 and DSPC/DSPG/cholesterol 4:3:3 as initial test systems. Upon their addition to the cells, the liposomes were degraded almost instantaneously by sPLA2 releasing the encapsulated luciferin, which provided readout from the luciferase...

  2. Lipid conjugated prodrugs for enzyme-triggered liposomal drug delivery to tumors

    DEFF Research Database (Denmark)

    Clausen, Mads Hartvig

    2011-01-01

    For some time we have been developing novel enzyme-triggered prodrugs for drug delivery targeting cancer. The liposomal prodrugs take advantage of the EPR effect to localize to tumors and of the local over-expression of secretory phospholipase A2 in tumors. Compared to conventional liposomal drug...... delivery systems, our prodrug-lipid conjugates have two main advantages: 1) the drugs are covalently linked to the lipids and thus leakage is circumvented and 2) the lipophilic bilayer of the formulated liposomes effectively shields the drugs from the aqueous environment in vivo. Consequently, the strategy...

  3. Nanoparticle-stabilized liposomes for pH-responsive gastric drug delivery.

    Science.gov (United States)

    Thamphiwatana, Soracha; Fu, Victoria; Zhu, Jingying; Lu, Diannan; Gao, Weiwei; Zhang, Liangfang

    2013-10-01

    We report a novel pH-responsive gold nanoparticle-stabilized liposome system for gastric antimicrobial delivery. By adsorbing small chitosan-modified gold nanoparticles (diameter ~10 nm) onto the outer surface of negatively charged phospholipid liposomes (diameter ~75 nm), we show that at gastric pH the liposomes have excellent stability with limited fusion ability and negligible cargo releases. However, when the stabilized liposomes are present in an environment with neutral pH, the gold stabilizers detach from the liposomes, resulting in free liposomes that can actively fuse with bacterial membranes. Using Helicobacter pylori as a model bacterium and doxycycline as a model antibiotic, we demonstrate such pH-responsive fusion activity and drug release profile of the nanoparticle-stabilized liposomes. Particularly, at neutral pH the gold nanoparticles detach, and thus the doxycycline-loaded liposomes rapidly fuse with bacteria and cause superior bactericidal efficacy as compared to the free doxycycline counterpart. Our results suggest that the reported liposome system holds a substantial potential for gastric drug delivery; it remains inactive (stable) in the stomach lumen but actively interacts with bacteria once it reaches the mucus layer of the stomach where the bacteria may reside.

  4. Selective partitioning of cholesterol and a model drug into liposomes of varying size

    DEFF Research Database (Denmark)

    Decker, Christiane; Fahr, Alfred; Kuntsche, Judith

    2012-01-01

    The resistance of a lipid bilayer with respect to a bending deformation generally depends on the presence of membrane additives such as sterols, cosurfactants, peptides, and drugs. As a consequence, the partitioning of membrane additives into liposomes becomes selective with respect to liposome s...

  5. Evaluation of the physicochemical properties of liposomes as potential carriers of anticancer drugs: spectroscopic study

    International Nuclear Information System (INIS)

    Pentak, Danuta

    2016-01-01

    Vesicle size and composition are a critical parameter for determining the circulation half-life of liposomes. Size influences the degree of drug encapsulation in liposomes. The geometry, size, and properties of liposomes in an aqueous environment have to be described to enable potential applications of liposome systems as drug carriers. The characteristics of multiple thermotropic phase transitions are also an important consideration in liposomes used for analytical and bioanalytical purposes. The aim of this study was to evaluate the physicochemical properties of liposomes which accommodate hydrophilic and amphiphilic drugs used in cancer therapy. The studied liposomes were prepared with the involvement of the modified reverse-phase evaporation method (mREV). The prepared liposomes had a diameter of 70–150 nm. The analyzed compounds were 1-β-d-arabinofuranosylcytosine, cyclophosphamide, and ifosfamide. In literature, there is no information about simultaneous incorporation of cytarabine, ifosfamide, and cyclophosphamide, in spite of the fact that these drugs have been used for more than 30 years. A combination of the examined drugs is used in CODOX-M/IVAC therapy. CODOX-M/IVAC (cyclophosphamide, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, and high-dose cytarabine) is one of the currently preferred intensive-dose chemotherapy regimens for Burkitt lymphoma (BL). The present research demonstrates the pioneering studies of incorporation of ifosfamide into liposome vesicles, location of and competition between the analyzed drugs and liposome vesicles. The applied methods were nuclear magnetic resonance (NMR), atomic force microscopy (AFM), differential scanning calorimetry (DSC).Graphical Abstract.

  6. Evaluation of the physicochemical properties of liposomes as potential carriers of anticancer drugs: spectroscopic study

    Energy Technology Data Exchange (ETDEWEB)

    Pentak, Danuta, E-mail: danuta.pentak@us.edu.pl [University of Silesia, Department of Materials Chemistry and Chemical Technology, Institute of Chemistry (Poland)

    2016-05-15

    Vesicle size and composition are a critical parameter for determining the circulation half-life of liposomes. Size influences the degree of drug encapsulation in liposomes. The geometry, size, and properties of liposomes in an aqueous environment have to be described to enable potential applications of liposome systems as drug carriers. The characteristics of multiple thermotropic phase transitions are also an important consideration in liposomes used for analytical and bioanalytical purposes. The aim of this study was to evaluate the physicochemical properties of liposomes which accommodate hydrophilic and amphiphilic drugs used in cancer therapy. The studied liposomes were prepared with the involvement of the modified reverse-phase evaporation method (mREV). The prepared liposomes had a diameter of 70–150 nm. The analyzed compounds were 1-β-d-arabinofuranosylcytosine, cyclophosphamide, and ifosfamide. In literature, there is no information about simultaneous incorporation of cytarabine, ifosfamide, and cyclophosphamide, in spite of the fact that these drugs have been used for more than 30 years. A combination of the examined drugs is used in CODOX-M/IVAC therapy. CODOX-M/IVAC (cyclophosphamide, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, and high-dose cytarabine) is one of the currently preferred intensive-dose chemotherapy regimens for Burkitt lymphoma (BL). The present research demonstrates the pioneering studies of incorporation of ifosfamide into liposome vesicles, location of and competition between the analyzed drugs and liposome vesicles. The applied methods were nuclear magnetic resonance (NMR), atomic force microscopy (AFM), differential scanning calorimetry (DSC).Graphical Abstract.

  7. Liposomes containing alkylated methotrexate analogues for phospholipase A(2) mediated tumor targeted drug delivery

    DEFF Research Database (Denmark)

    Kaasgaard, Thomas; Andresen, Thomas Lars; Jensen, Simon Skøde

    2009-01-01

    Two lipophilic methotrexate analogues have been synthesized and evaluated for cytotoxicity against KATO III and HT-29 human colon cancer cells. Both analogues contained a C-16-alkyl chain attached to the gamma-carboxylic acid and one of the analogues had an additional benzyl group attached...... cytotoxicity was incorporated into liposomes that were designed to be particularly Susceptible to a liposome degrading enzyme, secretory phospholipase A(2) (sPLA(2)), which is found in high concentrations in tumors of several different cancer types. Liposome incorporation was investigated by differential...... of the MTX-liposomes against KATO III and HT-29 cancer cells was found to be independent of sPLA(2) hydrolysis, indicating that the alkylated MTX-analogue was available for cancer cell uptake even in the absence of liposome hydrolysis. Using a DSC based method for assessing the anchoring stability...

  8. Thermo-responsive magnetic liposomes for hyperthermia-triggered local drug delivery.

    Science.gov (United States)

    Dai, Min; Wu, Cong; Fang, Hong-Ming; Li, Li; Yan, Jia-Bao; Zeng, Dan-Lin; Zou, Tao

    2017-06-01

    We prepared and characterised thermo-responsive magnetic liposomes, which were designed to combine features of magnetic targeting and thermo-responsive control release for hyperthermia-triggered local drug delivery. The particle size and zeta-potential of the thermo-responsive magnetic ammonium bicarbonate (MagABC) liposomes were about 210 nm and -14 mV, respectively. The MagABC liposomes showed encapsulation efficiencies of about 15% and 82% for magnetic nanoparticles (mean crystallite size 12 nm) and doxorubicin (DOX), respectively. The morphology of the MagABC liposomes was visualised using transmission electron microscope (TEM). The MagABC liposomes showed desired thermo-responsive release. The MagABC liposomes, when physically targeted to tumour cells in culture by a permanent magnetic field yielded a substantial increase in intracellular accumulation of DOX as compared to non-magnetic ammonium bicarbonate (ABC) liposomes. This resulted in a parallel increase in cytotoxicity for DOX loaded MagABC liposomes over DOX loaded ABC liposomes in tumour cells.

  9. Nanographene oxide as a switch for CW/pulsed NIR laser triggered drug release from liposomes.

    Science.gov (United States)

    Sahu, Abhishek; Kim, Manse; Ryu, Jooyeon; Son, Joon-Gon; Lee, Eunji; Noh, Do Young; Tae, Giyoong

    2018-01-01

    The application of pulsed and continuous wave (CW) lasers in nanomedicine has increased significantly over the last decade. Near infrared (NIR) lasers can be used for the precise control of drug release at the target site in a non-invasive manner. In this study, we have prepared nanographene oxide (nGO, size ~40nm) integrated liposomes (size ~900nm). The nGOs were not simply adsorbed onto the liposome surface but was embedded inside the liposomes as characterized by cryo-TEM, selected area electron diffraction (SAED), and fluorescence quenching studies. The embedded nGOs could act as a molecular switch for NIR light controlled drug release from the liposomes. Calcein was encapsulated into the liposome as a model drug to evaluate the efficiency of light controlled release. An on-demand pulsatile drug release was achieved by irradiation of CW/pulsed NIR lasers into the nGO-liposome suspension. Triggering with a pulsed laser resulted in larger release of calcein with a minimal temperature increase (~2°C) of the liposome solution, compared to lower release rate and a significant temperature increase (~8°C) by a CW laser with the same light energy, suggesting two separate mechanisms and different potential applications depending on the laser type. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. Development of a novel cell-based assay system EPISSAY for screening epigenetic drugs and liposome formulated decitabine

    International Nuclear Information System (INIS)

    Lim, Sue Ping; Callen, David F; Kumar, Raman; Akkamsetty, Yamini; Wang, Wen; Ho, Kristen; Neilsen, Paul M; Walther, Diego J; Suetani, Rachel J; Prestidge, Clive

    2013-01-01

    Despite the potential of improving the delivery of epigenetic drugs, the subsequent assessment of changes in their epigenetic activity is largely dependent on the availability of a suitable and rapid screening bioassay. Here, we describe a cell-based assay system for screening gene reactivation. A cell-based assay system (EPISSAY) was designed based on a silenced triple-mutated bacterial nitroreductase TMnfsB fused with Red-Fluorescent Protein (RFP) expressed in the non-malignant human breast cell line MCF10A. EPISSAY was validated using the target gene TXNIP, which has previously been shown to respond to epigenetic drugs. The potency of a epigenetic drug model, decitabine, formulated with PEGylated liposomes was also validated using this assay system. Following treatment with DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors such as decitabine and vorinostat, increases in RFP expression were observed, indicating expression of RFP-TMnfsB. The EPISSAY system was then used to test the potency of decitabine, before and after PEGylated liposomal encapsulation. We observed a 50% higher potency of decitabine when encapsulated in PEGylated liposomes, which is likely to be due to its protection from rapid degradation. The EPISSAY bioassay system provides a novel and rapid system to compare the efficiencies of existing and newly formulated drugs that reactivate gene expression

  11. Two cholesterol derivative-based PEGylated liposomes as drug delivery system, study on pharmacokinetics and drug delivery to retina

    Science.gov (United States)

    Geng, Shengyong; Yang, Bin; Wang, Guowu; Qin, Geng; Wada, Satoshi; Wang, Jin-Ye

    2014-07-01

    In this study, two cholesterol derivatives, (4-cholesterocarbonyl-4‧-(N,N,N-triethylamine butyloxyl bromide) azobenzene (CAB) and 4-cholesterocarbonyl-4‧-(N,N-diethylamine butyloxyl) azobenzene (ACB), one of which is positively charged while the other is neutral, were synthesized and incorporated with phospholipids and cholesterol to form doxorubicin (DOX)-loaded liposomes. PEGylation was achieved by including 1,2-distearoyl-sn-glycero-3-phosphatiylethanol-amine-N-[methoxy-(polyethylene glycol)-2000 (DSPE-PEG2000). Our results showed that PEGylated liposomes displayed significantly improved stability and the drug leakage was decreased compared to the non-PEGylated ones in vitro. The in vivo study with rats also revealed that the pharmacokinetics and circulation half-life of DOX were significantly improved when liposomes were PEGylated (p derivative ACB played some role in improving liposomes’ stability in systemic circulation compared to the conventional PC liposome and the positively charged CAB liposome, with or without PEGylation. In addition, in the case of local drug delivery, the positively charged PEG-liposome not only delivered much more of the drug into the rats’ retinas (p < 0.001), but also maintained much longer drug retention time compared to the neutral PEGylated liposomes.

  12. Novel vaginal drug delivery system: deformable propylene glycol liposomes-in-hydrogel.

    Science.gov (United States)

    Vanić, Željka; Hurler, Julia; Ferderber, Kristina; Golja Gašparović, Petra; Škalko-Basnet, Nataša; Filipović-Grčić, Jelena

    2014-03-01

    Deformable propylene glycol-containing liposomes (DPGLs) incorporating metronidazole or clotrimazole were prepared and evaluated as an efficient drug delivery system to improve the treatment of vaginal microbial infections. The liposome formulations were optimized based on sufficient trapping efficiencies for both drugs and membrane elasticity as a prerequisite for successful permeability and therapy. An appropriate viscosity for vaginal administration was achieved by incorporating the liposomes into Carbopol hydrogel. DPGLs were able to penetrate through the hydrogel network more rapidly than conventional liposomes. In vitro studies of drug release from the liposomal hydrogel under conditions simulating human treatment confirmed sustained and diffusion-based drug release. Characterization of the rheological and textural properties of the DPGL-containing liposomal hydrogels demonstrated that the incorporation of DPGLs alone had no significant influence on mechanical properties of hydrogels compared to controls. These results support the great potential of DPGL-in-hydrogel as an efficient delivery system for the controlled and sustained release of antimicrobial drugs in the vagina.

  13. Assessment of laser-induced release of drugs from liposomes: An in vitro study

    International Nuclear Information System (INIS)

    Khoobehi, B.; Char, C.A.; Peyman, G.A.

    1990-01-01

    We evaluated the characteristics of laser-induced release of an antimetabolite (cytosine arabinoside) from temperature-sensitive liposomes. Previous work had shown that a laser would induce breakdown of liposomes when a dye was encapsulated within the liposomes. The present investigation was performed to determine if release could be induced from liposomes that did not contain dye. In vitro, dynamic studies of the release of the drug from liposomes diluted in blood (flowing in a capillary tube at 40 microns/min) were conducted using an argon dye laser operating either in the blue-green mode (488/514 nm) or in the dye mode (577 nm). A radio-labeled marker was used to monitor the drug release. The results showed that the drug could indeed be released from liposomes that did not contain dye, at energy levels that are not likely to be harmful to the tissue. At identical power levels, the release of the drug was greater at 577 nm than at 488/514 nm, probably owing to the greater light absorbance of hemoglobin at the longer wavelength. The results indicate the potential for the site-specific release of a variety of molecules in the ocular vasculature

  14. Clinical developments of chemotherapeutic nanomedicines: Polymers and liposomes for delivery of camptothecins and platinum (II) drugs

    KAUST Repository

    Kieler-Ferguson, Heidi M.

    2013-01-17

    For the past 40 years, liposomal and polymeric delivery vehicles have been studied as systems capable of modulating the cytotoxicity of small molecule chemotherapeutics, increasing tumor bearing animal survival times, and improving drug targeting. Although a number of macromolecular-drug conjugates have progressed to clinical trials, tuning drug release to maintain efficacy in conjunction with controlling drug toxicity has prevented the clinical adoption of many vehicles. In this article, we review the motivations for and approaches to polymer and liposomal delivery with regard to camptothecin and cisplatin delivery. WIREs Nanomed Nanobiotechnol 2013, 5:130-138. doi: 10.1002/wnan.1209 For further resources related to this article, please visit the WIREs website. Conflict of interest: Drs Kieler-Ferguson and Fréchet declare no conflicts of interest. Dr Szoka is the founder of a liposome drug delivery company that is not working on any of the compounds mentioned in this article. © 2013 Wiley Periodicals, Inc.

  15. Preparation and Characterization of Escherichia coli Liposomes as a New Drug Delivery System to Colon Cancer

    Directory of Open Access Journals (Sweden)

    Mohammad Kargar

    2016-06-01

    Full Text Available Introduction: Liposomes are spherical vesicles composed of concentric phospholipid bilayers that can entrap hydrophilic, hydrophobic drugs. Liposomes can be prepared from natural phospholipids, synthetic lipids or bacterial lipids. The aim of this study was to formulate liposome from bacterial lipids and evaluate physicochemical properties. Materials and methods: This study was performed experimentally on E.coli. The lipids were extracted from E.coli. using chloroform and methanol. Film method was used for preparing nano-systems and methylene blue was used as a drug model. Then their particle sizes were determined using particle sizer. The release methylene blue was carried out using dialysis membrane. Also, trailing them in cancer cells was evaluated by using carboxyfluorescein. Results: The average particle size of E.coli. liposomal was 338 nm. Encapsulation efficiency was 53.33 ± 2.88% and the value of release after 24 h was 97.54% ± 0.00. Liposomes could deliver the carboxyfluorescein to cancer cells. Discussion and conclusion: The results of this study demonstrated that bacterial liposome has probably a suitable nano-particle such as particle size and desirable loading and it is possible to use them as drug delivery system.

  16. trans-Double Bond-Containing Liposomes as Potential Carriers for Drug Delivery

    Directory of Open Access Journals (Sweden)

    Giorgia Giacometti

    2017-11-01

    Full Text Available The use of liposomes has been crucial for investigations in biomimetic chemical biology as a membrane model and in medicinal chemistry for drug delivery. Liposomes are made of phospholipids whose biophysical characteristics strongly depend on the type of fatty acid moiety, where natural unsaturated lipids always have the double bond geometry in the cis configuration. The influence of lipid double bond configuration had not been considered so far with respect to the competence of liposomes in delivery. We were interested in evaluating possible changes in the molecular properties induced by the conversion of the double bond from cis to trans geometry. Here we report on the effects of the addition of trans-phospholipids supplied in different amounts to other liposome constituents (cholesterol, neutral phospholipids and cationic surfactants, on the size, ζ-potential and stability of liposomal formulations and on their ability to encapsulate two dyes such as rhodamine B and fluorescein. From a biotechnological point of view, trans-containing liposomes proved to have different characteristics from those containing the cis analogues, and to influence the incorporation and release of the dyes. These results open new perspectives in the use of the unnatural lipid geometry, for the purpose of changing liposome behavior and/or of obtaining molecular interferences, also in view of synergic effects of cell toxicity, especially in antitumoral strategies.

  17. Stimulus-responsive liposomes as smart nanoplatforms for drug delivery applications.

    Science.gov (United States)

    Zangabad, Parham Sahandi; Mirkiani, Soroush; Shahsavari, Shayan; Masoudi, Behrad; Masroor, Maryam; Hamed, Hamid; Jafari, Zahra; Taghipour, Yasamin Davatgaran; Hashemi, Hura; Karimi, Mahdi; Hamblin, Michael R

    2018-02-01

    Liposomes are known to be promising nanoparticles (NPs) for drug delivery applications. Among different types of self-assembled NPs, liposomes stand out for their non-toxic nature, and their possession of dual hydrophilic-hydrophobic domains. Advantages of liposomes include the ability to solubilize hydrophobic drugs, the ability to incorporate different hydrophilic and lipophilic drugs at the same time, lessening the exposure of host organs to potentially toxic drugs and allowing modification of the surface by a variety of different chemical groups. This modification of the surface, or of the individual constituents, may be used to achieve two important goals. Firstly, ligands for active targeting can be attached that are recognized by cognate receptors over-expressed on the target cells of tissues. Secondly, modification can be used to impart a stimulus-responsive or "smart" character to the liposomes, whereby the cargo is released on demand only when certain internal stimuli (pH, reducing agents, specific enzymes) or external stimuli (light, magnetic field or ultrasound) are present. Here, we review the field of smart liposomes for drug delivery applications.

  18. Liposomal Tumor Targeting in Drug Delivery Utilizing MMP-2- and MMP-9-Binding Ligands

    Directory of Open Access Journals (Sweden)

    Oula Penate Medina

    2011-01-01

    Full Text Available Nanotechnology offers an alternative to conventional treatment options by enabling different drug delivery and controlled-release delivery strategies. Liposomes being especially biodegradable and in most cases essentially nontoxic offer a versatile platform for several different delivery approaches that can potentially enhance the delivery and targeting of therapies to tumors. Liposomes penetrate tumors spontaneously as a result of fenestrated blood vessels within tumors, leading to known enhanced permeability and subsequent drug retention effects. In addition, liposomes can be used to carry radioactive moieties, such as radiotracers, which can be bound at multiple locations within liposomes, making them attractive carriers for molecular imaging applications. Phage display is a technique that can deliver various high-affinity and selectivity peptides to different targets. In this study, gelatinase-binding peptides, found by phage display, were attached to liposomes by covalent peptide-PEG-PE anchor creating a targeted drug delivery vehicle. Gelatinases as extracellular targets for tumor targeting offer a viable alternative for tumor targeting. Our findings show that targeted drug delivery is more efficient than non-targeted drug delivery.

  19. A liposomal drug platform overrides peptide ligand targeting to a cancer biomarker, irrespective of ligand affinity or density.

    Directory of Open Access Journals (Sweden)

    Bethany Powell Gray

    Full Text Available One method for improving cancer treatment is the use of nanoparticle drugs functionalized with targeting ligands that recognize receptors expressed selectively by tumor cells. In theory such targeting ligands should specifically deliver the nanoparticle drug to the tumor, increasing drug concentration in the tumor and delivering the drug to its site of action within the tumor tissue. However, the leaky vasculature of tumors combined with a poor lymphatic system allows the passive accumulation, and subsequent retention, of nanosized materials in tumors. Furthermore, a large nanoparticle size may impede tumor penetration. As such, the role of active targeting in nanoparticle delivery is controversial, and it is difficult to predict how a targeted nanoparticle drug will behave in vivo. Here we report in vivo studies for αvβ6-specific H2009.1 peptide targeted liposomal doxorubicin, which increased liposomal delivery and toxicity to lung cancer cells in vitro. We systematically varied ligand affinity, ligand density, ligand stability, liposome dosage, and tumor models to assess the role of active targeting of liposomes to αvβ6. In direct contrast to the in vitro results, we demonstrate no difference in in vivo targeting or efficacy for H2009.1 tetrameric peptide liposomal doxorubicin, compared to control peptide and no peptide liposomes. Examining liposome accumulation and distribution within the tumor demonstrates that the liposome, and not the H2009.1 peptide, drives tumor accumulation, and that both targeted H2009.1 and untargeted liposomes remain in perivascular regions, with little tumor penetration. Thus H2009.1 targeted liposomes fail to improve drug efficacy because the liposome drug platform prevents the H2009.1 peptide from both actively targeting the tumor and binding to tumor cells throughout the tumor tissue. Therefore, using a high affinity and high specificity ligand targeting an over-expressed tumor biomarker does not guarantee

  20. Influence of the Flexible Liposomes on the Skin Deposition of a Hydrophilic Model Drug, Carboxyfluorescein: Dependency on Their Composition

    Directory of Open Access Journals (Sweden)

    Mohamed Badran

    2012-01-01

    Full Text Available This study focuses on the effect of different flexible liposomes containing sodium cholate, Tween 80, or cineol on skin deposition of carboxyfluorescein (CF. Size distribution, morphology, zeta potential, and stability of the prepared vesicles were evaluated. The influence of these systems on the skin deposition of CF utilizing rat skin as membrane model was investigated. Results showed that all of the investigated liposomes had almost spherical shapes with low polydispersity (PDI < 0.3 and particles size range from 83 to 175 nm. All liposomal formulations exhibited negative zeta potential, good drug entrapment efficiency, and stability. In vitro skin deposition data showed that flexible liposomes gave significant deposition of CF on the skin compared to conventional liposomes and drug solutions. This study revealed that flexible liposomes, containing cineole, were able to deliver higher amount of CF suggesting that the hydrophilic drugs delivery to the skin was strictly correlated to the vesicle composition.

  1. Phytosome and Liposome: The Beneficial Encapsulation Systems in Drug Delivery and Food Application

    Directory of Open Access Journals (Sweden)

    Nayyer Karimi

    2015-06-01

    Full Text Available Due to poor solubility in lipids, many of bioactive components (Nutraceutical materials show less bioactivity than optimal state in water solution. Phytosomes improve absorption and bioavailability of biomaterials. Liposomes, spherical shaped nanocarriers, were discovered in the 1960s by bangham. Due to their composition, variability and structural properties, liposomes and phytosomes are extremely versatile, leading to a large number of applications including pharmaceutical, cosmetics and food industrial fields. They are advanced forms of herbal formulations containing the bioactive phytoconstituents of herb extracts such as flavonoids, glycosides and terpenoids, which have good ability to transit from a hydrophilic environment into the lipid friendly environment of the outer cell membrane. They have better bioavailability and actions than the conventional herbal extracts containing dosage. Phytosome technology has increasing effect on the bioavailability of herbal extracts including ginkgo biloba, grape seed, green tea, milk thistle, ginseng, etc., and can be developed for various therapeutic uses or dietary supplements. Liposomes are composed of bilayer membranes, which are made of lipid molecules. They form when phospholipids are dispersed in aqueous media and exposed to high shear rates by using micro-fluidization or colloid mill. The mechanism for formation of liposomes is mainly the hydrophilic–hydrophobic interactions between phospholipids and water molecules. Here, we attempt to review the features of phytosomes and liposomes as well as their preparation methods and capacity in food and drug applications. Generally, it is believed that phytosomes and liposomes are suitable delivery systems for nutraceuticals, and can be widely used in food industry.

  2. Tumor Endothelial Cell-Specific Drug Delivery System Using Apelin-Conjugated Liposomes

    Science.gov (United States)

    Kawahara, Hiroki; Naito, Hisamichi; Takara, Kazuhiro; Wakabayashi, Taku; Kidoya, Hiroyasu; Takakura, Nobuyuki

    2013-01-01

    Background A drug delivery system specifically targeting endothelial cells (ECs) in tumors is required to prevent normal blood vessels from being damaged by angiogenesis inhibitors. The purpose of this study was to investigate whether apelin, a ligand for APJ expressed in ECs when angiogenesis is taking place, can be used for targeting drug delivery to ECs in tumors. Methods and Results Uptake of apelin via APJ stably expressed in NIH-3T3 cells was investigated using TAMRA (fluorescent probe)-conjugated apelin. Both long and short forms of apelin (apelin 36 and apelin 13) were taken up, the latter more effectively. To improve efficacy of apelin- liposome conjugates, we introduced cysteine, with its sulfhydryl group, to the C terminus of apelin 13, resulting in the generation of apelin 14. In turn, apelin 14 was conjugated to rhodamine-encapsulating liposomes and administered to tumor-bearing mice. In the tumor microenvironment, we confirmed that liposomes were incorporated into the cytoplasm of ECs. In contrast, apelin non-conjugated liposomes were rarely found in the cytoplasm of ECs. Moreover, non-specific uptake of apelin-conjugated liposomes was rarely detected in other normal organs. Conclusions ECs in normal organs express little APJ; however, upon hypoxic stimulation, such as in tumors, ECs start to express APJ. The present study suggests that apelin could represent a suitable tool to effectively deliver drugs specifically to ECs within tumors. PMID:23799018

  3. Tumor endothelial cell-specific drug delivery system using apelin-conjugated liposomes.

    Directory of Open Access Journals (Sweden)

    Hiroki Kawahara

    Full Text Available BACKGROUND: A drug delivery system specifically targeting endothelial cells (ECs in tumors is required to prevent normal blood vessels from being damaged by angiogenesis inhibitors. The purpose of this study was to investigate whether apelin, a ligand for APJ expressed in ECs when angiogenesis is taking place, can be used for targeting drug delivery to ECs in tumors. METHODS AND RESULTS: Uptake of apelin via APJ stably expressed in NIH-3T3 cells was investigated using TAMRA (fluorescent probe-conjugated apelin. Both long and short forms of apelin (apelin 36 and apelin 13 were taken up, the latter more effectively. To improve efficacy of apelin- liposome conjugates, we introduced cysteine, with its sulfhydryl group, to the C terminus of apelin 13, resulting in the generation of apelin 14. In turn, apelin 14 was conjugated to rhodamine-encapsulating liposomes and administered to tumor-bearing mice. In the tumor microenvironment, we confirmed that liposomes were incorporated into the cytoplasm of ECs. In contrast, apelin non-conjugated liposomes were rarely found in the cytoplasm of ECs. Moreover, non-specific uptake of apelin-conjugated liposomes was rarely detected in other normal organs. CONCLUSIONS: ECs in normal organs express little APJ; however, upon hypoxic stimulation, such as in tumors, ECs start to express APJ. The present study suggests that apelin could represent a suitable tool to effectively deliver drugs specifically to ECs within tumors.

  4. Targeted liposomes for cytosolic drug delivery to tumor cells

    NARCIS (Netherlands)

    Mastrobattista, E.

    2001-01-01

    In this thesis, a Trojan horse strategy with antibody-targeted liposomes has been followed to obtain cytosolic delivery of biotherapeutics to tumor cells in vitro. This strategy involves targeting of immunoliposomes to specific receptors on tumor cells that result in receptor-mediated uptake of the

  5. Oleanolic acid liposomes with polyethylene glycol modification: promising antitumor drug delivery

    Directory of Open Access Journals (Sweden)

    Gao D

    2012-07-01

    Full Text Available Dawei Gao, Shengnan Tang, Qi TongApplied Chemical Key Laboratory of Hebei Province, College of Environmental and Chemical Engineering, Yanshan University, Qinhuangdao, ChinaBackground: Oleanolic acid is a pentacyclic triterpene present in many fruits and vegetables, and has received much attention on account of its biological properties. However, its poor solubility and low bioavailability limit its use. The objective of this study was to encapsulate oleanolic acid into nanoliposomes using the modified ethanol injection method.Methods: The liposomes contain a hydrophobic oleanolic acid core, an amphiphilic soybean lecithin monolayer, and a protective hydrophilic polyethylene glycol (PEG coating. During the preparation process, the formulations described were investigated by designing 34 orthogonal experiments as well as considering the effects of different physical characteristics. The four factors were the ratios of drug to soybean phosphatidylcholine (w/w, cholesterol (w/w, PEG-2000 (w/w, and temperature of phosphate-buffered saline at three different levels. We identified the optimized formulation which showed the most satisfactory lipid stability and particle formation. The morphology of the liposomes obtained was determined by transmission electron microscopy and atomic force microscopy. The existence of PEG in the liposome component was validated by Fourier transform infrared spectrum analysis.Results: The PEGylated liposomes dispersed individually and had diameters of around 110–200 nm. Encapsulation efficiency was more than 85%, as calculated by high-performance liquid chromatography and Sephadex® gel filtration. Furthermore, when compared with native oleanolic acid, the liposomal formulations showed better stability in vitro. Finally, the cytotoxicity of the oleanolic acid liposomes was evaluated using a microtiter tetrazolium assay.Conclusion: These results suggest that PEGylated liposomes would serve as a potent delivery vehicle

  6. Dual drug delivery using 'smart' liposomes for triggered release of anticancer agents

    Energy Technology Data Exchange (ETDEWEB)

    Jain, Ankit; Gulbake, Arvind; Jain, Ashish; Shilpi, Satish; Hurkat, Pooja; Jain, Sanjay K., E-mail: drskjainin@yahoo.com [Dr. Hari Singh Gour Vishwavidyalaya, Pharmaceutics Research Projects Laboratory, Department of Pharmaceutical Sciences (India)

    2013-07-15

    Ovarian cancer is one of the most fatal gynecologic cancers. In this debut study, dual approach using synergistically active combination of paclitaxel-topotecan (Pac-Top; 20:1, w/w) is investigated with utilization of characteristic features of tumor micro-environment and additionally overexpressed folate receptors (FR-{alpha}) to achieve targeting to tumor site. Various liposomes namely liposomes, PEGylated liposomes, and FR-targeted PEGylated liposomes with lipid compositions viz. DPPC:DMPG (85.5:9.5), DPPC:DMPG:mPEG{sub 2000}-DSPE (85.5:9.5:5), and DPPC:DMPG:mPEG{sub 2000}-DSPE:DSPE-PEG-folate (85.5:9.5:4.5:0.5), respectively, were developed using thin film casting method. These were nanometric in size around 200 nm. In vitro drug release study showed initial burst release followed by sustained release for more than 72 h at physiological milieu (37 {+-} 0.5 Degree-Sign C, pH 7.4) while burst release (i.e., more than 90 %) within 5 min at simulated tumor milieu (41 {+-} 1 Degree-Sign C, pH 4). SRB cytotoxicity assay in OVCAR-3 cell line revealed Pac-Top free (20:1, w/w) to be more toxic (GI{sub 50} = 6.5 {mu}g/ml) than positive control (Adriamycin, GI{sub 50} = 9.1 {mu}g/ml) and FR-targeted PEGylated liposomes GI{sub 50} (14.7 {mu}g/ml). Moreover, florescence microscopy showed the highest cell uptake of FR-targeted PEGylated liposomes so called 'smart liposomes' which has not only mediated effective targeting to FR-{alpha} but also triggered release of drugs upon hyperthermia.

  7. Dual drug delivery using "smart" liposomes for triggered release of anticancer agents

    Science.gov (United States)

    Jain, Ankit; Gulbake, Arvind; Jain, Ashish; Shilpi, Satish; Hurkat, Pooja; Jain, Sanjay K.

    2013-07-01

    Ovarian cancer is one of the most fatal gynecologic cancers. In this debut study, dual approach using synergistically active combination of paclitaxel-topotecan (Pac-Top; 20:1, w/w) is investigated with utilization of characteristic features of tumor micro-environment and additionally overexpressed folate receptors (FR-α) to achieve targeting to tumor site. Various liposomes namely liposomes, PEGylated liposomes, and FR-targeted PEGylated liposomes with lipid compositions viz. DPPC:DMPG (85.5:9.5), DPPC:DMPG:mPEG2000-DSPE (85.5:9.5:5), and DPPC:DMPG:mPEG2000-DSPE:DSPE-PEG-folate (85.5:9.5:4.5:0.5), respectively, were developed using thin film casting method. These were nanometric in size around 200 nm. In vitro drug release study showed initial burst release followed by sustained release for more than 72 h at physiological milieu (37 ± 0.5 °C, pH 7.4) while burst release (i.e., more than 90 %) within 5 min at simulated tumor milieu (41 ± 1 °C, pH 4). SRB cytotoxicity assay in OVCAR-3 cell line revealed Pac-Top free (20:1, w/w) to be more toxic (GI50 = 6.5 μg/ml) than positive control (Adriamycin, GI50 = 9.1 μg/ml) and FR-targeted PEGylated liposomes GI50 (14.7 μg/ml). Moreover, florescence microscopy showed the highest cell uptake of FR-targeted PEGylated liposomes so called "smart liposomes" which has not only mediated effective targeting to FR-α but also triggered release of drugs upon hyperthermia.

  8. Effects of liposomes with polyisoprenoids, potential drug carriers, on the cardiovascular and excretory system in rats.

    Science.gov (United States)

    Gawrys, Olga; Polkowska, Marta; Roszkowska-Chojecka, Malwina; Gawarecka, Katarzyna; Chojnacki, Tadeusz; Swiezewska, Ewa; Masnyk, Marek; Chmielewski, Marek; Rafałowska, Janina; Kompanowska-Jezierska, Elżbieta

    2014-04-01

    The unpredictable side effects of a majority currently used drugs are the substantial issue, in which patients and physicians are forced to deal with. Augmenting the therapeutic efficacy of drugs may prove more fruitful than searching for the new ones. Since recent studies show that new cationic derivatives of polyisoprenoid alcohols (APrens) might exhibit augmenting properties, we intend to use them as a component of liposomal drug carriers. In this study we investigate if these compounds do not per se cause untoward effects on the living organism. Male Sprague-Dawley rats received for four weeks daily injections (0.5 ml sc) of liposomes built of dioleoyl phosphatidylethanolamine (DOPE), liposomes built of DOPE and APren-7 (ratio 10:1) or water solvent. Weekly, rats were observed in metabolic cages (24h); blood and urine were sampled for analysis; body weight (BW) and systolic blood pressure (SBP) were determined. After chronic experiment, kidneys and heart were harvested for histological and morphometric analysis. The 4-week BW increments were in the range of 97 ± 4 to 102 ± 4%, intergroup differences were not significant. Microalbuminuria was the lowest in the group receiving liposomes with APren-7 (0.22 ± 0.03 mg/day). Water and food intake, plasma and urine parameters were similar in all groups. Newly designed liposomes containing APren-7 did not affect functions of the excretory and cardiovascular systems, and renal morphology; therefore we find them suitable as a component of liposomal drug carriers. Copyright © 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  9. Application of Coiled Coil Peptides in Liposomal Anticancer Drug Delivery Using a Zebrafish Xenograft Model.

    Science.gov (United States)

    Yang, Jian; Shimada, Yasuhito; Olsthoorn, René C L; Snaar-Jagalska, B Ewa; Spaink, Herman P; Kros, Alexander

    2016-08-23

    The complementary coiled coil forming peptides E4 [(EIAALEK)4] and K4 [(KIAALKE)4] are known to trigger liposomal membrane fusion when tethered to lipid vesicles in the form of lipopeptides. In this study, we examined whether these coiled coil forming peptides can be used for drug delivery applications. First, we prepared E4 peptide modified liposomes containing the far-red fluorescent dye TO-PRO-3 iodide (E4-Lipo-TP3) and confirmed that E4-liposomes could deliver TP3 into HeLa cells expressing K4 peptide on the membrane (HeLa-K) under cell culture conditions in a selective manner. Next, we prepared doxorubicin-containing E4-liposomes (E4-Lipo-DOX) and confirmed that E4-liposomes could also deliver DOX into HeLa-K cells. Moreover, E4-Lipo-DOX showed enhanced cytotoxicity toward HeLa-K cells compared to free doxorubicin. To prove the suitability of E4/K4 coiled coil formation for in vivo drug delivery, we injected E4-Lipo-TP3 or E4-Lipo-DOX into zebrafish xenografts of HeLa-K. As a result, E4-liposomes delivered TP3 to the implanted HeLa-K cells, and E4-Lipo-DOX could suppress cancer proliferation in the xenograft when compared to nontargeted conditions (i.e., zebrafish xenograft with free DOX injection). These data demonstrate that coiled coil formation enables drug selectivity and efficacy in vivo. It is envisaged that these findings are a step forward toward biorthogonal targeting systems as a tool for clinical drug delivery.

  10. Drug release from liposome coated hydrogels for soft contact lenses: the blinking and temperature effect.

    Science.gov (United States)

    Paradiso, P; Colaço, R; Mata, J L G; Krastev, R; Saramago, B; Serro, A P

    2017-10-01

    In this article, liposome-based coatings aiming to control drug release from therapeutic soft contact lenses (SCLs) materials are analyzed. A PHEMA based hydrogel material loaded with levofloxacin is used as model system for this research. The coatings are formed by polyelectrolyte layers containing liposomes of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and DMPC + cholesterol (DMPC + CHOL). The effect of friction and temperature on the drug release is investigated. The aim of the friction tests is to simulate the blinking of the eyelid in order to verify if the SCLs materials coated with liposomes are able to keep their properties, in particular the drug release ability. It was observed that under the study conditions, friction did not affect significantly the drug release from the liposome coated PHEMA material. In contrast, increasing the temperature of release leads to an increase of the drug diffusion rate through the hydrogel. This phenomenon is recorded both in the control and in the coated samples. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 1799-1807, 2017. © 2016 Wiley Periodicals, Inc.

  11. Alginate microgels loaded with temperature sensitive liposomes for magnetic resonance imageable drug release and microgel visualization

    NARCIS (Netherlands)

    van Elk, M.; Lorenzato, C.; Ozbakir, B.; Oerlemans, C.; Storm, Gerrit; Nijsen, F.; Deckers, R.; Vermonden, T.; Hennink, W.E.

    2015-01-01

    The objective of this study was to prepare and characterize alginate microgels loaded with temperature sensitive liposomes, which release their payload after mild hyperthermia. It is further aimed that by using these microgels both the drug release and the microgel deposition can be visualized by

  12. Impedimetric toxicity assay in microfluidics using free and liposome-encapsulated anticancer drugs

    DEFF Research Database (Denmark)

    Caviglia, Claudia; Zor, Kinga; Montini, Lucia

    2015-01-01

    In this work, we have developed a microfluidic cytotoxicity assay for a cell culture and detection platform, which enables both fluid handling and electrochemical/optical detection. The cytotoxic effect of anticancer drugs doxorubicin (DOX), oxaliplatin (OX) as well as OX-loaded liposomes, develo...

  13. Docetaxel-loaded liposomes: The effect of lipid composition and purification on drug encapsulation and in vitro toxicity.

    Science.gov (United States)

    Pereira, Sara; Egbu, Raphael; Jannati, Gemma; Al-Jamal, Wafa' T

    2016-11-30

    Docetaxel (DTX)-loaded liposomes have been formulated to overcome DTX solubility issue, improve its efficacy and reduce its toxicity. This study investigated the effect of steric stabilisation, varying liposome composition, and lipid:drug molar ratio on drug loading and on the physicochemical properties of the DTX-loaded liposomes. Size exclusion chromatography (SEC) was used to remove free DTX from the liposomal formulation, and its impact on drug loading and in vitro cytotoxicity was also evaluated. Liposomes composed of fluid, unsaturated lipid (DOPC:Chol:DSPE-PEG 2000 ) showed the highest DTX loading compared to rigid, saturated lipids (DPPC:Chol:DSPE-PEG 2000 and DSPC:Chol:DSPE-PEG 2000 ). The inclusion of PEG showed a minimum effect on DTX encapsulation. Decreasing lipid:drug molar ratio from 40:1 to 5:1 led to an improvement in the loading capacities of DOPC-based liposomes only. Up to 3.6-fold decrease in drug loading was observed after liposome purification, likely due to the loss of adsorbed and loosely entrapped DTX in the SEC column. Our in vitro toxicity results in PC3 monolayer showed that non-purified, DTX-loaded DOPC:Chol liposomes were initially (24h) more potent than the purified ones, due to the fast action of the surface- adsorbed drug. However, we hypothesize that over time (48 and 72h) the purified, DTX-loaded DOPC:Chol liposomes became more toxic due to high intracellular release of encapsulated DTX. Finally, our cytotoxicity results in PC3 spheroids showed the superior activity of DTX-loaded liposomes compared to free DTX, which could overcome the DTX poor tissue penetration, drug resistance, and improve its therapeutic efficacy following systemic administration. Crown Copyright © 2016. Published by Elsevier B.V. All rights reserved.

  14. Biophysical mechanisms of phospholipase A2 activation and their use in liposome-based drug delivery

    DEFF Research Database (Denmark)

    Jørgensen, Kaj; Davidsen, Jesper; Mouritsen, Ole G.

    2002-01-01

    reviewed. Results obtained from a variety of experimental and theoretical studies of PLA(2) activity on lipid-bilayer substrates are then presented which provide insight into the biophysical mechanisms of PLA(2) activation on lipid bilayers and liposomes of different composition. The insight...... into these mechanisms has been used to propose a novel principle for liposomal drug targeting, release, and absorption triggered by secretory PLA(2).(C) 2002 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved....

  15. Complement activation as a bioequivalence issue relevant to the development of generic liposomes and other nanoparticulate drugs

    Energy Technology Data Exchange (ETDEWEB)

    Szebeni, Janos, E-mail: jszebeni2@gmail.com [Nanomedicine Research and Education Center, Semmelweis University, Budapest & SeroScience Ltd, Budapest (Hungary); Storm, Gert [Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht (Netherlands)

    2015-12-18

    Liposomes are known to activate the complement (C) system, which can lead in vivo to a hypersensitivity syndrome called C activation-related pseudoallergy (CARPA). CARPA has been getting increasing attention as a safety risk of i.v. therapy with liposomes, whose testing is now recommended in bioequivalence evaluations of generic liposomal drug candidates. This review highlights the adverse consequences of C activation, the unique symptoms of CARPA triggered by essentially all i.v. administered liposomal drugs, and the various features of vesicles influencing this adverse immune effect. For the case of Doxil, we also address the mechanism of C activation and the opsonization vs. long circulation (stealth) paradox. In reviewing the methods of assessing C activation and CARPA, we delineate the most sensitive porcine model and an algorithm for stepwise evaluation of the CARPA risk of i.v. liposomes, which are proposed for standardization for preclinical toxicology evaluation of liposomal and other nanoparticulate drug candidates. - Highlights: • Outlining of difficulties in generic development of liposomal drugs. • New regulatory requirements to evaluate CARPA in preclinical studies. • Review of complement activation by liposomes and its adverse consequences (CARPA). • Assays of C activation in vitro and CARPA in vivo, with the porcine test in focus. • Decision tree how to handle the risk of CARPA assessed by a battery of tests.

  16. Dual drug delivery using “smart” liposomes for triggered release of anticancer agents

    International Nuclear Information System (INIS)

    Jain, Ankit; Gulbake, Arvind; Jain, Ashish; Shilpi, Satish; Hurkat, Pooja; Jain, Sanjay K.

    2013-01-01

    Ovarian cancer is one of the most fatal gynecologic cancers. In this debut study, dual approach using synergistically active combination of paclitaxel–topotecan (Pac–Top; 20:1, w/w) is investigated with utilization of characteristic features of tumor micro-environment and additionally overexpressed folate receptors (FR-α) to achieve targeting to tumor site. Various liposomes namely liposomes, PEGylated liposomes, and FR-targeted PEGylated liposomes with lipid compositions viz. DPPC:DMPG (85.5:9.5), DPPC:DMPG:mPEG 2000 –DSPE (85.5:9.5:5), and DPPC:DMPG:mPEG 2000 –DSPE:DSPE–PEG–folate (85.5:9.5:4.5:0.5), respectively, were developed using thin film casting method. These were nanometric in size around 200 nm. In vitro drug release study showed initial burst release followed by sustained release for more than 72 h at physiological milieu (37 ± 0.5 °C, pH 7.4) while burst release (i.e., more than 90 %) within 5 min at simulated tumor milieu (41 ± 1 °C, pH 4). SRB cytotoxicity assay in OVCAR-3 cell line revealed Pac–Top free (20:1, w/w) to be more toxic (GI 50 = 6.5 μg/ml) than positive control (Adriamycin, GI 50 = 9.1 μg/ml) and FR-targeted PEGylated liposomes GI 50 (14.7 μg/ml). Moreover, florescence microscopy showed the highest cell uptake of FR-targeted PEGylated liposomes so called “smart liposomes” which has not only mediated effective targeting to FR-α but also triggered release of drugs upon hyperthermia

  17. Reversal of the multidrug resistance by drug combination using multifunctional liposomes

    Science.gov (United States)

    Patel, Niravkumar R.

    One of the major obstacles to the success of cancer chemotherapy is the multi-drug resistance (MDR) that results due mainly to the over-expression of drug efflux transporter pumps such as P-glycoprotein (P-gp). Highly efficacious third generation P-gp inhibitors, like tariquidar, have shown promising results against MDR. However, P-gp is also expressed in normal tissues like the blood-brain barrier, gastrointestinal tract, liver and kidney. It is therefore important to limit the exposure of P-gp inhibitors to normal tissues and increase their co-localization with anticancer agents in tumor tissues to maximize the efficacy of a P-gp inhibitor. To minimize non-specific binding and increase its delivery to tumor tissues, liposomes, self-assembling phospholipid vesicles, were chosen as a drug delivery vehicle. The liposome has been identified as a system capable of carrying molecules with diverse physicochemical properties. It can also alter the pharmacokinetic profile of loaded molecules which is a concern with both tariquidar and paclitaxel. Liposomes can easily be surface-modified rendering them cell-specific as well as organelle-specific. The main objective of present study was to develop an efficient liposomal delivery system which would deliver therapeutic molecules of interest to tumor tissues and avoid interaction with normal tissues. In this study, the co-delivery of tariquidar and paclitaxel into tumor cells to reverse the MDR using long-circulating cationic liposomes was investigated. SKOV-3TR, the resistant variant of SKOV-3 and MCF-7/ADR, the resistant variant of MCF-7 were used as model cell lines. Uniform liposomal formulations were generated with high incorporation efficiency and no apparent decrease in tariquidar potency towards P-gp. Tariquidar- and paclitaxel- co-loaded long-circulating liposomes showed significant re-sensitization of SKOV-3TR and MCF-7/ADR for paclitaxel in vitro. Further modification of these liposomes with antitumor 2C5 resulted

  18. Development of a glucose-sensitive drug delivery device: Microencapsulated liposomes and poly(2-ethylacrylic acid)

    Science.gov (United States)

    Kanokpanont, Sorada

    The current study is the development a self-regulated, glucose responsive drug delivery system, using dioleoylphosphatidylcholine (DOPC) liposomes, a pH sensitive polymer, poly (2-ethylacrylic acid)(PEAA), and the feed back reaction of glucose with glucose oxidase enzyme (GO). The thesis investigates the use of PEAR and liposomes to work inside a microcapsule in response to the glucose level of the environment, by following the release of fluorescence probes, 8-aminonapthalene-1,3,6-trisulfonic acid, disodium salt/p-xylene-bis-pyridimuim bromide (ANTS/DPX) and a model protein, myoglobin. The continuing studies of PEAR and liposome interaction indicated an evidence of the previous hypothesis of two-mode release at different pHs. Differential scanning calorimetric studies of DOPC and PEAA complexes revealed the possibility of polymer adsorption to the liposomes in the pH range 5.5--7.0 and insertion in the liposome bilayer at pH pH, PEAR concentration, presence of cholesterol in the liposomes, Ca 2+, and the concentration of sodium alginate. We have also shown possibilities of anchoring PEAR on to liposome by covalent conjugation although this led to inactivation of the polymer. It is also possible to entrap small molecular weight PEAA in liposomes. The evidence of the pH-induced protein release by the interaction of PEAA and liposomes was first demonstrated in this thesis. Kinetic parameters of GO were estimated to use as a basis for determination optimal concentration in the capsules. The pH reduction inside the capsule due to GO reaction showed positive results for the use of GO in a non-buffered system. The procedure of liquid-core alginate capsules was modified to facilitate the pH-responsive release of ANTS/DPX and myoglobin. The capsules responded to high blood glucose concentration by releasing myoglobin within 30 minutes. Although more studies are required to improve the response of the system to the normal blood glucose and to control the total protein

  19. Theoretical Assessment of Fluorinated Phospholipids in the Design of Liposomal Drug-Delivery Systems

    DEFF Research Database (Denmark)

    Madsen, Jesper J.united st; Fristrup, Peter; Peters, Günther H.J.

    2016-01-01

    ,alpha-difluoro (F-2-ProAEL) conjugates of (R)-1-O-hexadecyl-2-palmitoyl-sn-glycero-3-phoshocholineglycerol (ProAEL). Our results provide a theoretical assessment of the potential usefulness of these fluorinated lipids in the rational design of liposomal drug-delivery systems. The a-fluorine-substituted phospholipid...... properties and that are still subjects for important and pharmaceutically proven drug-delivery mechanisms....

  20. NIR responsive liposomal system for rapid release of drugs in cancer therapy.

    Science.gov (United States)

    Chen, Ming-Mao; Liu, Yuan-Yuan; Su, Guang-Hao; Song, Fei-Fei; Liu, Yan; Zhang, Qi-Qing

    2017-01-01

    To design a rapid release liposomal system for cancer therapy, a NIR responsive bubble-generating thermosensitive liposome (BTSL) system combined with photothermal agent (Cypate), doxorubicin (DOX), and NH 4 HCO 3 was developed. Cypate/DOX-BTSL exhibited a good aqueous stability, photostability, and photothermal effect. In vitro release suggested that the amounts of DOX released from BTSL were obviously higher than that of (NH 4 ) 2 SO 4 liposomes at 42°C. After NIR irradiation, the hyperthermic temperature induced by Cypate led to the decomposition of NH 4 HCO 3 and the generation of a large number of CO 2 bubbles, triggering a rapid release of drugs. Confocal laser scanning microscope and acridine orange staining indicated that Cypate/DOX-BTSL upon irradiation could facilitate to disrupt the lysosomal membranes and realize endolysosomal escape into cytosol, improving the intracellular uptake of DOX clearly. MTT and trypan blue staining implied that the cell damage of Cypate/DOX-BTSL with NIR irradiation was more severe than that in the groups without irradiation. In vivo results indicated that Cypate/DOX-BTSL with irradiation could dramatically increase the accumulation of DOX in tumor, inhibit tumor growth, and reduce systemic side effects of DOX. These data demonstrated that Cypate/DOX-BTSL has the potential to be used as a NIR responsive liposomal system for a rapid release of drugs in thermochemotherapy.

  1. Ultrasound sensitive eLiposomes containing doxorubicin for drug targeting therapy.

    Science.gov (United States)

    Lin, Chung-Yin; Javadi, Marjan; Belnap, David M; Barrow, Jeffery R; Pitt, William G

    2014-01-01

    This study describes a novel nanocarrier of emulsion liposomes (eLiposomes) composed of a perfluoropentane nanodroplet within the aqueous interior of a DPPC liposome, along with the anticancer drug doxorubicin (Dox). The eLiposome containing Dox (eLipoDox) displayed good release of Dox upon insonation with low intensity ultrasound at 20-kHz, 1.0-MHz and 3.0-MHz. More release occurs in vitro at 20-kHz than at the higher frequencies. Controlled delivery was demonstrated by applying ultrasound (US) to HeLa tumor cells in vitro. The confocal images of Dox release to cells indicate that eLipoDox is an effective carrier of chemotherapeutic agent, and releases Dox to the cell cytosol upon insonation. This novel drug delivery system promises to provide more effective US therapy and tumor treatment and has the potential to reduce the side effects of cardiotoxicity caused by Dox. In this paper, an ultrasound-sensitive doxorubicine-carrying nanoliposome delivery system is reported. Doxorubicin release as a result of ultrasound exposure is clearly demonstrated, paving the way to potential clinical applications with the aim of reducing the systemic toxicity and enhanced local delivery of this compound. © 2013.

  2. Lipid composition has significant effect on targeted drug delivery properties of NGR-modified liposomes.

    Science.gov (United States)

    Chen, Jun; Lin, Aihua; Peng, Pei; Wang, Yong; Gu, Wei; Liu, Yiming

    2016-05-01

    The Asn-Gly-Arg (NGR) motif has previously been demonstrated to specifically bind to CD13, which is selectively overexpressed in tumor vasculature and some tumor cells (e.g. HT1080). It was reported that NGR-modified stealth liposomes (NGR-SL) could be prepared with different lipid composition, such as 1,2-dipalmitoyl-sn-glycero-phosphatidylcholine (DPPC), hydrogenated soy posphatidylcholine (HSPC) and soy posphatidylcholine (SPC). In the present study, NGR-modified liposomes were prepared with DPPC, HSPC, SPC or the mixture of HSPC and SPC. The resultant liposomes with different lipid composition were compared in terms of cell uptake, antitumor efficacy and targeted drug delivery efficiency using HT1080 tumor model. It was found that NGR-SL composed of the mixture of HSPC and SPC was able to improve targeted drug delivery efficiency to tumor producing the most significant antitumor activity. Collectively, the NGR-modified liposomes composed of the mixture of HSPC and SPC are promising carriers for the treatment of tumor. Besides NGR ligand, lipid composition could also significantly affect the targeted delivery efficiency to the tumor.

  3. Gemcitabine hydrochloride-loaded liposomes and nanoparticles: comparison of encapsulation efficiency, drug release, particle size, and cytotoxicity.

    Science.gov (United States)

    Yalcin, Tahir Emre; Ilbasmis-Tamer, Sibel; Ibisoglu, Burçin; Özdemir, Aysun; Ark, Mustafa; Takka, Sevgi

    2018-01-01

    The aim of this study is to formulate and compare the physicochemical properties of negatively charged liposomes and poly(lactide-co-glycolide) (PLGA) nanoparticles loaded with gemcitabine hydrochloride. The influence of the formulation variables on the liposome and nanoparticle properties on particle size, zeta potential, encapsulation efficiency, and drug release was evaluated. Although the PEGylated nanoparticles and PEGylated liposomes were of the same size (∼200 nm), the encapsulation efficiency was 1.4 times higher for PEGylated liposomes than for PEGylated nanoparticles. The optimized formulation of PEGylated liposomes and PEGylated nanoparticles had 26.1 ± 0.18 and 18.8 ± 1.52% encapsulation efficiency, respectively. The release of drug from the PEGylated liposomes and PEGylated nanoparticles exhibited a biphasic pattern that was characterized by a fast initial release during the first 2 h followed by a slower continuous release. Transmission electron microscopy (TEM) images identified separate circular structures of the liposomes and nanoparticles. The in vitro cytotoxicity of the optimized formulations was assessed in MCF-7 and MDA-MB-231 cells, and the results showed that the cytotoxicity effect of the gemcitabine hydrochloride-loaded liposomes and nanoparticles was more than commercial product Gemko ® and gemcitabine hydrochloride solution.

  4. Rational design of liposomal drug delivery systems, a review: Combined experimental and computational studies of lipid membranes, liposomes and their PEGylation

    Czech Academy of Sciences Publication Activity Database

    Bunker, A.; Magarkar, Aniket; Viitala, T.

    2016-01-01

    Roč. 1858, č. 10 (2016), s. 2334-2352 ISSN 0005-2736 Institutional support: RVO:61388963 Keywords : nanomedicine * liposome * drug delivery * molecular dynamics simulation * label-free analytics * PEGylation Subject RIV: CF - Physical ; Theoretical Chemistry Impact factor: 3.498, year: 2016

  5. Secreted phospholipase A(2) as a new enzymatic trigger mechanism for localised liposomal drug release and absorption in diseased tissue

    DEFF Research Database (Denmark)

    Davidsen, Jesper; Jørgensen, K.; Andresen, Thomas Lars

    2003-01-01

    Polymer-coated liposomes can act as versatile drug-delivery systems due to long vascular circulation time and passive targeting by leaky blood vessels in diseased tissue. We present an experimental model system illustrating a new principle for improved and programmable drug-delivery, which takes ......-based proenhancers or prodestabilisers into the liposome carrier, which automatically becomes activated by PLA2 only at the diseased target sites, such as inflamed or cancerous tissue....

  6. Resolution V fractional factorial Design for Screening of factors affecting weakly basic drugs liposomal systems.

    Science.gov (United States)

    El-Helaly, Sara Nageeb; Habib, Basant A; Abd El-Rahman, Mohamed K

    2018-04-21

    This study aims to investigate factors affecting weakly basic drugs liposomal systems. Resolution V fractional factorial design (2 V 5-1 ) is used as an example of screening designs that would better be used as a wise step before proceeding with detailed factors effects or optimization studies. Five factors probable to affect liposomal systems of weakly basic drugs were investigated using Amisulpride as a model drug. Factors studied were; A: Preparation technique B: Phosphatidyl choline (PhC) amount (mg) C: Cholesterol: PhC molar ratio, D: Hydration volume (ml) and E: Sonication type. Levels investigated were; Ammonium sulphate-pH gradient technique or Transmembrane zinc chelation-pH gradient technique, 200 or 400 mg, 0 or 0.5, 10 or 20 ml and bath or probe sonication for A, B, C, D and E respectively. Responses measured were Particle size (PS) (nm), Zeta potential (ZP) (mV) and Entrapment efficiency percent (EE%). Ion selective electrode was used as a novel method for measuring unentrapped drug concentration and calculating entrapment efficiency without the need for liposomal separation. Factors mainly affecting the studied responses were Cholesterol: PhC ratio and hydration volume for PS, preparation technique for ZP and preparation technique and hydration volume for EE%. The applied 2 V 5-1 design enabled the use of only 16 trial combinations for screening the influence of five factors on weakly basic drugs liposomal systems. This clarifies the value of the use of screening experiments before extensive investigation of certain factors in detailed optimization studies. Copyright © 2017. Published by Elsevier B.V.

  7. Immobilization of aloin encapsulated into liposomes in layer-by-layer films for transdermal drug delivery.

    Science.gov (United States)

    Xavier, Aline Carla Farrapo; de Moraes, Marli Leite; Ferreira, Marystela

    2013-04-01

    Layer-by-layer (LbL) films have been exploited in drug delivery systems that may be used in the form of patches, but the encapsulation of poor water soluble drugs and their release with a controlled rate are still major challenges to be faced. In this paper, we demonstrate the controlled release of aloin (barbaloin), an important component of the widely used Aloe vera, encapsulated into liposomes and immobilized in LbL films with a polyelectrolyte. With a systematic study using fluorescence spectroscopy of aloin release from solutions and from LbL films with different phospholipid liposomes, we inferred that optimized release was achieved with aloin incorporated into palmitoyl oleyl phosphatidyl glycerol (POPG) or dipalmitoyl phosphatidyl glycerol (DPPG) liposomes immobilized in LbL films. Significantly, with this optimized system aloin was almost completely released within 30 h, with a small release rate at the end, which followed a sharp release in the first 5h. Upon comparing the rates of the distinct systems, we conclude that the main factors controlling the release are the electrostatic interactions involving the negatively charged phospholipids. Because these interactions can be tuned in LbL films, the approach used here opens the way for new drug delivery systems to be developed with fine control of the drug release. Copyright © 2012 Elsevier B.V. All rights reserved.

  8. Peptide-Mediated Liposomal Drug Delivery System Targeting Tumor Blood Vessels in Anticancer Therapy

    Directory of Open Access Journals (Sweden)

    Han-Chung Wu

    2010-01-01

    Full Text Available Solid tumors are known to recruit new blood vessels to support their growth. Therefore, unique molecules expressed on tumor endothelial cells can function as targets for the antiangiogenic therapy of cancer. Current efforts are focusing on developing therapeutic agents capable of specifically targeting cancer cells and tumor-associated microenvironments including tumor blood vessels. These therapies hold the promise of high efficacy and low toxicity. One recognized strategy for improving the therapeutic effectiveness of conventional chemotherapeutics is to encapsulate anticancer drugs into targeting liposomes that bind to the cell surface receptors expressed on tumor-associated endothelial cells. These anti-angiogenic drug delivery systems could be used to target both tumor blood vessels as well as the tumor cells, themselves. This article reviews the mechanisms and advantages of various present and potential methods using peptide-conjugated liposomes to specifically destroy tumor blood vessels in anticancer therapy.

  9. Novel local drug delivery system using thermoreversible gel in combination with polymeric microspheres or liposomes.

    Science.gov (United States)

    Arai, Takao; Benny, Ofra; Joki, Tatsuhiro; Menon, Lata G; Machluf, Marcelle; Abe, Toshiaki; Carroll, Rona S; Black, Peter M

    2010-04-01

    The purpose of our study was to evaluate the application of thermoreversible gelation polymer (TGP) as a local drug delivery system for malignant glioma. Polymeric microspheres or liposomes loaded with doxorubicin (sphere-dox or lipo-dox) were combined with TGP to provide continuous drug delivery of doxorubicin (dox) for kinetic release studies and cell viability assays on glioma cell lines in vitro. For in vivo studies, TGP loaded with dox alone (TGP-dox) was combined with sphere-dox or lipo-dox. Their antitumor effects on subcutaneous human glioma xenografts were evaluated in nude mice. In vitro, TGP combined with sphere-dox or lipo-dox released dox for up to 30 days. In vivo, TGP-dox combined with sphere-dox or lipo-dox inhibited subcutaneous glioma tumor growth until day 32 and day 38, respectively. TGP in combination with microspheres or liposomes successfully prolonged the release of dox and its antitumor effects.

  10. Bacterial Toxin-Triggered Drug Release from Gold Nanoparticle-Stabilized Liposomes for the Treatment of Bacterial Infection

    Science.gov (United States)

    Pornpattananangkul, Dissaya; Zhang, Li; Olson, Sage; Aryal, Santosh; Obonyo, Marygorret; Vecchio, Kenneth; Huang, Chun-Ming; Zhang, Liangfang

    2011-01-01

    We report a new approach to selectively delivering antimicrobials to the sites of bacterial infections by utilizing bacterial toxins to activate drug release from gold nanoparticle-stabilized phospholipid liposomes. The binding of chitosan modified gold nanoparticles to the surface of liposomes can effectively prevent them from fusing with one another and from undesirable payload release in regular storage or physiological environments. However, once these protected liposomes “see” bacteria that secrete toxins, the toxins will insert into the liposome membranes and form pores, through which the encapsulated therapeutic agents are released. The released drugs subsequently impose antimicrobial effects on the toxin-secreting bacteria. Using methicillin-resistant Staphycoccus aureus (MRSA) as a model bacterium and vacomycin as a model anti-MRSA antibiotic, we demonstrate that the synthesized gold nanoparticle-stabilized liposomes can completely release the encapsulated vacomycin within 24 h in the presence of MRSA bacteria and lead to inhibition of MRSA growth as effective as an equal amount of vacomycin loaded liposomes (without nanoparticle stabilizers) and free vacomycin. This bacterial toxin enabled drug release from nanoparticle-stabilized liposomes provides a new, safe and effective approach for the treatment of bacterial infections. This technique can be broadly applied to treat a variety of infections caused by bacteria that secrete pore-forming toxins. PMID:21344925

  11. Liposomal 64Cu-PET Imaging of Anti-VEGF Drug Effects on Liposomal Delivery to Colon Cancer Xenografts.

    Science.gov (United States)

    Blocker, Stephanie J; Douglas, Kirk A; Polin, Lisa Anne; Lee, Helen; Hendriks, Bart S; Lalo, Enxhi; Chen, Wei; Shields, Anthony F

    2017-01-01

    Liposomes (LP) deliver drug to tumors due to enhanced permeability and retention (EPR). LP were labeled with 64 Cu for positron emission tomography (PET) to image tumor localization. Bevacizumab (bev), a VEGF targeted antibody, may modify LP delivery by altering tumor EPR and this change can also be imaged. Objective : Assess the utility of 64 Cu-labeled LP for PET in measuring altered LP delivery early after treatment with bev. Methods: HT-29 human colorectal adenocarcinoma tumors were grown subcutaneously in SCID mice. Empty LP MM-DX-929 (Merrimack Pharmaceuticals, Inc. Cambridge, MA) were labeled with 64 CuCl 2 chelated with 4-DEAP-ATSC. Tumor-bearing mice received ~200-300 μCi of 64 Cu-MM-DX-929 and imaged with microPET. All mice were scanned before and after the treatment period, in which half of the mice received bev for one week. Scans were compared for changes in LP accumulation during this time. Initially, tissues were collected after the second PET for biodistribution measurements and histological analysis. Subsequent groups were divided for further treatment. Tumor growth following bev treatment, with or without LP-I, was assessed compared to untreated controls. Results : PET scans of untreated mice showed increased uptake of 64 Cu-MM-DX-929, with a mean change in tumor SUV max of 43.9%±6.6% (n=10) after 7 days. Conversely, images of treated mice showed that liposome delivery did not increase, with changes in SUV max of 7.6%±4.8% (n=12). Changes in tumor SUV max were significantly different between both groups (p=0.0003). Histology of tumor tissues indicated that short-term bev was able to alter vessel size. Therapeutically, while bev monotherapy, LP-I monotherapy, and treatment with bev followed by LP-I all slowed HT-29 tumor growth compared to controls, combination provided no therapeutic benefit. Conclusions: PET with tracer LP 64 Cu-MM-DX-929 can detect significant differences in LP delivery to colon tumors treated with bev when compared to

  12. Evaluation of pH-responsive liposomes containing amino acid-based zwitterionic lipids for improving intracellular drug delivery in vitro and in vivo.

    Science.gov (United States)

    Obata, Yosuke; Tajima, Shoji; Takeoka, Shinji

    2010-03-03

    We developed pH-responsive liposomes containing synthetic glutamic acid-based zwitterionic lipids and evaluated their properties both in vitro and in vivo with the aim of constructing an efficient liposome-based systemic drug delivery system. The glutamic acid-based lipids; 1,5-dihexadecyl N-glutamyl-L-glutamate (L1) and 1,5-dihexadecyl N,N-diglutamyl-lysyl-L-glutamate (L2) were synthesized as a pH-responsive component of liposomes that respond to endosomal pH. The zeta potential of liposomes containing L1 or L2 was positive when the solution pH was below 4.6 or 5.6, respectively, but negative at higher pH values. The pH-responsive liposomes showed improved fusogenic potential to an endosome-mimicking anionic membrane at acidic pH, where the zeta potential of the liposomes was positive. We then prepared doxorubicin (DOX)-encapsulating liposomes containing L1 or L2, and clarified by confocal microscopic studies that the contents were rapidly transferred into both the cytoplasm and nucleus. Release of DOX from the endosomes mediated by the pH-responsive liposomes dramatically inhibited cancer cell growth. The L2-liposomes were slightly more effective than L1-liposomes as a drug delivery system. Intravenously injected L2-liposomes displayed blood persistence comparable to that of conventional phospholipid (PC)-based liposomes. Indeed, the antitumor efficacy of L2-liposomes was higher than that of PC-based liposomes against a xenograft breast cancer tumor in vivo. Thus, the high performance of L2-liposomes results from both efficient intracellular drug delivery and comparable blood persistence in comparison with the conventional PC-based liposomes in vitro and in vivo. Copyright 2009 Elsevier B.V. All rights reserved.

  13. An efficient PEGylated liposomal nanocarrier containing cell-penetrating peptide and pH-sensitive hydrazone bond for enhancing tumor-targeted drug delivery

    Directory of Open Access Journals (Sweden)

    Ding Y

    2015-10-01

    Full Text Available Yuan Ding,1,* Dan Sun,1,* Gui-Ling Wang,1 Hong-Ge Yang,1 Hai-Feng Xu,1 Jian-Hua Chen,2 Ying Xie,1,3 Zhi-Qiang Wang4 1Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing, 2School of Medicine, Jianghan University, Wuhan, 3State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, People’s Republic of China; 4Department of Chemistry and Biochemistry, Kent State University Geauga, Burton, OH, USA *These authors contributed equally to this work Abstract: Cell-penetrating peptides (CPPs as small molecular transporters with abilities of cell penetrating, internalization, and endosomal escape have potential prospect in drug delivery systems. However, a bottleneck hampering their application is the poor specificity for cells. By utilizing the function of hydration shell of polyethylene glycol (PEG and acid sensitivity of hydrazone bond, we constructed a kind of CPP-modified pH-sensitive PEGylated liposomes (CPPL to improve the selectivity of these peptides for tumor targeting. In CPPL, CPP was directly attached to liposome surfaces via coupling with stearate (STR to avoid the hindrance of PEG as a linker on the penetrating efficiency of CPP. A PEG derivative by conjugating PEG with STR via acid-degradable hydrazone bond (PEG2000-Hz-STR, PHS was synthesized. High-performance liquid chromatography and flow cytometry demonstrated that PHS was stable at normal neutral conditions and PEG could be completely cleaved from liposome surface to expose CPP under acidic environments in tumor. An optimal CPP density on liposomes was screened to guaranty a maximum targeting efficiency on tumor cells as well as not being captured by normal cells that consequently lead to a long circulation in blood. In vitro and in vivo studies indicated, in 4 mol% CPP of lipid modified system, that CPP exerted higher efficiency on internalizing the liposomes into

  14. Effect of liposomes on rheological and syringeability properties of hyaluronic acid hydrogels intended for local injection of drugs.

    Science.gov (United States)

    El Kechai, Naila; Bochot, Amélie; Huang, Nicolas; Nguyen, Yann; Ferrary, Evelyne; Agnely, Florence

    2015-06-20

    The aim of this work was to thoroughly study the effect of liposomes on the rheological and the syringeability properties of hyaluronic acid (HA) hydrogels intended for the local administration of drugs by injection. Whatever the characteristics of the liposomes added (neutral, positively or negatively charged, with a corona of polyethylene glycol chains, size), the viscosity and the elasticity of HA gels increased in a lipid concentration-dependent manner. Indeed, liposomes strengthened the network formed by HA chains due to their interactions with this polymer. The nature and the resulting effects of these interactions depended on liposome composition and concentration. The highest viscosity and elasticity were observed with liposomes covered by polyethylene glycol chains while neutral liposomes displayed the lowest effect. Despite their high viscosity at rest, all the formulations remained easily injectable through needles commonly used for local injections thanks to the shear-thinning behavior of HA gels. The present study demonstrates that rheological and syringeability tests are both necessary to elucidate the behavior of such systems during and post injection. In conclusion, HA liposomal gels appear to be a promising and versatile formulation platform for a wide range of applications in local drug delivery when an injection is required. Copyright © 2015 Elsevier B.V. All rights reserved.

  15. 188Re-Liposome Can Induce Mitochondrial Autophagy and Reverse Drug Resistance for Ovarian Cancer: From Bench Evidence to Preliminary Clinical Proof-of-Concept

    Directory of Open Access Journals (Sweden)

    Chia-Ming Chang

    2017-04-01

    Full Text Available Despite standard treatment, about 70% of ovarian cancer will recur. Cancer stem cells (CSCs have been implicated in the drug-resistance mechanism. Several drug resistance mechanisms have been proposed, and among these, autophagy plays a crucial role for the maintenance and tumorigenicity of CSCs. Compared to their differentiated counterparts, CSCs have been demonstrated to display a significantly higher level of autophagy flux. Moreover, mitophagy, a specific type of autophagy that selectively degrades excessive or damaged mitochondria, is shown to contribute to cancer progression and recurrence in several types of tumors. Nanomedicine has been shown to tackle the CSCs problem by overcoming drug resistance. In this work, we developed a nanomedicine, 188Re-liposome, which was demonstrated to target autophagy and mitophagy in the tumor microenvironment. Of note, the inhibition of autophagy and mitophagy could lead to significant tumor inhibition in two xenograft animal models. Lastly, we presented two cases of recurrent ovarian cancer, both in drug resistance status that received a level I dose from a phase I clinical trial. Both cases developing drug resistance showed drug sensitivity to 188Re-liposome. These results suggest that inhibition of autophagy and mitophagy by a nanomedicine may be a novel strategy to overcome drug resistance in ovarian cancer.

  16. Cyclic RGD peptide-modified liposomal drug delivery system: enhanced cellular uptake in vitro and improved pharmacokinetics in rats

    Directory of Open Access Journals (Sweden)

    Chen Z

    2012-07-01

    Full Text Available Zhongya Chen,1,2 Jiaxin Deng,1,2 Yan Zhao,1,2 Tao Tao1,21National Pharmaceutical Engineering Research Center, 2Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai, People's Republic of ChinaBackground: Integrins αvβ3 and αvβ5, both of which specifically recognize the Arg-Gly-Asp (RGD motif, are overexpressed on many solid tumors and in tumor neovasculature. Thus, coupling the RGD motif to the liposomal surface for achieving active targeting can be a promising strategy for the treatment of tumors.Methods: Cyclo(Arg-Gly-Asp-D-Phe-Cys (cRGD was covalently coupled with the liposomal membrane surface, followed by coating with poly(ethylene glycol (PEG using the post-insertion technique. The coupling efficiency of cRGD was determined. Doxorubicin as a model anticancer drug was loaded into liposomes using an ammonium sulfate gradient method to investigate the encapsulation efficiency, cellular uptake by the integrin-overexpressing human glioma cell line U87MG in vitro, and pharmacokinetic properties in Sprague-Dawley rats.Results: cRGD was conjugated to the liposomal surface by a thiol-maleimide coupling reaction. The coupling efficiency reached 98%. The encapsulation efficiency of doxorubicin in liposomes was more than 98%. The flow cytometry test result showed that cRGD-modified liposomes (RGD-DXRL-PEG had higher cell uptake by U87MG cells, compared with nontargeted liposomes (DXRL-PEG. The cellular uptake was significantly inhibited in the presence of excess free cRGD. Both the targeted (t1/2 = 24.10 hours and non-targeted (t1/2 = 25.32 hours liposomes showed long circulating properties in rat plasma. The area under the curve of the targeted and nontargeted liposomes was 6.4-fold and 8.3-fold higher than that of doxorubicin solution, respectively.Conclusion: This study indicates preferential targeting and long circulating properties for cRGD-modified liposomes in vivo, which could be used as

  17. Influence of Lipid Composition, pH, and Temperature on Physicochemical Properties of Liposomes with Curcumin as Model Drug.

    Science.gov (United States)

    Roy, Biplab; Guha, Pritam; Bhattarai, Ravi; Nahak, Prasant; Karmakar, Gourab; Chettri, Priyam; Panda, Amiya Kumar

    2016-01-01

    The physicochemical properties of large unilamellar vesicles (LUVs) were assessed with respect to lipid composition, pH, time, and temperature by monitoring their size, zeta potential, drug payload, and thermal behavior. A conventional thin film hydration technique was employed to prepare liposomes from soy phosphatidylcholine (SPC), dipalmitoylphosphatidylcholine (DPPC), dipalmitoylphosphatidylglycerol (DPPG), and a 7:3 (M/M) mixture of DPPC+DPPG along with 30 mole% cholesterol in each combination. While the size of liposomes depended on lipid composition, pH and temperature, the zeta potential was found to be independent of the pH of the medium, although it varied with liposome type. Spherical morphology and bilayer were observed by electron microscopy. The phase transition temperature increased with decreasing pH. Membrane micro-viscosity showed the highest value for SPC, and membrane rigidity increased with increasing pH. The entrapment efficiency of liposomes with reference to curcumin was as follows: DPPC>DPPC+DPPG>DPPG>SPC. Sustained release of curcumin was observed for all liposomes. Curcumin-loaded liposomes exhibited substantial antibacterial activity against the gram-positive bacteria Bacillus amyloliquefaciens. Additional studies are needed to improve the understanding of the effect of formulation variables on the physicochemical stability of liposomes.

  18. New Ways of Imaging Uptake and Intracellular Fate of Liposomal Drug Carrier Systems inside Individual Cells, Based on Raman Microscopy

    Science.gov (United States)

    Matthäus, Christian; Kale, Amit; Chernenko, Tatyana; Torchilin, Vladimir; Diem, Max

    2009-01-01

    Recent developments, combining Raman spectroscopy with optical microscopy, provide a new noninvasive technique to assess and image cellular processes. Of particular interest are the uptake mechanisms of various cytologically active compounds. In order to distinguish the species of interest from their cellular environment spectroscopically, compounds may be labeled with deuterium. Here, we apply Raman microspectroscopy to follow the uptake of liposomal drug carrier systems that have been introduced to deliver biologically active compounds to their site of action within human breast adenocarcinoma MCF-7 cells. The distribution patterns of liposomes and liposomes surface-modified with a cell-penetrating peptide (TAT-peptide, TATp) have been imaged over time. The spectroscopic information obtained provides a clear evidence for variable rates, as well as different efficiencies of liposome uptake depending on their surface properties. Depending on the experimental setup, the technique may be applied to fixed or living cell organisms. PMID:18197626

  19. On-chip microreactor system for the production of nano-emulsion loaded liposomes: towards targeted delivery of lipophilic drugs

    NARCIS (Netherlands)

    Langelaan, M.L.P.; Emmelkamp, J.; Segers, M.J.A.; Lenting, H.B.M.

    2011-01-01

    An on-chip microreactor system for the production of novel nano-biodevices is presented. This nano-biodevice consists of a nano-emulsion loaded with lipophilic drugs, entrapped in liposomes. These nano-biodevices can be equipped with targeting molecules for higher drug efficiency. The microreactor

  20. Investigations of the influence of liposome composition on vesicle stability and drug transfer in human plasma: a transfer study.

    Science.gov (United States)

    Holzschuh, Stephan; Kaeß, Kathrin; Bossa, Guilherme Volpe; Decker, Christiane; Fahr, Alfred; May, Sylvio

    2018-03-01

    Liposomal delivery constitutes a promising approach for i.v. administration of temoporfin (mTHPC) because lipid membranes can host these drug molecules. This study investigates the transfer and release of mTHPC to plasma proteins and stability of various liposomal formulations. To this end, we employed traces of radioactive markers and studied the effects of fatty acid chain length and the degree of saturation in the lipophilic tail, addition of cholesterol and PEGylation of the membrane surface and different drug-to-lipid ratios (DLRs). Liposomes were incubated in human plasma for various incubation times. Drawn samples were separated by asymmetrical flow field-flow fractionation (AF4). Drug was recovered in four fractions identified as albumin, high-density lipoprotein (HDL), low-density lipoprotein (LDL) and liposomes. Our results suggest that mTHPC fits best into fluid, unmodified bilayers when the drug-to-lipid ratio is low. Membrane rigidification as well as the presence of cholesterol and PEGyated lipids reduced the ability of the membrane to accommodate the drug but simultaneously improved the vesicle stability in plasma. Both mechanisms jointly affect the total degree of mTHPC release. We analyzed our data using a kinetic model that suggests the drug to be associated with the host membrane in two distinct states of which only one interacts directly with the plasma compartment.

  1. Efficient drug delivery to lung epithelial lining fluid by aerosolization of ciprofloxacin incorporated into PEGylated liposomes for treatment of respiratory infections.

    Science.gov (United States)

    Chono, Sumio; Suzuki, Hirokazu; Togami, Kohei; Morimoto, Kazuhiro

    2011-04-01

    The efficacy of aerosolization of ciprofloxacin (CPFX) incorporated into PEGylated liposomes (PEGylated CPFX-liposomes) for the treatment of respiratory infections was evaluated. PEGylated CPFX-liposomes with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-n-[methoxy(polyethylene glycol)-2000] (particle size: 100 nm) were prepared, and the drug distribution characteristics in lung epithelial lining fluid (ELF) following aerosolization of PEGylated CPFX-liposomes were examined in rats. Furthermore, the antibacterial effects of PEGylated CPFX-liposomes in ELF were evaluated by pharmacokinetic/pharmacodynamic analysis. The elimination rate of CPFX from ELF following aerosolization of PEGylated CPFX-liposomes was significantly slower than that of CPFX incorporated into unmodified liposomes (unmodified CPFX-liposomes; particle size: 100 nm). According to pharmacokinetic/pharmacodynamic analysis, the PEGylated CPFX-liposomes exhibited potent antibacterial effects against pathogenic microorganisms in ELF. This study shows that PEGylated CPFX-liposomes are a useful aerosol-based pulmonary drug delivery system for the treatment of respiratory infections.

  2. Degradable Polymersomes for Targeted Drug Delivery

    Science.gov (United States)

    Petersen, Matthew Alan

    Chemotherapy today is often accompanied by major side effects due to delivery of toxic drugs to healthy tissue in addition to diseased cells. Targeted drug delivery offers the possibility of minimizing these side effects by specific delivery to cancer cells using targeted nanocarriers that enhance drug accumulation in tumors and facilitate target-specific cellular uptake. Polymersomes, vesicles self-assembled from polymeric amphiphiles, are an attractive targeted vehicle, as they are capable of encapsulating both hydrophobic and hydrophilic drugs, have lengthy circulation times in vivo, and can employ degradable functionality for triggered release of payload and clearance from the body. This thesis reports on efforts to enhance the capabilities of degradable polymersomes for targeted delivery. First, targeting functionality is incorporated into polymersomes of the block copolymer poly(ethylene oxide)-b-poly(gamma-methyl-epsilon-caprolactone) by incorporating the reactive vinyl sulfone group into the amphiphile's hydrophilic terminus, allowing site-selective reaction with cysteine-functionalized targeting peptides following self-assembly. The performance of targeted delivery using this polymersome is then evaluated in vitro. Binding and delivery to model cell lines for targeted and bystander cells is tracked using nontargeted polymersomes and compared to that for polymersomes using a high- or low-affinity ligand. Polymer degradation is also tracked both in simple media and during cellular delivery. Finally, a new monomer is developed incorporating acid-labile acetal functionality into a cyclic polyester. The polymerization of this monomer to two distinct polymers is also characterized and the degradation behavior of both polymers evaluated.

  3. EXPERIMENTAL LIPOSOMAL VIRAL VACCINE SAFETY

    Directory of Open Access Journals (Sweden)

    Romanova OA

    2016-12-01

    experimental influenza vaccine further modification through acylation antigenic component.Results and discussion. Among the vaccines with the antigenic component modification and addition of adjuvants, the highest production of specific influenza antibodies was observed after administration liposomes №2.2 sample, which was made on the basis of antigen Vaxigrip with negatively charged liposomal formulation, the addition of adjuvants and modification antigenic composition, the second ranked liposomes №2.1, without antigenic modification. The study identified regarding the frequency of local reactions, assessed by visual observations, among experimental animals in injection site after legalized vaccines or newly samples weren`t characterized by the formation of swelling, hardening of tissue hyperemia or painful local reactions throughout the observation time.Experimental mice also haven`t fever for the 5 days after manipulation, which is the main criterion of systemic adverse reactions after they administered vaccine preparations. Also after use of experimental drugs and drug comparison, subjective, wasn`t happened abnormalities in general condition animals, including a decrease in appetite, digestive disorders, changes in activity and more. These observations, however, do not allow to conclude the complete safety newly created experimental vaccine and require additional evaluation tests. As base component for building experimental liposomal vaccine used the fosfatydilholin (FH.FH is a substrate for activation lipid peroxidation. Lecithin liposomes, that are liposomal vaccine structural and functional components, are exposed to a variety number of physical and chemical factors. One of biochemical events, that happen to them, are lipid peroxidation, accompanied by free radicals appearance in the system and, ultimately, causes phospholipid bi-layer membranes degradation by a violation of their permeability and lysis. In this regard, system safety control and liposomal drug

  4. Motion Compensated Ultrasound Imaging Allows Thermometry and Image Guided Drug Delivery Monitoring from Echogenic Liposomes.

    Science.gov (United States)

    Ektate, Kalyani; Kapoor, Ankur; Maples, Danny; Tuysuzoglu, Ahmet; VanOsdol, Joshua; Ramasami, Selvarani; Ranjan, Ashish

    2016-01-01

    Ultrasound imaging is widely used both for cancer diagnosis and to assess therapeutic success, but due to its weak tissue contrast and the short half-life of commercially available contrast agents, it is currently not practical for assessing motion compensated contrast-enhanced tumor imaging, or for determining time-resolved absolute tumor temperature while simultaneously reporting on drug delivery. The objectives of this study were to: 1) develop echogenic heat sensitive liposomes (E-LTSL) and non-thermosensitive liposomes (E-NTSL) to enhance half-life of contrast agents, and 2) measure motion compensated temperature induced state changes in acoustic impedance and Laplace pressure of liposomes to monitor temperature and doxorubicin (Dox) delivery to tumors. LTSL and NTSL containing Dox were co-loaded with an US contrast agent (perfluoropentane, PFP) using a one-step sonoporation method to create E-LTSL and E-NTSL. To determine temperature induced intensity variation with respect to the state change of E-LTSL and E-NTSL in mouse colon tumors, cine acquisition of 20 frames/second for about 20 min (or until wash out) at temperatures of 42°C, 39.5°C, and 37°C was performed. A rigid rotation and translation was applied to each of the "key frames" to adjust for any gross motion that arose due to motion of the animal or the transducer. To evaluate the correlation between ultrasound (US) intensity variation and Dox release at various temperatures, treatment (5 mg Dox/kg) was administered via a tail vein once tumors reached a size of 300-400 mm(3), and mean intensity within regions of interest (ROIs) defined for each sample was computed over the collected frames and normalized in the range of [0,1]. When the motion compensation technique was applied, a > 2-fold drop in standard deviation in mean image intensity of tumor was observed, enabling a more robust estimation of temporal variations in tumor temperatures for 15-20 min. due to state change of E-LTSL and E

  5. Nanoparticle-Stabilized Liposomes for pH-Responsive Gastric Drug Delivery

    OpenAIRE

    Thamphiwatana, Soracha; Fu, Victoria; Zhu, Jingying; Lu, Diannan; Gao, Weiwei; Zhang, Liangfang

    2013-01-01

    We report a novel pH-responsive gold nanoparticle-stabilized liposome system for gastric antimicrobial delivery. By adsorbing small chitosan-modified gold nanoparticles (diameter ~ 10 nm) onto the outer surface of negatively charged phospholipid liposomes (diameter ~ 75 nm), we show that at gastric pH the liposomes have excellent stability with limited fusion ability and negligible cargo releases. However when the stabilized liposomes are present in an environment with neutral pH, the gold st...

  6. Channel Protein-Containing Liposomes as Delivery Vehicles for the Controlled Release of Drugs-Optimization of the Lipid Composition

    NARCIS (Netherlands)

    Šmisterová, J.; Deemter, M. van; Schaaf, G. van der; Meijberg, W.; Robillard, G.

    2005-01-01

    In the design of liposomal drug formulations containing a controllable channel protein (MscL), the lipid composition is dictated in part by this membrane protein. This work addresses the question whether therapeutically optimal lipid compositions (phospholipid with high Tm/cholesterol/PEG) are

  7. Biophysical mechanisms of phospholipase A2 activation and their use in liposome-based drug delivery

    DEFF Research Database (Denmark)

    Jørgensen, Kaj; Davidsen, Jesper; Mouritsen, Ole G.

    2002-01-01

    Secretory phospholipase A(2) (PLA(2)) is a ubiquitous water-soluble enzyme found in venom, pancreatic, and cancerous fluid. It is also known to play a role in membrane remodeling processes as well as in cellular signaling cascades. PLA(2) is interfacially active and functions mainly on organized ...... into these mechanisms has been used to propose a novel principle for liposomal drug targeting, release, and absorption triggered by secretory PLA(2).(C) 2002 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved.......Secretory phospholipase A(2) (PLA(2)) is a ubiquitous water-soluble enzyme found in venom, pancreatic, and cancerous fluid. It is also known to play a role in membrane remodeling processes as well as in cellular signaling cascades. PLA(2) is interfacially active and functions mainly on organized...... reviewed. Results obtained from a variety of experimental and theoretical studies of PLA(2) activity on lipid-bilayer substrates are then presented which provide insight into the biophysical mechanisms of PLA(2) activation on lipid bilayers and liposomes of different composition. The insight...

  8. Mechanism and kinetics of the loss of poorly soluble drugs from liposomal carriers studied by a novel flow field-flow fractionation-based drug release-/transfer-assay

    DEFF Research Database (Denmark)

    Hinna, Askell Hvid; Hupfeld, Stefan; Kuntsche, Judith

    2016-01-01

    Liposomes represent a versatile drug formulation approach e.g. for improving the water-solubility of poorly soluble drugs but also to achieve drug targeting and controlled release. For the latter applications it is essential that the drug remains associated with the liposomal carrier during transit...... in the vascular bed. A range of in vitro test methods has been suggested over the years for prediction of the release of drug from liposomal carriers. The majority of these fail to give a realistic prediction for poorly water-soluble drugs due to the intrinsic tendency of such compounds to remain associated......)21H,23H-porphine). p-THPP is structurally similar to temoporfin, a photosensitizer which is under clinical evaluation in a liposomal formulation. Mechanistic insights were gained by varying the donor-to-acceptor lipid mass ratio, size and lamellarity of the liposomes. Drug transfer kinetics from one...

  9. Influence of the Flexible Liposomes on the Skin Deposition of a Hydrophilic Model Drug, Carboxyfluorescein: Dependency on Their Composition

    Science.gov (United States)

    Badran, Mohamed; Shalaby, Khaled; Al-Omrani, Abdullah

    2012-01-01

    This study focuses on the effect of different flexible liposomes containing sodium cholate, Tween 80, or cineol on skin deposition of carboxyfluorescein (CF). Size distribution, morphology, zeta potential, and stability of the prepared vesicles were evaluated. The influence of these systems on the skin deposition of CF utilizing rat skin as membrane model was investigated. Results showed that all of the investigated liposomes had almost spherical shapes with low polydispersity (PDI cineole, were able to deliver higher amount of CF suggesting that the hydrophilic drugs delivery to the skin was strictly correlated to the vesicle composition. PMID:22536120

  10. Environment-responsive multifunctional liposomes.

    Science.gov (United States)

    Kale, Amit A; Torchilin, Vladimir P

    2010-01-01

    Liposomal nanocarriers anchored with a cell-penetrating peptide and a pH-sensitive PEG-shield where later has ability to provide simultaneously better systemic circulation and site-specific exposure of cell penetrating peptide. PEG chains were incorporated into the liposome membrane via the PEG-attached phosphatidylethanolamine (PE) residue with PEG and PE being conjugated with the lowered pH-degradable hydrazone bond (PEG-HZ-PE), while cell-penetrating peptide (TATp) was added as TATp-PEG-PE conjugate. Under normal conditions, liposome-grafted PEG "shielded" liposome-attached TATp moieties, since the PEG spacer for TATp attachment (PEG(1000)) was shorter than protective PEG(2000). PEGylated liposomes accumulate in targets via the EPR effect, but inside the "acidified" tumor or ischemic tissues lose their PEG coating because of the lowered pH-induced hydrolysis of HZ and penetrate inside cells via the now-exposed TATp moieties. pH-responsive behavior of these constructs is successfully tested in cell cultures in vitro as well as in tumors in experimental mice in vivo. These nanocarriers also showed enhanced pGFP transfection efficiency upon intratumoral administration in mice, compared to control pH nonsensitive counterpart. These results can be considered as an important step in the development of tumor-specific stimuli-sensitive drug and gene delivery systems.

  11. Controlled release of a sparingly water-soluble anticancer drug through pH-responsive functionalized gold-nanoparticle-decorated liposomes.

    Science.gov (United States)

    Adhikari, Chandan; Das, Anupam; Chakraborty, Anjan

    2015-03-16

    The binding and detachment of carboxyl-modified gold nanoparticles from liposomes is used for controlled drug delivery. This study reveals that the binding and detachment of nanoparticles from liposomes depends on the degree of hydration of the liposomes. Liposomes with a lower hydration level undergo stronger electrostatic interactions with negatively charged gold nanoparticles, thus leading to a slower detachment of the carboxyl-modified gold nanoparticles under gastric conditions. Therefore, under gastric conditions, gold-nanoparticle-decorated dipalmitoylphosphatidylcholine (DPPC) liposomes exhibit an at least ten-times-slower drug release compared to gold-nanoparticle-decorated 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) liposomes, although both liposomes in the bare state fail to pursue controlled release. Our study also reveals that one can modulate the drug-release rate by simply varying the concentration of nanoparticles. This study highlights a novel strategy for the controlled release of drug molecules from liposomes. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  12. Mapping knowledge translation and innovation processes in Cancer Drug Development: the case of liposomal doxorubicin.

    Science.gov (United States)

    Fajardo-Ortiz, David; Duran, Luis; Moreno, Laura; Ochoa, Hector; Castaño, Victor M

    2014-09-03

    We explored how the knowledge translation and innovation processes are structured when theyresult in innovations, as in the case of liposomal doxorubicin research. In order to map the processes, a literature network analysis was made through Cytoscape and semantic analysis was performed by GOPubmed which is based in the controlled vocabularies MeSH (Medical Subject Headings) and GO (Gene Ontology). We found clusters related to different stages of the technological development (invention, innovation and imitation) and the knowledge translation process (preclinical, translational and clinical research), and we were able to map the historic emergence of Doxil as a paradigmatic nanodrug. This research could be a powerful methodological tool for decision-making and innovation management in drug delivery research.

  13. Preparation, characterization and in vitro antimicrobial activity of liposomal ceftazidime and cefepime against Pseudomonas aeruginosa strains

    Science.gov (United States)

    Torres, Ieda Maria Sapateiro; Bento, Etiene Barbosa; Almeida, Larissa da Cunha; de Sá, Luisa Zaiden Carvalho Martins; Lima, Eliana Martins

    2012-01-01

    Pseudomonas aeruginosa is an opportunistic microorganism with the ability to respond to a wide variety of environmental changes, exhibiting a high intrinsic resistance to a number of antimicrobial agents. This low susceptibility to antimicrobial substances is primarily due to the low permeability of its outer membrane, efflux mechanisms and the synthesis of enzymes that promote the degradation of these drugs. Cephalosporins, particularty ceftazidime and cefepime are effective against P. aeruginosa, however, its increasing resistance has limited the usage of these antibiotics. Encapsulating antimicrobial drugs into unilamellar liposomes is an approach that has been investigated in order to overcome microorganism resistance. In this study, antimicrobial activity of liposomal ceftazidime and cefepime against P. aeruginosa ATCC 27853 and P. aeruginosa SPM-1 was compared to that of the free drugs. Liposomal characterization included diameter, encapsulation efficiency and stability. Minimum Inhibitory Concentration (MIC) was determined for free and liposomal forms of both drugs. Minimum Bactericidal Concentration (MBC) was determined at concentrations 1, 2 and 4 times MIC. Average diameter of liposomes was 131.88 nm and encapsulation efficiency for cefepime and ceftazidime were 2.29% end 5.77%, respectively. Improved stability was obtained when liposome formulations were prepared with a 50% molar ratio for cholesterol in relation to the phospholipid. MIC for liposomal antibiotics for both drugs were 50% lower than that of the free drug, demonstrating that liposomal drug delivery systems may contribute to increase the antibacterial activity of these drugs. PMID:24031917

  14. Propylene glycol-embodying deformable liposomes as a novel drug delivery carrier for vaginal fibrauretine delivery applications.

    Science.gov (United States)

    Li, Wei-Ze; Hao, Xu-Liang; Zhao, Ning; Han, Wen-Xia; Zhai, Xi-Feng; Zhao, Qian; Wang, Yu-E; Zhou, Yong-Qiang; Cheng, Yu-Chuan; Yue, Yong-Hua; Fu, Li-Na; Zhou, Ji-Lei; Wu, Hong-Yu; Dong, Chun-Jing

    2016-03-28

    The purpose of this work was to develop and characterize the fibrauretine (FN) loaded propylene glycol-embodying deformable liposomes (FDL), and evaluate the pharmacokinetic behavior and safety of FDL for vaginal drug delivery applications. FDL was characterized for structure, particle size, zeta potential, deformability and encapsulation efficiency; the ability of FDL to deliver FN across vagina tissue in vitro and the distribution behavior of FN in rat by vaginal drug delivery were investigated, the safety of FDL to the vagina of rabbits and rats as well as human vaginal epithelial cells (VK2/E6E7) were also evaluated. Results revealed that: (i) the FDL have a closed spherical shape and lamellar structure with a homogeneous size of 185±19nm, and exhibited a negative charge of -53±2.7mV, FDL also have a good flexibility with a deformability of 92±5.6 (%phospholipids/min); (ii) the dissolving capacity of inner water phase and hydrophilicity of phospholipid bilayers of deformable liposomes were increased by the presence of propylene glycol, this may be elucidated by the fluorescent probes both lipophilic Nile red and hydrophilic calcein that were filled up the entire volume of the FDL uniformly, so the FDL with a high entrapment capacity (were calculated as percentages of total drug) for FN was 78±2.14%; (iii) the permeability of FN through vaginal mucosa was obviously improved by propylene glycol-embodying deformable liposomes, no matter whether the FN loaded in liposomes or not, although FN loaded in liposomes caused the highest permeability and drug reservoir in vagina; (iv) the FN mainly aggregated in the vagina and uterus, then the blood, spleen, liver, kidney, heart and lungs for vaginal drug delivery, this indicating vaginal delivery of FDL have a better 'vaginal local targeting effect'; and (v) the results of safety evaluation illustrate that the FDL is non-irritant and well tolerated in vivo, thereby establishing its vaginal drug delivery potential

  15. Fine and Clean Photothermally Controlled NIR Drug Delivery from Biocompatible Nickel-bis(dithiolene)-Containing Liposomes.

    Science.gov (United States)

    Mebrouk, Kenny; Ciancone, Mathieu; Vives, Thomas; Cammas-Marion, Sandrine; Benvegnu, Thierry; Le Goff-Gaillard, Catherine; Arlot-Bonnemains, Yannick; Fourmigué, Marc; Camerel, Franck

    2017-11-08

    This work demonstrates that metal-bis(dithiolene) complexes can be efficiently incorporated inside organic nanocarriers and, that under near-infrared (NIR) irradiation, their high photothermal activity can be finely used to release encapsulated drugs on demand. In contrast to gold nanoparticles and other organic NIR dyes, nickel-bis(dithiolene) complexes do not produce singlet oxygen under irradiation, a highly desirable characteristic to preserve the chemical integrity and activity of the loaded drug during the NIR-triggered release from the nanocarriers. Finally, cytotoxicity experiments performed on various cell lines have shown that the incorporation of such metal complexes do not increase the toxicity of the final liposomal formulation. These results offer great promise for the development of innovative biocompatible drug nanocargos that are able to safely deliver their content on demand under NIR laser irradiation. Moreover, this work demonstrates that metal-bis(dithiolene) complexes, owing to their versatility of functionalization and metal complexation, are attractive photothermal agents for the development of original NIR-responsive materials for application not only in biotechnology but also in materials science. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  16. Multifunctional liposomes for nasal delivery of the anti-Alzheimer drug tacrine hydrochloride

    DEFF Research Database (Denmark)

    Corace, Giuseppe; Angeloni, Cristina; Malaguti, Marco

    2014-01-01

    Abstract The purpose of this study was the development of multifunctional liposomes for nasal administration of tacrine hydrochloride. Liposomes were prepared using traditional excipients (cholesterol and phosphatidylcholine), partly enriched with α-tocopherol and/or Omega3 fatty acids...... permeability, which can be related to liposome fusion with cellular membrane, a hypothesis, which was also supported by cellular uptake studies. Finally, the addition of α-tocopherol without Omega3 fatty acids, was found to increase the neuroprotective activity and antioxidant properties of liposomes....

  17. The efficacy and safety of the targeted drug combined with adriamycin liposome solution for HER-2-positive breast cancer

    Directory of Open Access Journals (Sweden)

    Zi-Ping Zhou

    2017-05-01

    Full Text Available Objective: To study the efficacy and safety of the targeted drug trastuzumab combined with adriamycin liposome solution for HER-2-positive breast cancer. Methods: A total of 112 patients with breast cancer who received chemotherapy in Department of Cardiothoracic Breast Surgery, Guangdong TongJiang Hospital between May 2014 and April 2016 were selected as the research subjects and divided into two groups by random number table, liposome group received trastuzumab + adriamycin liposome chemotherapy, and the control group received trastuzumab + adriamycin chemotherapy. Before chemotherapy as well as 4 weeks and 8 weeks after chemotherapy, serum levels of tumor markers, cytokines and myocardial injury indexes were detected, the electrocardiography was conducted and the degree of myocardial injury was determined. Results: 4 weeks and 8 weeks after chemotherapy, serum CEA, CA15-3, TPS, CTGF, TGF-β, TSGF, VEGF and MK levels of both groups were significantly lower than those before chemotherapy, serum CK-MB and cTnI levels were significantly higher than those before chemotherapy, limb leads QRS amplitudes and chest leads QRS amplitudes were significantly lower than those before chemotherapy, serum CEA, CA15-3, TPS, CTGF, TGF-β, TSGF, VEGF, MK, CK-MB and cTnI levels of liposome group were significantly lower than those of control group, and the limb leads QRS amplitudes and chest lead QRS amplitudes were significantly higher than those of control group. Conclusion: Targeted drug combined with adriamycin liposome therapy for HER-2-positive breast cancer can improve the curative effect and reduce the cardiotoxicity.

  18. Urothelium-adherent, ion-triggered liposome-in-gel system as a platform for intravesical drug delivery.

    Science.gov (United States)

    GuhaSarkar, Shruti; More, Prachi; Banerjee, Rinti

    2017-01-10

    Instillations of therapeutic agents into the urinary bladder have limited efficacy due to drug washout and inadequate attachment to and penetration into the bladder wall. Instilled nanoparticles alone have low stability and high susceptibility to washout, while gel-based systems are difficult to administer and retain. To overcome disadvantages of current technologies, a biodegradable, in situ-gelling liposome-in-gel (LP-Gel) system was developed for instillation into the bladder, composed of nano-sized, fluidizing liposomes incorporated into a "smart" biopolymeric, urine-triggered hydrogel. The liposomes are optimized for their fluidizing composition in order to enhance cellular penetration through the urothelial barrier, while the hydrogel co-delivers the suspended nanocarriers and enhances adhesion on the mucin layer of the urothelium. The composite system thus mimics both the lipid membranes and mucosal layer that comprise the urothelial barrier. LP-Gel showed appreciable cytotoxicity in rat and human bladder cancer cells, and instillation into rat bladder showed enhanced adhesion on the urothelium and increased penetration into the bladder wall. Instillation of paclitaxel-loaded LP-Gel showed drug retention for at least 7days, substantially higher than free drug (few hours), and with negligible systemic levels. The LP-Gel platform system thus facilitates prolonged drug localization in the bladder, showing potential use in intravesical applications. Copyright © 2016. Published by Elsevier B.V.

  19. Physicochemical interactions among α-eleostearic acid-loaded liposomes applied to the development of drug delivery systems

    Science.gov (United States)

    Nogueira, Alessandro Oliveira de Moraes; de Sousa, Robson Simplício; Pereira, Luiza Silveira; Mallmann, Christian; da Silva Ferreira, Ailton; Clementin, Rosilene Maria; de Lima, Vânia Rodrigues

    2018-02-01

    In this study, α-eleostearic acid-loaded (α-ESA-loaded) dimyristoylphosphatidylcholine (DMPC) liposomes had their physicochemical properties characterized by horizontal attenuated total reflectance Fourier transform infrared (HATR-FTIR) spectroscopy, nuclear magnetic resonance (NMR) and differential scanning calorimetry (DSC). In vitro thiobarbituric acid reactive substance (TBARS) assays were performed to obtain preliminary information on the oxidative potential of the system. An α-ESA-promoted ordering effect in the lipid phosphate region was observed. It was associated with a rotation restriction due to an increase in the amount of lipid group hydrogen bonds. The fatty acid was responsible for the reduction in the degree of hydration of carbonyl groups located in the interfacial region of lipids. α-ESA disordered the DMPC methylene acyl chains by trans-gauche isomerization and increased its rotation rate. TBARS results showed pro-oxidant behavior on liposomes, induced by α-ESA. The discussion about the responses considered the degree of saturation of phosphatidylcholines and suggested that the α-ESA oxidative effects may be modulated by the liposome lipid composition. The versatility of liposomal carriers may be promising for the development of efficacious α-ESA-based drug delivery systems. Results described in this study contribute to the selection of adequate material to produce them.

  20. The use of asymmetrical flow field-flow fractionation with on-line detection in the study of drug retention within liposomal nanocarriers and drug transfer kinetics

    DEFF Research Database (Denmark)

    Hinna, Askell Hvid; Hupfeld, Stefan; Kuntsche, Judith

    2016-01-01

    , the latter serving as a model mimicking biological sinks in the body. The donor- and acceptor-liposomes were subsequently separated using asymmetrical flow field-flow fractionation (AF4), during which the sample is exposed to a large volume of eluent which corresponds to a dilution factor of approximately...... drug transfer and drug release to the aqueous phase. By sampling at specific incubation times, the release and transfer kinetics of the model compound p-THPP (5,10,15,20-tetrakis(4-hydroxyphenyl)21H,23H-porphine) was determined. p-THPP is structurally closely related to the photosensitizer temoporfin......Due to their solubilizing capabilities, liposomes (phospholipid vesicles) are suited for designing formulations for intravenous administration of drug compounds which are poorly water-soluble. Despite the good in-vitro stability of such formulations with minimal drug leakage, upon i.v. injection...

  1. Design of Hybrid Gels Based on Gellan-Cholesterol Derivative and P90G Liposomes for Drug Depot Applications

    Directory of Open Access Journals (Sweden)

    Nicole Zoratto

    2017-05-01

    Full Text Available Gels are extensively studied in the drug delivery field because of their potential benefits in therapeutics. Depot gel systems fall in this area, and the interest in their development has been focused on long-lasting, biocompatible, and resorbable delivery devices. The present work describes a new class of hybrid gels that stem from the interaction between liposomes based on P90G phospholipid and the cholesterol derivative of the polysaccharide gellan. The mechanical properties of these gels and the delivery profiles of the anti-inflammatory model drug diclofenac embedded in such systems confirmed the suitability of these hybrid gels as a good candidate for drug depot applications.

  2. Spectroscopic Study of the Interaction of Carboxyl-Modified Gold Nanoparticles with Liposomes of Different Chain Lengths and Controlled Drug Release by Layer-by-Layer Technology.

    Science.gov (United States)

    Kanwa, Nishu; De, Soumya Kanti; Adhikari, Chandan; Chakraborty, Anjan

    2017-12-21

    In this article, we investigate the interactions of carboxyl-modified gold nanoparticles (AuC) with zwitterionic phospholipid liposomes of different chain lengths using a well-known membrane probe PRODAN by steady-state and time-resolved spectroscopy. We use three zwitterionic lipids, namely, dipalmitoylphosphatidylcholine (DPPC), 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), and 1,2-dilauroyl-sn-glycero-3-phosphocholine (DLPC), which are widely different in their phase transition temperatures to form liposome-AuC assemblies. The steady-state and time-resolved studies indicate that the AuC brings in stability toward liposomes by local gelation. We observe that the bound AuC detach from the surface of the liposomes under pH ≈ 5 due to protonation of the carboxyl group, thus eliminating the electrostatic interaction between nanoparticles and head groups of liposomes. The detachment rate of AuC from the liposome-AuC assemblies is different for the aforementioned liposomes due to differences in their fluidity. We exploited the phenomena for the controlled release of a prominent anticancer drug Doxorubicin (DOX) under acidic conditions for different zwitterionic liposomes. The drug release rate was further optimized by coating of liposome-AuC assemblies with oppositely charged polymer (P), polydiallyldimethylammonium chloride, followed by a mixture of lipids L (DMPC:DMPG) and again with a polymer in a layer-by-layer fashion to obtain capsule-like structures. This system is highly stable for weeks, as confirmed by field-emission scanning electron microscopy (FE-SEM) and confocal laser scanning microscopy (CLSM) imaging, and inhibits premature release. The layer coating was confirmed by hydrodynamic size and zeta potential measurements of the systems. The capsules obtained are of immense importance as they can control release of the drug from the systems to a large extent.

  3. Mechanism and kinetics of the loss of poorly soluble drugs from liposomal carriers studied by a novel flow field-flow fractionation-based drug release-/transfer-assay.

    Science.gov (United States)

    Hinna, Askell Hvid; Hupfeld, Stefan; Kuntsche, Judith; Bauer-Brandl, Annette; Brandl, Martin

    2016-06-28

    Liposomes represent a versatile drug formulation approach e.g. for improving the water-solubility of poorly soluble drugs but also to achieve drug targeting and controlled release. For the latter applications it is essential that the drug remains associated with the liposomal carrier during transit in the vascular bed. A range of in vitro test methods has been suggested over the years for prediction of the release of drug from liposomal carriers. The majority of these fail to give a realistic prediction for poorly water-soluble drugs due to the intrinsic tendency of such compounds to remain associated with liposome bilayers even upon extensive dilution. Upon i.v. injection, in contrast, rapid drug loss often occurs due to drug transfer from the liposomal carriers to endogenous lipophilic sinks such as lipoproteins, plasma proteins or membranes of red blood cells and endothelial cells. Here we report on the application of a recently introduced in vitro predictive drug transfer assay based on incubation of the liposomal drug carrier with large multilamellar liposomes, the latter serving as a biomimetic model sink, using flow field-flow fractionation as a tool to separate the two types of liposomes. By quantifying the amount of drug remaining associated with the liposomal drug carrier as well as that transferred to the acceptor liposomes at distinct times of incubation, both the kinetics of drug transfer and release to the water phase could be established for the model drug p-THPP (5,10,15,20-tetrakis(4-hydroxyphenyl)21H,23H-porphine). p-THPP is structurally similar to temoporfin, a photosensitizer which is under clinical evaluation in a liposomal formulation. Mechanistic insights were gained by varying the donor-to-acceptor lipid mass ratio, size and lamellarity of the liposomes. Drug transfer kinetics from one liposome to another was found rate determining as compared to redistribution from the outermost to the inner concentric bilayers, such that the overall

  4. Development and optimization of a new processing approach for manufacturing topical liposomes-in-hydrogel drug formulations by dual asymmetric centrifugation.

    Science.gov (United States)

    Ingebrigtsen, Sveinung G; Škalko-Basnet, Nataša; Holsæter, Ann Mari

    2016-09-01

    The objective of the present study was to utilize dual asymmetric centrifugation (DAC) as a novel processing approach for the production of liposomes-in-hydrogel formulations. Lipid films of phosphatidylcholine, with and without chloramphenicol (CAM), were hydrated and homogenized by DAC to produce liposomes in the form of vesicular phospholipid gels with a diameter in the size range of 200-300 nm suitable for drug delivery to the skin. Different homogenization processing parameters were investigated along with the effect of adding propylene glycol (PG) to the formulations prior to homogenization. The produced liposomes were incorporated into a hydrogel made of 2.5% (v/v) soluble β-1,3/1,6-glucan (SBG) and mixed by DAC to achieve a homogenous liposomes-in-hydrogel-formulation suitable for topical application. CAM-containing liposomes with a vesicle diameter of 282 ± 30 nm and polydispersity index (PI) of 0.13 ± 0.02 were successfully produced by DAC after 50 min centrifugation at 3500 rpm, and homogenously (centrifugation time to 2 min and 55 s, producing liposomes of 230 ± 51 nm and PI of 0.25 ± 0.04. All formulations had an entrapment efficiency of approximately 50%. We managed to develop a relatively fast and reproducible new method for the production of liposomes-in-hydrogel formulations by DAC.

  5. Effects of Micro-environmental pH of Liposome on Chemical Stability of Loaded Drug.

    Science.gov (United States)

    Shao, Xiao-Ru; Wei, Xue-Qin; Zhang, Shu; Fu, Na; Lin, Yun-Feng; Cai, Xiao-Xiao; Peng, Qiang

    2017-08-23

    Liposome is a promising carrier system for delivering bioactive molecules. However, the successful delivery of pH-sensitive molecules is still limited by the intrinsic instability of payloads in physiological environment. Herein, we developed a special liposome system that possesses an acidic micro-environment in the internal aqueous chamber to improve the chemical stability of pH-sensitive payloads. Curcumin-loaded liposomes (Cur-LPs) with varied internal pH values (pH 2.5, 5.0, or 7.4) were prepared. These Cur-LPs have similar particle size of 300 nm, comparable physical stabilities and analogous in vitro release profiles. Interestingly, the chemical stability of liposomal curcumin in 50% fetal bovine serum and its anticancer efficacy in vitro are both micro-environmental pH-dependent (Cur-LP-2.5 > Cur-LP-5.0 > Cur-LP-7.4). This serum stability still has space to be further enhanced to improve the applicability of Cur-LP. In conclusion, creating an acidic micro-environment in the internal chamber of liposome is feasible and efficient to improve the chemical stability of pH-sensitive payloads.

  6. Pharmaceutical characterization of novel tenofovir liposomal formulations for enhanced oral drug delivery: in vitro pharmaceutics and Caco-2 permeability investigations

    Directory of Open Access Journals (Sweden)

    Spinks CB

    2017-02-01

    Full Text Available Crystal B Spinks,1 Ahmed S Zidan,2,3 Mansoor A Khan,4 Muhammad J Habib,1 Patrick J Faustino2 1Department of Pharmaceutical Sciences, School of Pharmacy, Howard University, Washington, DC, 2Division of Product Quality Research, Office of Pharmaceutical Quality, Food and Drug Administration, Silver Spring, MD, USA; 3Faculty of Pharmacy, Zagazig University, Zagazig, Egypt; 4Irma Lerma Rangel College of Pharmacy, Texas A&M Health Science Center, College Station, TX, USA Abstract: Tenofovir, currently marketed as the prodrug tenofovir disoproxil fumarate, is used clinically to treat patients with HIV/AIDS. The oral bioavailability of tenofovir is relatively low, limiting its clinical effectiveness. Encapsulation of tenofovir within modified long-circulating liposomes would deliver this hydrophilic anti-HIV drug to the reticuloendothelial system for better therapeutic efficacy. The objectives of the current study were to prepare and pharmaceutically characterize model liposomal tenofovir formulations in an attempt to improve their bioavailability. The entrapment process was performed using film hydration method, and the formulations were characterized in terms of encapsulation efficiency and Caco-2 permeability. An efficient reverse-phase high-performance liquid chromatography method was developed and validated for tenofovir quantitation in both in vitro liposomal formulations and Caco-2 permeability samples. Separation was achieved isocratically on a Waters Symmetry C8 column using 10 mM Na2PO4/acetonitrile pH 7.4 (95:5 v/v. The flow rate was 1 mL/min with a 12 min elution time. Injection volume was 10 µL with ultraviolet detection at 270 nm. The method was validated according to United States Pharmacopeial Convention category I requirements. The obtained result showed that tenofovir encapsulation within the prepared liposomes was dependent on the employed amount of the positive charge-imparting agent. The obtained results indicated that

  7. Nanodrug-enhanced radiofrequency tumor ablation: effect of micellar or liposomal carrier on drug delivery and treatment efficacy.

    Directory of Open Access Journals (Sweden)

    Marwan Moussa

    Full Text Available To determine the effect of different drug-loaded nanocarriers (micelles and liposomes on delivery and treatment efficacy for radiofrequency ablation (RFA combined with nanodrugs.Fischer 344 rats were used (n = 196. First, single subcutaneous R3230 tumors or normal liver underwent RFA followed by immediate administration of i.v. fluorescent beads (20, 100, and 500 nm, with fluorescent intensity measured at 4-24 hr. Next, to study carrier type on drug efficiency, RFA was combined with micellar (20 nm or liposomal (100 nm preparations of doxorubicin (Dox; targeting HIF-1α or quercetin (Qu; targeting HSP70. Animals received RFA alone, RFA with Lipo-Dox or Mic-Dox (1 mg i.v., 15 min post-RFA, and RFA with Lipo-Qu or Mic-Qu given 24 hr pre- or 15 min post-RFA (0.3 mg i.v.. Tumor coagulation and HIF-1α or HSP70 expression were assessed 24 hr post-RFA. Third, the effect of RFA combined with i.v. Lipo-Dox, Mic-Dox, Lipo-Qu, or Mic-Qu (15 min post-RFA compared to RFA alone on tumor growth and animal endpoint survival was evaluated. Finally, drug uptake was compared between RFA/Lipo-Dox and RFA/Mic-Dox at 4-72 hr.Smaller 20 nm beads had greater deposition and deeper tissue penetration in both tumor (100 nm/500 nm and liver (100 nm (p<0.05. Mic-Dox and Mic-Qu suppressed periablational HIF-1α or HSP70 rim thickness more than liposomal preparations (p<0.05. RFA/Mic-Dox had greater early (4 hr intratumoral doxorubicin, but RFA/Lipo-Dox had progressively higher intratumoral doxorubicin at 24-72 hr post-RFA (p<0.04. No difference in tumor growth and survival was seen between RFA/Lipo-Qu and RFA/Mic-Qu. Yet, RFA/Lipo-Dox led to greater animal endpoint survival compared to RFA/Mic-Dox (p<0.03.With RF ablation, smaller particle micelles have superior penetration and more effective local molecular modulation. However, larger long-circulating liposomal carriers can result in greater intratumoral drug accumulation over time and reduced tumor growth. Accordingly

  8. Small Angle X-ray and Neutron Scattering: Powerful Tools for Studying the Structure of Drug-Loaded Liposomes

    Science.gov (United States)

    Di Cola, Emanuela; Grillo, Isabelle; Ristori, Sandra

    2016-01-01

    Nanovectors, such as liposomes, micelles and lipid nanoparticles, are recognized as efficient platforms for delivering therapeutic agents, especially those with low solubility in water. Besides being safe and non-toxic, drug carriers with improved performance should meet the requirements of (i) appropriate size and shape and (ii) cargo upload/release with unmodified properties. Structural issues are of primary importance to control the mechanism of action of loaded vectors. Overall properties, such as mean diameter and surface charge, can be obtained using bench instruments (Dynamic Light Scattering and Zeta potential). However, techniques with higher space and time resolution are needed for in-depth structural characterization. Small-angle X-ray (SAXS) and neutron (SANS) scattering techniques provide information at the nanoscale and have therefore been largely used to investigate nanovectors loaded with drugs or other biologically relevant molecules. Here we revise recent applications of these complementary scattering techniques in the field of drug delivery in pharmaceutics and medicine with a focus to liposomal carriers. In particular, we highlight those aspects that can be more commonly accessed by the interested users. PMID:27043614

  9. Small Angle X-ray and Neutron Scattering: Powerful Tools for Studying the Structure of Drug-Loaded Liposomes

    Directory of Open Access Journals (Sweden)

    Emanuela Di Cola

    2016-03-01

    Full Text Available Nanovectors, such as liposomes, micelles and lipid nanoparticles, are recognized as efficient platforms for delivering therapeutic agents, especially those with low solubility in water. Besides being safe and non-toxic, drug carriers with improved performance should meet the requirements of (i appropriate size and shape and (ii cargo upload/release with unmodified properties. Structural issues are of primary importance to control the mechanism of action of loaded vectors. Overall properties, such as mean diameter and surface charge, can be obtained using bench instruments (Dynamic Light Scattering and Zeta potential. However, techniques with higher space and time resolution are needed for in-depth structural characterization. Small-angle X-ray (SAXS and neutron (SANS scattering techniques provide information at the nanoscale and have therefore been largely used to investigate nanovectors loaded with drugs or other biologically relevant molecules. Here we revise recent applications of these complementary scattering techniques in the field of drug delivery in pharmaceutics and medicine with a focus to liposomal carriers. In particular, we highlight those aspects that can be more commonly accessed by the interested users.

  10. Small Angle X-ray and Neutron Scattering: Powerful Tools for Studying the Structure of Drug-Loaded Liposomes.

    Science.gov (United States)

    Di Cola, Emanuela; Grillo, Isabelle; Ristori, Sandra

    2016-03-28

    Nanovectors, such as liposomes, micelles and lipid nanoparticles, are recognized as efficient platforms for delivering therapeutic agents, especially those with low solubility in water. Besides being safe and non-toxic, drug carriers with improved performance should meet the requirements of (i) appropriate size and shape and (ii) cargo upload/release with unmodified properties. Structural issues are of primary importance to control the mechanism of action of loaded vectors. Overall properties, such as mean diameter and surface charge, can be obtained using bench instruments (Dynamic Light Scattering and Zeta potential). However, techniques with higher space and time resolution are needed for in-depth structural characterization. Small-angle X-ray (SAXS) and neutron (SANS) scattering techniques provide information at the nanoscale and have therefore been largely used to investigate nanovectors loaded with drugs or other biologically relevant molecules. Here we revise recent applications of these complementary scattering techniques in the field of drug delivery in pharmaceutics and medicine with a focus to liposomal carriers. In particular, we highlight those aspects that can be more commonly accessed by the interested users.

  11. Drug ‘‘supersaturation’’ states induced by polymeric micelles and liposomes: A mechanistic investigation into permeability enhancements

    DEFF Research Database (Denmark)

    Di Cagno, Massimiliano; Luppi, Barbara

    2013-01-01

    entrapped plus non-entrapped in the carriers) as well as the concentration of molecularly dissolved drug (i.e. fraction non-entrapped into carriers) were characterized. Subsequently, the permeability of hydrocortisone was assessed for each type of formulation using the in-vitro sheep nasal mucosa...... liposome formulations as well as d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) micelle dispersions and polyvinylpyrrolidone (PVP) supersaturated solutions were prepared in order to increase the apparent solubility of HC. Both the apparent solubility of hydrocortisone (i.e. amount of drug...... permeability assay. In all formulations where solubilizing agents are present, an enhanced flux of HC (compared to the pure drug powder suspension) is observed. The expected linear correlation between apparent solubilities and fluxes was not found. Whereas, the concentrations of molecularly dissolved HC were...

  12. Dynamical and structural properties of lipid membranes in relation to liposomal drug delivery systems

    DEFF Research Database (Denmark)

    Jørgensen, Kent; Høyrup, Lise Pernille Kristine; Pedersen, Tina B.

    2001-01-01

    The structural and dynamical properties of DPPC liposomes containing lipopolymers (PEG-lipids) and charged DPPS lipids have been,studied in relation to the lipid membrane interaction of enzymes and peptides. The results suggest that both the lipid membrane structure and dynamics and in particular...

  13. Cationic liposomal drug delivery system for specific targeting of human cd14+ monocytes in whole blood

    DEFF Research Database (Denmark)

    2013-01-01

    blood when compared to adherence to granulocytes, T-lymphocytes, B- lymphocytes and/or NK cells in freshly drawn blood, to a lipid-based pharmaceutical composition comprising said liposomes and their use in monocytic associated prophylaxis, treatment or amelioration of a condition such as cancer...

  14. Multiseed liposomal drug delivery system using micelle gradient as driving force to improve amphiphilic drug retention and its anti-tumor efficacy.

    Science.gov (United States)

    Zhang, Wenli; Li, Caibin; Jin, Ya; Liu, Xinyue; Wang, Zhiyu; Shaw, John P; Baguley, Bruce C; Wu, Zimei; Liu, Jianping

    2018-11-01

    To improve drug retention in carriers for amphiphilic asulacrine (ASL), a novel active loading method using micelle gradient was developed to fabricate the ASL-loaded multiseed liposomes (ASL-ML). The empty ML were prepared by hydrating a thin film with empty micelles. Then the micelles in liposomal compartment acting as 'micelle pool' drove the drug to be loaded after the outer micelles were removed. Some reasoning studies including critical micelle concentration (CMC) determination, influencing factors tests on entrapment efficiency (EE), structure visualization, and drug release were carried out to explore the mechanism of active loading, ASL location, and the structure of ASL-ML. Comparisons were made between pre-loading and active loading method. Finally, the extended drug retention capacity of ML was evaluated through pharmacokinetic, drug tissue irritancy, and in vivo anti-tumor activity studies. Comprehensive results from fluorescent and transmission electron microscope (TEM) observation, encapsulation efficiency (EE) comparison, and release studies demonstrated the formation of ML-shell structure for ASL-ML without inter-carrier fusion. The location of drug mainly in inner micelles as well as the superiority of post-loading to the pre-loading method , in which drug in micelles shifted onto the bilayer membrane was an additional positive of this delivery system. It was observed that the drug amphiphilicity and interaction of micelles with drug were the two prerequisites for this active loading method. The extended retention capacity of ML has been verified through the prolonged half-life, reduced paw-lick responses in rats, and enhanced tumor inhibition in model mice. In conclusion, ASL-ML prepared by active loading method can effectively load drug into micelles with expected structure and improve drug retention.

  15. Liposome-encapsulated chemotherapy

    DEFF Research Database (Denmark)

    Børresen, B.; Hansen, A. E.; Kjær, A.

    2018-01-01

    exist describing various liposomal drugs in healthy dogs. Also, some evidence for its use in veterinary cancer patients exists, especially in canine lymphoma, canine splenic hemangiosarcoma and feline soft tissue sarcoma, however, the results have not been overwhelming. Reasons for this may be related...... for liposomal therapy on an individual, non-histology-oriented, basis. Concurrently, new developments with active-release modified liposomes in experimental models and humans will likely be relevant for veterinary patients as well, and holds the potential to improve the therapeutic response. It, however, does...

  16. Exploiting the Metal-Chelating Properties of the Drug Cargo for In Vivo Positron Emission Tomography Imaging of Liposomal Nanomedicines

    DEFF Research Database (Denmark)

    Edmonds, Scott; Volpe, Alessia; Shmeeda, Hilary

    2016-01-01

    The clinical value of current and future nanomedicines can be improved by introducing patient selection strategies based on noninvasive sensitive whole-body imaging techniques such as positron emission tomography (PET). Thus, a broad method to radiolabel and track preformed nanomedicines...... such as liposomal drugs with PET radionuclides will have a wide impact in nanomedicine. Here, we introduce a simple and efficient PET radiolabeling method that exploits the metal-chelating properties of certain drugs (e.g., bisphosphonates such as alendronate and anthracyclines such as doxorubicin) and widely used...... ionophores to achieve excellent radiolabeling yields, purities, and stabilities with 89Zr, 52Mn, and 64Cu, and without the requirement of modification of the nanomedicine components. In a model of metastatic breast cancer, we demonstrate that this technique allows quantification of the biodistribution...

  17. Outcomes analysis of an alternative formulation of PEGylated liposomal doxorubicin in recurrent epithelial ovarian carcinoma during the drug shortage era

    Directory of Open Access Journals (Sweden)

    Berger JL

    2014-08-01

    Full Text Available Jessica L Berger, Ashlee Smith, Kristin K Zorn, Paniti Sukumvanich, Alexander B Olawaiye, Joseph Kelley, Thomas C Krivak Magee-Womens Hospital, University of Pittsburgh Medical Center, Division of Gynecologic Oncology, Pittsburgh, PA, USA Background: In response to the critical shortage of Doxil®, the US Food and Drug Administration (FDA allowed temporary importation of non-FDA-approved second-generation liposomal doxorubicin, Lipo-Dox®. Lipo-Dox utilizes a different liposomal particle than Doxil and demonstrates different pharmacokinetic properties. Its use has never been evaluated in a North American population. The objective of this study was to evaluate the efficacy and tolerability of Lipo-Dox at Magee-Womens Hospital, University of Pittsburgh Medical Center, for patients with recurrent epithelial ovarian cancer who were treated during the Doxil shortage. Methods: Patients treated with Lipo-Dox from January 2012 to December 2012 were identified retrospectively. Disease response was defined radiographically by RECIST (Response Evaluation Criteria in Solid Tumors or biochemically by CA-125 level if measurable disease was not present. Survival was defined from the start date of Lipo-Dox until the date of progression or death. Toxicity was assessed by the Gynecologic Oncology Group common toxicity criteria. Results: Eighteen patients with recurrent epithelial ovarian cancer who received Lipo-Dox were identified. These patients had a median of three prior treatment regimens. The median number of Lipo-Dox cycles given was 3.5 (range 1–8. No patients had a complete or partial response. Two patients had stable disease over a mean follow-up of 144.5 days. Fourteen patients had progressive disease, with a median time to progression of 82 days. Progression was based on CA-125 in four patients and RECIST in the remainder. Nine patients died from the disease. Conclusion: Although this represents a small, pretreated population, there were no clinical

  18. Development of Liposomal Formulation for Delivering Anticancer Drug to Breast Cancer Stem-Cell-Like Cells and its Pharmacokinetics in an Animal Model.

    Science.gov (United States)

    Ahmad, Ajaz; Mondal, Sujan Kumar; Mukhopadhyay, Debabrata; Banerjee, Rajkumar; Alkharfy, Khalid M

    2016-03-07

    The objective of the present study is to develop a liposomal formulation for delivering anticancer drug to breast cancer stem-cell-like cells, ANV-1, and evaluate its pharmacokinetics in an animal model. The anticancer drug ESC8 was used in dexamethasone (Dex)-associated liposome (DX) to form ESC8-entrapped liposome named DXE. ANV-1 cells showed high-level expression of NRP-1. To enhance tumor regression, we additionally adapted to codeliver the NRP-1 shRNA-encoded plasmid using the established DXE liposome. In vivo efficacy of DXE-NRP-1 was carried out in mice bearing ANV-1 cells as xenograft tumors and the extent of tumor growth inhibition was evaluated by tumor-size measurement. A significant difference in tumor volume started to reveal between DXE-NRP-1 group and DXE-Control group. DXE-NRP-1 group showed ∼4 folds and ∼2.5 folds smaller tumor volume than exhibited by untreated and DXE-Control-treated groups, respectively. DXE disposition was evaluated in Sprague-Dawley rats following an intraperitoneal dose (3.67 mg/kg of ESC8 in DXE). The plasma concentrations of ESC8 in the DXE formulation were measured by liquid chromatography mass spectrometry and pharmacokinetic parameters were determined using a noncompartmental analysis. ESC8 had a half-life of 11.01 ± 0.29 h, clearance of 2.10 ± 3.63 L/kg/h, and volume of distribution of 33.42 ± 0.83 L/kg. This suggests that the DXE liposome formulation could be administered once or twice daily for therapeutic efficacy. In overall, we developed a potent liposomal formulation with favorable pharmacokinetic and tumor regressing profile that could sensitize and kill highly aggressive and drug-resistive cancer stem-cell-like cells.

  19. Photo activation of HPPH encapsulated in “Pocket” liposomes triggers multiple drug release and tumor cell killing in mouse breast cancer xenografts

    Directory of Open Access Journals (Sweden)

    Sine J

    2014-12-01

    Full Text Available Jessica Sine,1,* Cordula Urban,2,* Derek Thayer,1 Heather Charron,2 Niksa Valim,2 Darrell B Tata,3 Rachel Schiff,4 Robert Blumenthal,1 Amit Joshi,2 Anu Puri1 1Membrane Structure and Function Section, Basic Research Laboratory, Center for Cancer Research, National Cancer Institute – Frederick, Frederick, MD, USA; 2Department of Radiology, Baylor College of Medicine, Houston, TX, USA; 3US Food and Drug Administration, CDRH/OSEL/Division of Physics, White Oak Campus, MD, USA; 4Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA *These authors contributed equally to this work Abstract: We recently reported laser-triggered release of photosensitive compounds from liposomes containing dipalmitoylphosphatidylcholine (DPPC and 1,2 bis(tricosa-10,12-diynoyl-sn-glycero-3-phosphocholine (DC8,9PC. We hypothesized that the permeation of photoactivated compounds occurs through domains of enhanced fluidity in the liposome membrane and have thus called them “Pocket” liposomes. In this study we have encapsulated the red light activatable anticancer photodynamic therapy drug 2-(1-Hexyloxyethyl-2-devinyl pyropheophorbide-a (HPPH (Ex/Em410/670 nm together with calcein (Ex/Em490/517 nm as a marker for drug release in Pocket liposomes. A mole ratio of 7.6:1 lipid:HPPH was found to be optimal, with >80% of HPPH being included in the liposomes. Exposure of liposomes with a cw-diode 660 nm laser (90 mW, 0–5 minutes resulted in calcein release only when HPPH was included in the liposomes. Further analysis of the quenching ratios of liposome-entrapped calcein in the laser treated samples indicated that the laser-triggered release occurred via the graded mechanism. In vitro studies with MDA-MB-231-LM2 breast cancer cell line showed significant cell killing upon treatment of cell-liposome suspensions with the laser. To assess in vivo efficacy, we implanted MDA-MB-231-LM2 cells containing the luciferase gene along the mammary fat pads

  20. A novel peptide enhances therapeutic efficacy of liposomal anti-cancer drugs in mice models of human lung cancer.

    Directory of Open Access Journals (Sweden)

    De-Kuan Chang

    Full Text Available Lung cancer is the leading cause of cancer-related mortality worldwide. The lack of tumor specificity remains a major drawback for effective chemotherapies and results in dose-limiting toxicities. However, a ligand-mediated drug delivery system should be able to render chemotherapy more specific to tumor cells and less toxic to normal tissues. In this study, we isolated a novel peptide ligand from a phage-displayed peptide library that bound to non-small cell lung cancer (NSCLC cell lines. The targeting phage bound to several NSCLC cell lines but not to normal cells. Both the targeting phage and the synthetic peptide recognized the surgical specimens of NSCLC with a positive rate of 75% (27 of 36 specimens. In severe combined immunodeficiency (SCID mice bearing NSCLC xenografts, the targeting phage specifically bound to tumor masses. The tumor homing ability of the targeting phage was inhibited by the cognate synthetic peptide, but not by a control or a WTY-mutated peptide. When the targeting peptide was coupled to liposomes carrying doxorubicin or vinorelbine, the therapeutic index of the chemotherapeutic agents and the survival rates of mice with human lung cancer xenografts markedly increased. Furthermore, the targeting liposomes increased drug accumulation in tumor tissues by 5.7-fold compared with free drugs and enhanced cancer cell apoptosis resulting from a higher concentration of bioavailable doxorubicin. The current study suggests that this tumor-specific peptide may be used to create chemotherapies specifically targeting tumor cells in the treatment of NSCLC and to design targeted gene transfer vectors or it may be used one in the diagnosis of this malignancy.

  1. Development of Nano-Liposomal Formulations of Epidermal Growth Factor Receptor Inhibitors and their Pharmacological Interactions on Drug-Sensitive and Drug-Resistant Cancer Cell Lines

    Science.gov (United States)

    Trummer, Brian J.

    A rapidly expanding understanding of molecular derangements in cancer cell function has led to the development of selective, targeted chemotherapeutic agents. Growth factor signal transduction networks are frequently activated in an aberrant fashion, particularly through the activity of receptor tyrosine kinases (RTK). This has spurred an intensive effort to develop receptor tyrosine kinase inhibitors (RTKI) that are targeted to specific receptors, or receptor subfamilies. Chapter 1 reviews the pharmacology, preclinical, and clinical aspects of RTKIs that target the epidermal growth factor receptor (EGFR). EGFR inhibitors demonstrate significant success at inhibiting phosphorylation-based signaling pathways that promote cancer cell proliferation. Additionally RTKIs have physicochemical and structural characteristics that enable them to function as inhibitors of multi-drug resistance transport proteins. Thus EGFR inhibitors and other RTKIs have both on-target and off-target activities that could be beneficial in cancer therapy. However, these agents exert a number of side effects, some of which arise from their hydrophobic nature and large in vivo volume of distribution. Side effects of the EGFR inhibitor gefitinib include skin rash, severe myelotoxicity when combined with certain chemotherapeutic agents, and impairment of the blood brain barrier to xenobiotics. Weighing the preclinical and clinical observations with the EGFR inhibitors, we developed the primary overall hypothesis of this research: that drug-carrier formulations of RTKIs such as the EGFR inhibitors could be developed based on nanoparticulate liposomal carriers. Theoretically, this carrier strategy would ameliorate toxicity and improve the biodistribution and tumor selectivity of these agents. We hypothesized specifically that liposomal formulations could shift the biodistribution of EGFR inhibitors such as gefitinib away from skin, bone marrow, and the blood brain barrier, and toward solid tumors

  2. Development of a liposome formulation for D-cycloserine local delivery.

    Science.gov (United States)

    Musumeci, Teresa; Ventura, Cinzia Anna; Giannone, Ignazio; Pignatello, Rosario; Puglisi, Giovanni

    2008-01-01

    Multilamellar liposomes loaded with D-cycloserine (D-CS) were prepared by a thin layer evaporation technique, followed by freezing and thawing cycles. Charged components and bioadhesive material, such as distearolylphosphatitylethanolamine covalently coupled with methoxypolyethyleneglycol, were used to prepare liposomes with different physico-chemical and technological properties. Negatively charged liposomes showed higher D-CS encapsulation efficiency (about 37%, w/w) than neutral and positively charged liposomes (about 5 and 17%, w/w, respectively). All formulations showed in vitro, after a burst effect, a prolonged release of the encapsulated drug. Lipid vesicles made of dipalmitoylphosphatidylcholine (DPPC) were used as a biomembrane model to evaluate in vitro the interaction of D-CS with biological membranes. Differential scanning calorimetry was used as a simple and noninvasive technique of analysis. D-CS was distributed in the aqueous compartments of liposomes for interaction with the phospholipid polar head-groups (enhancement of Delta H value). However, due to its high diffusibility the drug was also able to freely permeate through DPPC liposomes, altering during this passage the hydrophobic domains of the bilayers. Stability studies were performed at different temperatures and pH values to assay the integrity of the drug during the liposome production steps. D-CS was rapidly degraded at acidic pH, but no significant hydrolysis was observed at pH 7.4 after 7 days.

  3. Preparation of drug-in-cyclodextrin-in-liposomes at a large scale using a membrane contactor: Application to trans-anethole.

    Science.gov (United States)

    Gharib, Riham; Greige-Gerges, Hélène; Jraij, Alia; Auezova, Lizette; Charcosset, Catherine

    2016-12-10

    The present study aimed to prepare liposomes loaded with cyclodextrin/drug inclusion complexes at a pilot scale based on the ethanol injection technique. Anethole (ANE), a major component of anise and fennel essential oils, was used as a model of a volatile and highly hydrophobic drug. Membrane contactor (600mL) and a pilot plant (3L) were used for liposome production. The liposome preparations obtained were characterized for size, polydispersity index, zeta potential, morphology, stability and ANE release rate. All experimental set-ups were shown to be appropriate for the preparation of small, multilamellar vesicles with narrow size distribution and good stability at 4°C. The drug release study showed that only a small amount of ANE was released from liposome formulations after 21days of storage at 4°C. The loading rate of ANE was higher when ethanol was evaporated directly on the pilot plant compared to a rotary evaporation. Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. Prospects of liposomes using for creating of new forms of the medicinal and preventive preparations

    Directory of Open Access Journals (Sweden)

    M. A. Kisjakova

    2010-07-01

    Full Text Available Information on the structure, physical and chemical characteristics of the phospholipid vesicles (liposomes – the effective natural drug delivery system is presented. Types of liposomes, procedures of its productions, penetration mechanisms into cells and functional features of liposomal drugs are described. Data on production of liposomes with lactobacilli acellular homogenates and the methods of the liposomes structure control asre demonstrated.

  5. Optimization of the qualitative composition of liposomal drugs based on natural organomineral formations

    Science.gov (United States)

    Chzhu, O. P.; Shubenkova, E. G.

    2017-08-01

    Liposomal structures were developed on the basis of oil and water extracts of natural organomineral formations. These structures are natural compositions. The content of the main components in the preparations varies within the range of 20-25% of the lipophilic phase, 64-74% of the hydrophilic phase, 5-10% of the auxiliary component and the stabilizer on the phospholipid base is 1%. Phospholipids of natural origin were used as surface-active substances. The influence of hydrophilic and lipophilic auxiliary components on the content of neutral lipids in the surface lipid layer of the skin was studied. The developed preparations can be used as carriers of both hydrophilic and lipophilic active substances in pharmaceutical compositions, cosmetic and veterinary products on a natural basis.

  6. Liposome based radiosensitizer cancer therapy

    DEFF Research Database (Denmark)

    Pourhassan, Houman

    Liposome-encapsulated chemotherapeutics have been used in the treatment of a variety of cancers and are feasible for use as mono-therapeutics as well as for combination therapy in conjunction with other modalities. Despite widespread use of liposomal drugs in cancer patient care, insufficient drug...... biomolecules. By modulating the liposomal membrane, liposomes can become sensitive towards enzymatically-driven destabilization and/or functionalization, thereby allowing control of the release of encapsulated therapeutics within the diseased tissue upon intrinsic stimulation from tumor-associated enzymes...... in tumor-bearing mice.The safety and efficacy of sPLA2-sensitive liposomal L-OHP was assessed in sPLA2-deficient FaDu hypopharyngeal squamous cell carcinoma and sPLA2-expressing Colo205 colorectal adenocarcinoma. Also, the feasibility of multimodal cancer therapy employing L-OHP encapsulated in MMP...

  7. Folic acid-coupled nano-paclitaxel liposome reverses drug resistance in SKOV3/TAX ovarian cancer cells.

    Science.gov (United States)

    Tong, Lingxia; Chen, Wei; Wu, Jing; Li, Hongxia

    2014-03-01

    Chemotherapy could be used as an effective treatment for ovarian cancer and subsequent peritoneal metastasis. Administration of chemoagents in a targeted manner may bring the advantage of higher efficiency and lower drug resistance. In the present study, folate receptor (FR)-targeted nano-paclitaxel formulations were generated and tested for cytotoxicity in a peritoneal xenograft model of paclitaxel-resistant ovarian cancer and SKOV3/TAX cell lines. Immunocytochemical staining confirmed the expression of FR in both SKOV3 and SKOV3/TAX cells. The enrichment of the folic acid-coupled PEGylated nano-paclitaxel liposome (FA-NP) in FR-positive cells was visualized with fluorescence. The uptake of the FA-NP peaked at 4 h and was more robust than nontargeted PEGylated nano-paclitaxel liposome (NP). FA-NP but not NP markedly inhibited the growth of ovarian cancer cells and induced a two-fold increase in the doubling time. The cytotoxic effects of FA-NP were more potent than NP in both SKOV3 cells [50% of inhibition concentration (IC50), 5.67 vs. 50.2 μg/ml, FA-NP vs. NP] and SKOV3/TAX cells (IC50, 0.38 vs. >200 μg/ml, FA-NP vs. NP). FA-NP caused more G2-M cell cycle arrest and apoptotic changes in ovarian cancer cells than NP or regular paclitaxel. However, these effects were blunted in the presence of free FA, which competitively inhibited the receptor-mediated uptake of FA-NP particles. Intraperitoneal (i.p.) administration of FA-NP but not regular paclitaxel, NP, or vehicle significantly prolonged the survival and reduced tumor nodule number (2.9±0.3) in BALB/c nude mice. FA-NP also markedly enhanced the percentage of apoptotic cells in peritoneal xenografts of paclitaxel-resistant ovarian cancer cells (44.6±8.5 vs. 3.2±1.1% for vehicle, 22.4±5.9% for regular paclitaxel, and 35.2±7.7% for NP; PNP at the same dose failed to induce apoptosis (20.1±6.2%; PNP reversed the drug resistance in paclitaxel-resistant SKOV3/TAX ovarian cancer cells both in vitro and in

  8. Liposome: classification, preparation, and applications

    Science.gov (United States)

    Akbarzadeh, Abolfazl; Rezaei-Sadabady, Rogaie; Davaran, Soodabeh; Joo, Sang Woo; Zarghami, Nosratollah; Hanifehpour, Younes; Samiei, Mohammad; Kouhi, Mohammad; Nejati-Koshki, Kazem

    2013-02-01

    Liposomes, sphere-shaped vesicles consisting of one or more phospholipid bilayers, were first described in the mid-60s. Today, they are a very useful reproduction, reagent, and tool in various scientific disciplines, including mathematics and theoretical physics, biophysics, chemistry, colloid science, biochemistry, and biology. Since then, liposomes have made their way to the market. Among several talented new drug delivery systems, liposomes characterize an advanced technology to deliver active molecules to the site of action, and at present, several formulations are in clinical use. Research on liposome technology has progressed from conventional vesicles to `second-generation liposomes', in which long-circulating liposomes are obtained by modulating the lipid composition, size, and charge of the vesicle. Liposomes with modified surfaces have also been developed using several molecules, such as glycolipids or sialic acid. This paper summarizes exclusively scalable techniques and focuses on strengths, respectively, limitations in respect to industrial applicability and regulatory requirements concerning liposomal drug formulations based on FDA and EMEA documents.

  9. Core/Shell Nanofibers with Embedded Liposomes as a Drug Delivery System

    Czech Academy of Sciences Publication Activity Database

    Míčková, Andrea; Buzgo, Matej; Benada, Oldřich; Rampichová, Michala; Fišar, Z.; Filová, Eva; Tesařová, Martina; Lukáš, D.; Amler, Evžen

    2012-01-01

    Roč. 13, č. 4 (2012), s. 952-962 ISSN 1525-7797 R&D Projects: GA MŠk 2B06130; GA AV ČR(CZ) IAA500390702; GA ČR GAP304/10/1307 Grant - others:GA MŠk(CZ) MSM0021620849; GA MŠk(CZ) 4977751303; GA MŠk(CZ) GA UK 96610; GA MŠk(CZ) GA UK 80009; GA MŠk(CZ) GA UK 97110; GA MŠk(CZ) GA UK 330611; GA MŠk(CZ) GA UK 164010; MZd(CZ) NT12156; GA MŠk(CZ) ME10145; GA ČR(CZ) GA202/09/1151; GA MŠk(CZ) 1M0510 Program:GA; 1M Institutional research plan: CEZ:AV0Z50390703; CEZ:AV0Z50390512; CEZ:AV0Z50200510; CEZ:AV0Z60220518 Institutional support: RVO:60077344 ; RVO:61388971 ; RVO:68378041 Keywords : tissue Engineering applications * electrospun nanofibers * liposomes Subject RIV: FP - Other Medical Disciplines; BO - Biophysics (MBU-M); BO - Biophysics (BC-A) Impact factor: 5.371, year: 2012

  10. Target Nanoparticles for Therapy - SANS and DLS of Drug Carrier Liposomes and Polymer Nanoparticles

    Science.gov (United States)

    Nawroth, T.; Johnson, R.; Krebs, L.; Khoshakhlagh, P.; Langguth, P.; Hellmann, N.; Goerigk, G.; Boesecke, P.; Bravin, A.; Le Duc, G.; Szekely, N.; Schweins, R.

    2016-09-01

    T arget Nano-Pharmaceutics shall improve therapy and diagnosis of severe diseases, e.g. cancer, by individual targeting of drug-loaded nano-pharmaceuticals towards cancer cells, and drug uptake receptors in other diseases. Specific ligands, proteins or cofactors, which are recognized by the diseased cells or cells of food and drug uptake, are bound to the nanoparticle surface, and thus capable of directing the drug carriers. The strategy has two branches: a) for parenteral cancer medicine a ligand set (2-5 different, surface-linked) are selected according to the biopsy analysis of the patient tissue e.g. from tumor.; b) in the oral drug delivery part the drug transport is enforced by excipients/ detergents in combination with targeting materials for cellular receptors resulting in an induced drug uptake. Both targeting nanomaterials are characterized by a combination of SANS + DLS and SAXS or ASAXS in a feedback process during development by synthesis, nanoparticle assembly and formulation.

  11. Target Nanoparticles for Therapy - SANS and DLS of Drug Carrier Liposomes and Polymer Nanoparticles

    International Nuclear Information System (INIS)

    Nawroth, T; Johnson, R; Krebs, L; Khoshakhlagh, P; Langguth, P; Hellmann, N; Goerigk, G; Boesecke, P; Bravin, A; Duc, G Le; Szekely, N; Schweins, R

    2016-01-01

    T arget Nano-Pharmaceutics shall improve therapy and diagnosis of severe diseases, e.g. cancer, by individual targeting of drug-loaded nano-pharmaceuticals towards cancer cells, and drug uptake receptors in other diseases. Specific ligands, proteins or cofactors, which are recognized by the diseased cells or cells of food and drug uptake, are bound to the nanoparticle surface, and thus capable of directing the drug carriers. The strategy has two branches: a) for parenteral cancer medicine a ligand set (2-5 different, surface-linked) are selected according to the biopsy analysis of the patient tissue e.g. from tumor.; b) in the oral drug delivery part the drug transport is enforced by excipients/ detergents in combination with targeting materials for cellular receptors resulting in an induced drug uptake. Both targeting nanomaterials are characterized by a combination of SANS + DLS and SAXS or ASAXS in a feedback process during development by synthesis, nanoparticle assembly and formulation. (paper)

  12. Advances in Tumor Targeted Liposomes.

    Science.gov (United States)

    Jain, A; Jain, S K

    2018-04-15

    Cancer remains a deadly disease for effective treatment. Although anomalous tumor microenvironment is now widely exploited for targeted chemotherapy, safe and efficacious drug delivery to tumor cells is not still warranted. Liposomes are promising biodegradable and biocompatible nanocarriers having potential amenability for surface and internal modifications, and extraordinary capability to carry both hydrophilic as well as hydrophobhic drugs. Meticulous fabrication of liposomes with tumor selective ligand(s) and PEGylation reduces immunogenicity and increase target-specificity. This chapter focuses on critical developmental aspects of liposomes to target cancer cells exploiting Enhanced Permeability and Retention (EPR) effect and tumor-selective ligands such as folate, transferrin, peptides etc. Moreover, stimuli-responsive smart liposomes (triggers: pH, temperature, enzymes, magnetic field, ultrasound, and redox potential etc.) are also investigated for enhancement of drug delivery to tumors. This review summarizes advances in tumor-targeted liposomes via various means of targeting. This knowledgeable assemblage of advances in liposomal approaches will render new insights to formulators and budding scientists to design cancer targeted liposomes. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  13. Liposomes - experiment of magnetic resonance imaging application

    International Nuclear Information System (INIS)

    Mathieu, S.

    1987-01-01

    Most pharmaceutical research effort with liposomes has been involved with the investigation of their use as drug carriers to particular target organs. Recently there has been a growing interest in liposomes not only as carrier of drugs but as a tool for the introduction of various substances into the human body. In this study, liposome delivery of nitroxyl radicals as NMR contrast agent for improved tissue imaging is experimented in rats [fr

  14. Liposome-mediated functional expression of multiple drug resistance gene in human bone marrow CD34+ cells.

    Science.gov (United States)

    Cao, Wenjing; Zou, Ping

    2004-01-01

    The expression and functional activity of multiple drug resistance (MDR1) gene in human normal bone marrow CD34+ cells was observed. Human normal bone marrow CD34+ cells were enriched with magnetic cell sorting (MACS) system, and then liposome-mediated MDR1 gene was transferred into bone marrow CD34+ cells. Fluorescence-activated cell sorter was used to evaluate the expression and functional activity of P-glycoprotein (P-gp) encoded by MDR1 gene. It was found that the purity of bone marrow CD34+ cells was approximately (91 +/- 4.56)% and recovery rate was (72.3 +/- 2.36)% by MACS. The expression of P-gp in the transfected CD34+ cells was obviously higher than that in non-transfected CD34+ cells. The amount of P-gp in non-transfected CD34+ cells was (11.2 +/- 2.2)%, but increased to (23.6 +/- 2.34)% 48 h after gene transfection (PMRD1 transferring into human normal bone marrow CD34+ cells.

  15. Liposomes of dimeric artesunate phospholipid: A combination of dimerization and self-assembly to combat malaria.

    Science.gov (United States)

    Ismail, Muhammad; Ling, Longbing; Du, Yawei; Yao, Chen; Li, Xinsong

    2018-05-01

    Artemisinin and its derivatives are highly effective drugs in the treatment of P. falciparum malaria. However, their clinical applications face challenges because of short half-life, poor bioavailability and growing drug resistance. In this article, novel dimeric artesunate phospholipid (Di-ART-GPC) based liposomes were developed by combination of dimerization and self-assembly to address these shortcomings. Firstly, Di-ART-GPC conjugate was synthesized by a facile esterification of artesunate (ART) and glycerophosphorylcholine (GPC) and confirmed by MS, 1 H NMR and 13 C NMR. The conjugate was then assembled to form liposomes without excipient by thin film hydration method. The assembled Di-ART-GPC liposomes have typical multilamellar vesicle structure with bilayer morphology as determined by transmission electron microscopy (TEM) and cryogenic electron microscopy (cryo-EM). Moreover, the liposomes displayed an average hydrodynamic diameter of 190 nm and negative zeta potential at -20.35 mV as determined by Zetasizer. The loading capacity of ART was calculated approximately 77.6% by weight with this liposomal formulation after a simple calculation. In vitro drug release and degradation results showed that the Di-ART-GPC liposomes were stable in neutral physiological conditions but effectively degraded to release parent ART in simulated weakly acidic microenvironment. In vivo pharmacokinetics study revealed that Di-ART-GPC liposomes and conjugate have longer retention half-life in bloodstream. Importantly, Di-ART-GPC liposomes (IC 50 0.39 nM) and the conjugate (IC 50 1.90 nM) demonstrated excellent in vitro antiplasmodial activities without causing hemolysis of erythrocytes, which were superior to free ART (IC 50 5.17 nM) and conventional ART-loaded liposomes (IC 50 3.13 nM). Furthermore, the assembled liposomes resulted in enhanced parasites killing in P. berghei-infected mice in vivo with delayed recrudescence and improved survivability

  16. Temoporfin-loaded liposomes

    DEFF Research Database (Denmark)

    Kuntsche, Judith; Freisleben, Ines; Steiniger, Frank

    2010-01-01

    some problems associated with the commercial formulation Foscan where the drug is dissolved in a mixture of water-free ethanol and propylene glycol. The present study focuses on the physicochemical characterization of different liposome formulations with special emphasis on the influence of drug...... investigations indicate the presence of micellar structures in addition to vesicles. Lyophilization and reconstitution led to an alteration in the morphology but had overall no distinct influence on the colloidal stability....

  17. Targeted liposomes for drug delivery across the blood-brain barrier

    NARCIS (Netherlands)

    van Rooy, I.

    2011-01-01

    Our brain is protected by the blood-brain barrier (BBB). This barrier is formed by specialized endothelial cells of the brain vasculature and prevents toxic substances from entering the brain. The downside of this barrier is that many drugs that have been developed to cure brain diseases cannot

  18. Liposomes as a drug delivery system in photodynamic therapy for colon cancer treatment

    CSIR Research Space (South Africa)

    Maduray, K

    2010-01-01

    Full Text Available Photodynamic therapy (PDT) uses a drug termed a photosensitizer (PS), light (laser) of an appropriate wavelength and molecular oxygen (tissue) to elicit cell death of cancer cells. The objective of this study was to evaluate the enhancement of PDT...

  19. Effect of a controlled-release drug delivery system made of oleanolic acid formulated into multivesicular liposomes on hepatocellular carcinoma in vitro and in vivo

    Directory of Open Access Journals (Sweden)

    Luo YL

    2016-07-01

    Full Text Available Yuling Luo, Zhongbing Liu, Xiaoqin Zhang, Juan Huang, Xin Yu, Jinwei Li, Dan Xiong, Xiaoduan Sun, Zhirong Zhong Department of Pharmaceutical Sciences, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan,People’s Republic of ChinaAbstract: The aim of the present study was to develop a novel dosage form of multivesicular liposomes for oleanolic acid (OA to overcome its poor solubility, prolong therapeutic drug levels in the blood, and enhance the antitumor effect on hepatocellular carcinoma. OA-encapsulated multivesicular liposomes (OA-MVLs were prepared by a double-emulsion method, and the formulation was optimized by the central composite design. The morphology, particle size, and drug-loading efficiency of OA-MVLs were investigated. Furthermore, OA-MVLs were also characterized both in vitro and in vivo. The results showed that OA-MVLs were spherical particles with an average particle size of 11.57 µm and an encapsulation efficiency of 82.3%±0.61%. OA-MVLs exhibited a sustained-release pattern in vitro, which was fitted to Ritger–Peppas equation. OA-MVLs inhibited the growth of human HepG2 cells which was confirmed by the MTT assay and fluorescence microscopy detection. The in vivo release of OA from OA-MVLs exhibited a sustained manner, indicating a longer circulation time compared to OA solution. The in vivo toxicity study indicated that medium-dose OA-MVLs exerted no toxic effect on the hosts. Importantly, OA-MVLs suppressed the growth of murine H22 hepatoma and prolonged the survival of tumor-bearing mice. In conclusion, the poorly soluble OA could be encapsulated into MVLs to form a novel controlled-release drug delivery system. The present study may hold promise for OA-MVLs as a new dosage form for sustained-release drug delivery in cancer therapy.Keywords: oleanolic acid, multivesicular liposomes, murine hepatocellular carcinoma, controlled release, cancer therapy

  20. Glucocorticoids in nano-liposomes administered intravenously and subcutaneously to adjuvant arthritis rats are superior to the free drugs in suppressing arthritis and inflammatory cytokines.

    Science.gov (United States)

    Ulmansky, Rina; Turjeman, Keren; Baru, Moshe; Katzavian, Galia; Harel, Michal; Sigal, Alex; Naparstek, Yaakov; Barenholz, Yechezkel

    2012-06-10

    We have previously shown that intravenous (i.v.) treatment with sterically stabilized nano-liposomes (NSSL) actively remote-loaded with the glucocorticoid (GC) methylprednisolone hemisuccinate (NSSL-MPS) or betamethasone hemisuccinate (NSSL-BMS) significantly decreased severity of adjuvant arthritis in Lewis rats (a model of human rheumatoid arthritis) throughout all disease stages. Here, we compared i.v. or subcutaneous (s.c.) weekly treatment with each of the two NSSL-GC to weekly or daily treatment with the free drugs or with the TNF-α antagonists Infliximab and Etanercept. Therapeutic efficacy and effects on the profile of pro-inflammatory (IL-6, TNF-α, and INF-γ) and anti-inflammatory (IL-10 and TGF-β) cytokines in rat sera and splenocyte tissue culture supernatants were compared to those of the liposomal and free drugs. Both s.c. and i.v. NSSL-GC suppressed arthritis significantly, compared to higher doses of the free drugs or to TNF-α antagonists. NSSL-GC also suppressed the secretion of pro-inflammatory cytokines, but did not change the levels of TGF- β. The highly efficacious anti-inflammatory therapeutic feature of these nano-drugs makes them candidates for treatment of human rheumatoid arthritis. Copyright © 2011 Elsevier B.V. All rights reserved.

  1. Size-controlled, dual-ligand modified liposomes that target the tumor vasculature show promise for use in drug-resistant cancer therapy.

    Science.gov (United States)

    Takara, Kazuhiro; Hatakeyama, Hiroto; Kibria, Golam; Ohga, Noritaka; Hida, Kyoko; Harashima, Hideyoshi

    2012-08-20

    Anti-angiogenic therapy is a potential chemotherapeutic strategy for the treatment of drug resistant cancers. However, a method for delivering such drugs to tumor endothelial cells remains to be a major impediment to the success of anti-angiogenesis therapy. We designed liposomes (LPs) with controlled diameter of around 300 nm, and modified them with a specific ligand and a cell penetrating peptide (CPP) (a dual-ligand LP) for targeting CD13-expressing neovasculature in a renal cell carcinoma (RCC). We modified the LPs with an NGR motif peptide on the top of poly(ethylene glycol) and tetra-arginine (R4) on the surface of the liposome membrane as a specific and CPP ligand, respectively. The large size prevented extravasation of the dual-ligand LP, which allowed it to associate with target vasculature. While a single modification with either the specific or CPP ligand showed no increase in targetability, the dual-ligand enhanced the amount of delivered liposomes after systemic administration to OS-RC-2 xenograft mice. The anti-tumor activity of a dual-ligand LP encapsulating doxorubicin was evaluated and the results were compared with Doxil, which is clinically used to target tumor cells. Even though Doxil showed no anti-tumor activity, the dual-ligand LP suppressed tumor growth because the disruption of tumor vessels was efficiently induced. The comparison showed that tumor endothelial cells (TECs) were more sensitive to doxorubicin by 2 orders than RCC tumor cells, and the disruption of tumor vessels was efficiently induced. Collectively, the dual-ligand LP is promising carrier for the treatment of drug resistant RCC via the disruption of TECs. Copyright © 2012 Elsevier B.V. All rights reserved.

  2. Transfer kinetics from colloidal drug carriers and liposomes to biomembrane models: DSC studies

    Directory of Open Access Journals (Sweden)

    Maria Grazia Sarpietro

    2011-01-01

    Full Text Available The release of bioactive molecules by different delivery systems has been studied. We have proposed a protocol that takes into account a system that is able to carry out the uptake of a bioactive molecule released during the time, resembling an in vivo-like system, and for this reason we have used biomembrane models represented by multi-lamellar and unilamellar vesicles. The bioactive molecule loaded delivery system has been put in contact with the biomembrane model and the release has been evaluated, to consider the effect of the bioactive molecule on the biomembrane model thermotropic behavior, and to compare the results with those obtained when a pure drug interacts with the biomembrane model. The differential scanning calorimetry technique has been employed. Depending on the delivery system used, our research permits to evaluate the effect of different parameters on the bioactive molecule release, such as pH, drug loading degree, delivery system swelling, crosslinking agent, degree of cross-linking, and delivery system side chains.

  3. Ultrasonic shock-wave as a control mechanism for liposome drug delivery system for possible use in scaffold implanted to animals with iatrogenic articular cartilage defects

    Czech Academy of Sciences Publication Activity Database

    Míčková, Andrea; Tománková, K.; Kolářová, H.; Bajgar, R.; Kolář, P.; Šunka, P.; Plencner, Martin; Jakubová, Radka; Beneš, J.; Koláčná, Lucie; Plánka, L.; Nečas, A.; Amler, Evžen

    2008-01-01

    Roč. 77, č. 2 (2008), s. 285-289 ISSN 0001-7213 R&D Projects: GA AV ČR(CZ) 1ET400110403; GA AV ČR IAA500390702; GA MŠk 2B06130 Grant - others:GA MŠk(CZ) 1M0510 Program:1M Institutional research plan: CEZ:AV0Z50390512; CEZ:AV0Z50390703 Keywords : Liposome * Controlled drug delivery * Fluorescence Subject RIV: EA - Cell Biology Impact factor: 0.395, year: 2008

  4. Potential Effect of Liposomes and Liposome-Encapsulated Botulinum Toxin and Tacrolimus in the Treatment of Bladder Dysfunction

    Directory of Open Access Journals (Sweden)

    Joseph J. Janicki

    2016-03-01

    Full Text Available Bladder drug delivery via catheter instillation is a widely used treatment for recurrence of superficial bladder cancer. Intravesical instillation of liposomal botulinum toxin has recently shown promise in the treatment of overactive bladder and interstitial cystitis/bladder pain syndrome, and studies of liposomal tacrolimus instillations show promise in the treatment of hemorrhagic cystitis. Liposomes are lipid vesicles composed of phospholipid bilayers surrounding an aqueous core that can encapsulate hydrophilic and hydrophobic drug molecules to be delivered to cells via endocytosis. This review will present new developments on instillations of liposomes and liposome-encapsulated drugs into the urinary bladder for treating lower urinary tract dysfunction.

  5. Liposomally encapsulated diclofenac for sonophoresis induced systemic delivery.

    Science.gov (United States)

    Vyas, S P; Singh, R; Asati, R K

    1995-01-01

    Liposomes containing diclofenac, an anti-inflammatory agent were incorporated into an ointment base for topical application. The drug loaded liposomes were characterized for various physico-chemical attributes and drug efflux profile in in vitro. The systemic availability of drug from liposomes following topical application was evaluated in rats. The effect of sonophoresis on the drug release profile in vitro and systemic availability in vivo was established. The application of liposomal diclofenac resulted in localization of the drug at the site of application with slow systemic availability; however, with the application of ultrasound pulsed drug systemic levels could be achieved.

  6. pH and temperature dual-sensitive liposome gel based on novel cleavable mPEG-Hz-CHEMS polymeric vaginal delivery system

    Science.gov (United States)

    Chen, Daquan; Sun, Kaoxiang; Mu, Hongjie; Tang, Mingtan; Liang, Rongcai; Wang, Aiping; Zhou, Shasha; Sun, Haijun; Zhao, Feng; Yao, Jianwen; Liu, Wanhui

    2012-01-01

    Background In this study, a pH and temperature dual-sensitive liposome gel based on a novel cleavable hydrazone-based pH-sensitive methoxy polyethylene glycol 2000-hydrazone-cholesteryl hemisuccinate (mPEG-Hz-CHEMS) polymer was used for vaginal administration. Methods The pH-sensitive, cleavable mPEG-Hz-CHEMS was designed as a modified pH-sensitive liposome that would selectively degrade under locally acidic vaginal conditions. The novel pH-sensitive liposome was engineered to form a thermogel at body temperature and to degrade in an acidic environment. Results A dual-sensitive liposome gel with a high encapsulation efficiency of arctigenin was formed and improved the solubility of arctigenin characterized by Fourier transform infrared spectroscopy and differential scanning calorimetry. The dual-sensitive liposome gel with a sol-gel transition at body temperature was degraded in a pH-dependent manner, and was stable for a long period of time at neutral and basic pH, but cleavable under acidic conditions (pH 5.0). Arctigenin encapsulated in a dual-sensitive liposome gel was more stable and less toxic than arctigenin loaded into pH-sensitive liposomes. In vitro drug release results indicated that dual-sensitive liposome gels showed constant release of arctigenin over 3 days, but showed sustained release of arctigenin in buffers at pH 7.4 and pH 9.0. Conclusion This research has shed some light on a pH and temperature dual-sensitive liposome gel using a cleavable mPEG-Hz-CHEMS polymer for vaginal delivery. PMID:22679372

  7. Multifunctional gold coated thermo-sensitive liposomes for multimodal imaging and photo-thermal therapy of breast cancer cells

    Science.gov (United States)

    Rengan, Aravind Kumar; Jagtap, Madhura; de, Abhijit; Banerjee, Rinti; Srivastava, Rohit

    2013-12-01

    Plasmon resonant gold nanoparticles of various sizes and shapes have been extensively researched for their applications in imaging, drug delivery and photothermal therapy (PTT). However, their ability to degrade after performing the required function is essential for their application in healthcare. When combined with biodegradable liposomes, they appear to have better degradation capabilities. They degrade into smaller particles of around 5 nm that are eligible candidates for renal clearance. Distearoyl phosphatidyl choline : cholesterol (DSPC : CHOL, 8 : 2 wt%) liposomes have been synthesized and coated with gold by in situ reduction of chloro-auric acid. These particles of size 150-200 nm are analyzed for their stability, degradation capacity, model drug-release profile, biocompatibility and photothermal effects on cancer cells. It is observed that when these particles are subjected to low power continuous wave near infra-red (NIR) laser for more than 10 min, they degrade into small gold nanoparticles of size 5 nm. Also, the gold coated liposomes appear to have excellent biocompatibility and high efficiency to kill cancer cells through photothermal transduction. These novel materials are also useful in imaging using specific NIR dyes, thus exhibiting multifunctional properties for theranostics of cancer.Plasmon resonant gold nanoparticles of various sizes and shapes have been extensively researched for their applications in imaging, drug delivery and photothermal therapy (PTT). However, their ability to degrade after performing the required function is essential for their application in healthcare. When combined with biodegradable liposomes, they appear to have better degradation capabilities. They degrade into smaller particles of around 5 nm that are eligible candidates for renal clearance. Distearoyl phosphatidyl choline : cholesterol (DSPC : CHOL, 8 : 2 wt%) liposomes have been synthesized and coated with gold by in situ reduction of chloro-auric acid. These

  8. Liposome imaging agents in personalized medicine

    DEFF Research Database (Denmark)

    Petersen, Anncatrine Luisa; Hansen, Anders Elias; Gabizon, Alberto

    2012-01-01

    that selectively localize in tumor tissue can transport both drugs and imaging agents, which allows for a theranostic approach with great potential in personalized medicine. Radiolabeling of liposomes have for many years been used in preclinical studies for evaluating liposome in vivo performance and has been...... an important tool in the development of liposomal drugs. However, advanced imaging systems now provide new possibilities for non-invasive monitoring of liposome biodistribution in humans. Thus, advances in imaging and developments in liposome radiolabeling techniques allow us to enter a new arena where we...... start to consider how to use imaging for patient selection and treatment monitoring in connection to nanocarrier based medicines. Nanocarrier imaging agents could furthermore have interesting properties for disease diagnostics and staging. Here, we review the major advances in the development...

  9. Novel targeting of PEGylated liposomes for codelivery of TGF-β1 siRNA and four antitubercular drugs to human macrophages for the treatment of mycobacterial infection: a quantitative proteomic study

    Directory of Open Access Journals (Sweden)

    Niu NK

    2015-08-01

    Full Text Available Ning-Kui Niu,1–3 Juan-Juan Yin,3 Yin-Xue Yang,4 Zi-Li Wang,1 Zhi-Wei Zhou,3 Zhi-Xu He,5 Xiao-Wu Chen,6 Xueji Zhang,7 Wei Duan,8 Tianxin Yang,9 Shu-Feng Zhou3 1Department of Orthopedics, General Hospital of Tianjin Medical University, Tianjin, 2Department of Spinal Surgery, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, People’s Republic of China; 3Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA; 4Department of Colorectal Surgery, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, 5Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Center and Sino-US Joint Laboratory for Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, 6Department of General Surgery, The First People’s Hospital of Shunde Affiliated to Southern Medical University, Shunde, Foshan, Guangdong, 7Research Center for Bioengineering and Sensing Technology, University of Science and Technology Beijing, Beijing, People’s Republic of China; 8School of Medicine, Deakin University, Waurn Ponds, VIC, Australia; 9Department of Internal Medicine, University of Utah and Salt Lake Veterans Affairs Medical Center, Salt Lake City, UT, USA Abstract: Tuberculosis (TB is still a major public health issue in developing countries, and its chemotherapy is compromised by poor drug compliance and severe side effects. This study aimed to synthesize and characterize new multimodal PEGylated liposomes encapsulated with clinically commonly used anti-TB drugs with linkage to small interfering RNA (siRNA against transforming growth factor-β1 (TGF-β1. The novel NP-siRNA liposomes could target THP-1-derived human macrophages that were the host cells of mycobacterium infection. The biological effects of the NP-siRNA liposomes were evaluated on cell cycle distribution, apoptosis, autophagy, and the gene silencing efficiency of TGF-β1 siRNA in human

  10. Intravesical liposome therapy for interstitial cystitis.

    Science.gov (United States)

    Tyagi, Pradeep; Kashyap, Mahendra; Majima, Tsuyoshi; Kawamorita, Naoki; Yoshizawa, Tsuyoshi; Yoshimura, Naoki

    2017-04-01

    Over the past two decades, there has been lot of interest in the use of liposomes as lipid-based biocompatible carriers for drugs administered by the intravesical route. The lipidic bilayer structure of liposomes facilitates their adherence to the apical membrane surface of luminal cells in the bladder, and their vesicular shape allows them to co-opt the endocytosis machinery for bladder uptake after instillation. Liposomes have been shown to enhance the penetration of both water-soluble and insoluble drugs, toxins, and oligonucleotides across the bladder epithelium. Empty liposomes composed entirely of the endogenous phospholipid, sphingomyelin, could counter mucosal inflammation and promote wound healing in patients suffering from interstitial cystitis. Recent clinical studies have tested multilamellar liposomes composed entirely of sphingomyelin as a novel intravesical therapy for interstitial cystitis. In addition, liposomes have been used as a delivery platform for the instillation of botulinum toxin in overactive bladder patients. The present review discusses the properties of liposomes that are important for their intrinsic therapeutic effect, summarizes the recently completed clinical studies with intravesical liposomes and covers the latest developments in this field. © 2017 The Japanese Urological Association.

  11. Liposomal Formulation of Retinoids Designed for Enzyme Triggered Release

    DEFF Research Database (Denmark)

    Pedersen, Palle Jacob; Adolph, Sidsel Kramshøj; Subramanian, Arun Kumar

    2010-01-01

    The design of retinoid phospholipid prodrugs is described based on molecular dynamics simulations and cytotoxicity studies of synthetic retinoid esters. The prodrugs are degradable by secretory phospholipase A(2) IIA and have potential in liposomal drug delivery targeting tumors. We have synthesi...... displayed IC50 values in the range of 3-19 mu M toward HT-29 and Colo205 colon cancer cells in the presence of phospholipase A(2), while no significant cell death was observed in the absence of the enzyme....

  12. pH and temperature dual-sensitive liposome gel based on novel cleavable mPEG-Hz-CHEMS polymeric vaginal delivery system

    Directory of Open Access Journals (Sweden)

    Chen D

    2012-05-01

    Full Text Available Daquan Chen,1,2 Kaoxiang Sun,1,2 Hongjie Mu,1 Mingtan Tang,3 Rongcai Liang,1,2 Aiping Wang,1,2 Shasha Zhou,1 Haijun Sun,1 Feng Zhao,1 Jianwen Yao,1 Wanhui Liu1,21School of Pharmacy, Yantai University, 2State Key Laboratory of Longacting and Targeting Drug Delivery Systems, Yantai, 3School of Pharmaceutical Sciences, Shandong University, Jinan, People's Republic of ChinaBackground: In this study, a pH and temperature dual-sensitive liposome gel based on a novel cleavable hydrazone-based pH-sensitive methoxy polyethylene glycol 2000-hydrazone-cholesteryl hemisuccinate (mPEG-Hz-CHEMS polymer was used for vaginal administration.Methods: The pH-sensitive, cleavable mPEG-Hz-CHEMS was designed as a modified pH-sensitive liposome that would selectively degrade under locally acidic vaginal conditions. The novel pH-sensitive liposome was engineered to form a thermogel at body temperature and to degrade in an acidic environment.Results: A dual-sensitive liposome gel with a high encapsulation efficiency of arctigenin was formed and improved the solubility of arctigenin characterized by Fourier transform infrared spectroscopy and differential scanning calorimetry. The dual-sensitive liposome gel with a sol-gel transition at body temperature was degraded in a pH-dependent manner, and was stable for a long period of time at neutral and basic pH, but cleavable under acidic conditions (pH 5.0. Arctigenin encapsulated in a dual-sensitive liposome gel was more stable and less toxic than arctigenin loaded into pH-sensitive liposomes. In vitro drug release results indicated that dual-sensitive liposome gels showed constant release of arctigenin over 3 days, but showed sustained release of arctigenin in buffers at pH 7.4 and pH 9.0.Conclusion: This research has shed some light on a pH and temperature dual-sensitive liposome gel using a cleavable mPEG-Hz-CHEMS polymer for vaginal delivery.Keywords: mPEG-Hz-CHEMS polymer, pH-sensitive liposomes, thermosensitive

  13. Liposome as nanocarrier: Site targeted delivery in lung cancer

    Directory of Open Access Journals (Sweden)

    Najeeb Ullah

    2017-08-01

    Full Text Available Lung cancer is fatal and spreading rapidly worldwide. Different clinical strategies are applied to stop this cancer. As the lung is a delicate organ, special clinical applications must be used and nanodrugs delivery systems are the most important applications of all. This review discusses the lung problems such as lung cancer, lung inflammation and bronchi constrictions followed by repetitive intake of some drugs. The objective of this review is to study how nanodrug delivery systems were synthesized and used in lung disorder treatment especially in lung cancer. The authors studied some articles from 1989 to 2015. Liposome encapsulation was done in various ways for the delivery of different drugs such as metaproterenol into liposomes caused bronchodilation, immunoliposomes bearing antibodies for doxorubicin reduced 50% inhibitory effects, radioliposomes with high penetrating ability to peripheral airways, aerosol delivery systems with deep pulmonary deposition, polymeric drug delivery having potential to improve beneficial index of drug, solid lipid liposomes, liposomal gentamicin with altered different clinical susceptibilities of resistance, transferrin conjugated liposomes to deliver cytostatic drugs to site of lungs, anti-inflammatory drugs with mannosylated liposomes, liposomal suspensions with single stranded RNAs and peptide encapsulation of liposomes. This review indicates that many animals perished with intravenous administration of drugs but survived in liposomal targeting groups.

  14. Nanoparticle Stabilized Liposomes for Acne Therapy

    Science.gov (United States)

    Fu, Victoria

    Acne vulgaris is a common skin disease that affects over 40 million people in the United States alone. The main cause of acne vulgaris is Propionibacterium acnes (P. acnes), resides deep in the pores and follicles of the skin in order to feed on oil produced by the sebaceous glands. The liposome is a lipid based nanoparticle with numerous advantages over free drug molecules as an acne treatment alternative. Bare liposomes loaded with lauric acid (LipoLA) were found to show strong antimicrobial activity against P. acnes while generating minimal toxicity. However, the platform is limited by the spontaneous tendency of liposomes to fuse with each other. Attaching nanoparticles to the surface of liposomes can overcome this challenge by providing steric repulsion and reduce surface tension. Thus, carboxyl-functionalized gold nanoparticles (AuC) were attached to the surface of liposomes (AuC-liposomes) loaded with doxycycline, a general tetracycline antibiotic. These particles were found to have a diameter of 120 nm and a zeta potential of 20.0 mV. Both fluorescent and antimicrobial studies demonstrated that based on electrostatic interaction, negatively charged AuC attached to the liposome's positively charged surface and stabilized liposomes in a neutral pH environment (pH = 7.4). Upon entering the skin's acidic environment (pH = 4), AuC detached from the liposome's surface and liposomes could fuse with P. acnes residing in the pores. Furthermore, toxicity studies showed that AuC-liposomes did not induce any significant toxicity, while two of the leading over-the-counter therapies, benzoyl peroxide and salicylic acid, generated substantial skin irritation.

  15. Interaction of liposomal formulations of meta-tetra(hydroxyphenyl)chlorin (temoporfin) with serum proteins: protein binding and liposome destruction.

    Science.gov (United States)

    Reshetov, Vadzim; Zorin, Vladimir; Siupa, Agnieszka; D'Hallewin, Marie-Ange; Guillemin, François; Bezdetnaya, Lina

    2012-01-01

    mTHPC is a non polar photosensitizer used in photodynamic therapy. To improve its solubility and pharmacokinetic properties, liposomes were proposed as drug carriers. Binding of liposomal mTHPC to serum proteins and stability of drug carriers in serum are of major importance for PDT efficacy; however, neither was reported before. We studied drug binding to human serum proteins using size-exclusion chromatography. Liposomes destruction in human serum was measured by nanoparticle tracking analysis (NTA). Inclusion of mTHPC into conventional (Foslip(®)) and PEGylated (Fospeg(®)) liposomes does not affect equilibrium serum protein binding compared with solvent-based mTHPC. At short incubation times the redistribution of mTHPC from Foslip(®) and Fospeg(®) proceeds by both drug release and liposomes destruction. At longer incubation times, the drug redistributes only by release. The release of mTHPC from PEGylated vesicles is delayed compared with conventional liposomes, alongside with greatly decreased liposomes destruction. Thus, for long-circulation times the pharmacokinetic behavior of Fospeg(®) could be influenced by a combination of protein- and liposome-bound drug. The study highlights the modes of interaction of photosensitizer-loaded nanovesicles in serum to predict optimal drug delivery and behavior in vivo in preclinical models, as well as the novel application of NTA to assess the destruction of liposomes. © 2012 Wiley Periodicals, Inc. Photochemistry and Photobiology © 2012 The American Society of Photobiology.

  16. AlPcS4-PDT for gastric cancer therapy using gold nanorod, cationic liposome, and Pluronic® F127 nanomicellar drug carriers.

    Science.gov (United States)

    Xin, Jing; Wang, Sijia; Wang, Bing; Wang, Jiazhuang; Wang, Jing; Zhang, Luwei; Xin, Bo; Shen, Lijian; Zhang, Zhenxi; Yao, Cuiping

    2018-01-01

    As a promising photodynamic therapy (PDT) agent, Al(III) phthalocyanine chloride tetrasulfonic acid (AlPcS 4 ) provides deep penetration into tissue, high quantum yields, good photostability, and low photobleaching. However, its low delivery efficiency and high binding affinity to serum albumin cause its low penetration into cancer cells, further limiting its PDT effect on gastric cancer. In order to improve AlPcS 4 /PDT effect, the AlPcS 4 delivery sys tems with different drug carriers were synthesized and investigated. Gold nanorods, cationic liposomes, and Pluronic ® F127 nanomicellars were used to formulate the AlPcS 4 delivery systems. The anticancer effect was evaluated by CCK-8 assay and colony formation assay. The delivery efficiency of AlPcS 4 and the binding affinity to serum proteins were determined by fluorescence intensity assay. The apoptosis and necrosis ability, reactive oxygen species and singlet oxygen generation, mitochondrial transmembrane potential and ([Ca 2+ ] i ) concentration were further measured to evaluate the mechanism of cell death. The series of synthesized AlPcS 4 delivery systems with different drug carriers improve the limited PDT effect in varying degrees. In contrast, AlPcS 4 complex with gold nanorods has significant anticancer effects because gold nanorods are not only suitable for AlPcS 4 delivery, but also exhibit enhanced singlet oxygen generation effect and photothermal effect to induce cell death directly. Moreover, AlPcS 4 complex with cationic liposomes shows the potent inhibition effect because of its optimal AlPcS 4 delivery efficiency and ability to block serum albumin. In addition, AlPcS 4 complex with Pluronic F127 exhibits inferior PDT effect but presents lower cytotoxicity, slower dissociation rate, and longer retention time of incorporated drugs; thus, F127-AlPcS 4 is used for prolonged gastric cancer therapy. The described AlPcS 4 drug delivery systems provide promising agents for gastric cancer therapy.

  17. Effect of Lipid Composition on In Vitro Release and Skin Deposition of Curcumin Encapsulated Liposomes

    Directory of Open Access Journals (Sweden)

    Geethi Pamunuwa

    2016-01-01

    Full Text Available Liposomal encapsulation improves numerous physiochemical and biological properties of curcumin. The aim of this work was to impart slow release and skin delivery of curcumin via liposomal encapsulation. Liposomes were made using egg yolk phosphatidylcholine as the staple lipid while incorporating polysorbate 80 and stearylamine to prepare hybrid liposomes and positively charged liposomes, respectively. Negatively charged liposomes exhibited the highest encapsulation efficiencies (87.8±4.3% and loading capacities (3.4±0.2%. The sizes of all formulations were about 250 nm, while stearylamine increased the polydispersity index. Positively charged liposomes showed lower degradation temperatures than negatively charged liposomes by 10–15°C, attributable to the presence of stearylamine. The melting temperatures of positively charged liposomes (40–50°C were much higher than those of negatively charged liposomes (14-15°C, which may have affected release and skin deposition behavior of liposomes. The positively charged liposomes exhibited the slowest release of curcumin in phosphate buffered saline (pH 6.8 and the release profiles of all liposomal formulations conformed to the Gompertz model. The negatively charged liposomes facilitated the highest skin deposition of curcumin as revealed by studies conducted using excised pig ear skin. Concisely, positively and negatively charged liposomes were optimal for slow release and skin deposition of curcumin, respectively.

  18. Effect of chitosan coating on the characteristics of DPPC liposomes

    Directory of Open Access Journals (Sweden)

    Mohsen M. Mady

    2010-07-01

    Full Text Available Because it is both biocompatible and biodegradable, chitosan has been used to provide a protective capsule in new drug formulations. The present work reports on investigations into some of the physicochemical properties of chitosan-coated liposomes, including drug release rate, transmission electron microscopy (TEM, zeta potential and turbidity measurement. It was found that chitosan increases liposome stability during drug release. The coating of DPPC liposomes with a chitosan layer was confirmed by electron microscopy and the zeta potential of liposomes. The coating of liposomes by chitosan resulted in a marginal increase in the size of the liposomes, adding a layer of (92 ± 27.1 nm. The liposomal zeta potential was found to be increasingly positive as chitosan concentration increased from 0.1% to 0.3% (w/v, before stabilising at a relatively constant value. Turbidity studies revealed that the coating of DPPC liposomes with chitosan did not significantly modify the main phase transition temperature of DPPC at examined chitosan concentrations. The appropriate combination of liposomal and chitosan characteristics may produce liposomes with specific, prolonged and controlled release.

  19. Stimuli-responsive liposome-nanoparticle assemblies.

    Science.gov (United States)

    Preiss, Matthew R; Bothun, Geoffrey D

    2011-08-01

    Nanoscale assemblies are needed that achieve multiple therapeutic objectives, including cellular targeting, imaging, diagnostics and drug delivery. These must exhibit high stability, bioavailability and biocompatibility, while maintaining or enhancing the inherent activity of the therapeutic cargo. Liposome-nanoparticle assemblies (LNAs) combine the demonstrated potential of liposome-based therapies, with functional nanoparticles. Specifically, LNAs can be used to concentrate and shield the nanoparticles and, in turn, stimuli-responsive nanoparticles that respond to external fields can be used to control liposomal release. The ability to design LNAs via nanoparticle encapsulation, decoration or bilayer-embedment offers a range of configurations with different structures and functions. This paper reviews the current state of research and understanding of the design, characterization and performance of LNAs. A brief overview is provided on liposomes and nanoparticles for therapeutic applications, followed by a discussion of the opportunities and challenges associated with combining the two in a single assembly to achieve controlled release via light or radiofrequency stimuli. LNAs offer a unique opportunity to combine the therapeutic properties of liposomes and nanoparticles. Liposomes act to concentrate small nanoparticles and shield nanoparticles from the immune system, while the nanoparticle can be used to initiate and control drug release when exposed to external stimuli. These properties provide a platform to achieve nanoparticle-controlled liposomal release. LNA design and application are still in infancy. Research concentrating on the relationships among LNA structure, function and performance is essential for the future clinical use of LNAs.

  20. Liposomal encapsulation of dexamethasone modulates cytotoxicity, inflammatory cytokine response, and migratory properties of primary human macrophages

    NARCIS (Netherlands)

    Bartneck, M.; Peters, F.M.; Warzecha, K.T.; Bienert, M.; van Bloois, L.; Trautwein, C.; Lammers, Twan Gerardus Gertudis Maria; Tacke, F.

    2014-01-01

    The encapsulation of drugs into liposomes aims to enhance their efficacy and reduce their toxicity. Corticosteroid-loaded liposomes are currently being evaluated in patients suffering from rheumatoid arthritis, atherosclerosis, colitis, and cancer. Here, using several different fluorophore-labeled

  1. Advanced strategies in liposomal cancer therapy

    DEFF Research Database (Denmark)

    Andresen, Thomas Lars; Jensen, Simon Skøde; Jørgensen, Kent

    2005-01-01

    is therefore of great importance. In the first part of this review, we present current strategies in the drug delivery field, focusing on site-specific triggered drug release from liposomes in cancerous tissue. Currently marketed drug delivery systems lack the ability to actively release the carried drug...... have emerged ranging from externally triggered light- and thermo-sensitive liposomes to receptor targeted, pH- and enzymatically triggered liposomes relying on an endogenous trigger mechanism in the cancerous tissue. However, even though several of these strategies were introduced three decades ago......, none of them have yet led to marketed drugs and are still far from achieving this goal. The most advanced and prospective technologies are probably the prodrug strategies where nontoxic drugs are carried and activated specifically in the malignant tissue by overexpressed enzymes. In the second part...

  2. Metallomics in drug development

    DEFF Research Database (Denmark)

    Nguyen, Trinh Thi Nhu Tam; Ostergaard, Jesper; Stürup, Stefan

    2013-01-01

    A capillary electrophoresis inductively coupled plasma mass spectrometry method for separation of free cisplatin from liposome-encapsulated cisplatin and protein-bound cisplatin was developed. A liposomal formulation of cisplatin based on PEGylated liposomes was used as model drug formulation...... to plasma constituents in plasma samples. It was demonstrated that this approach is suitable for studies of the stability of liposome formulations as leakage of active drug from the liposomes and subsequent binding to biomolecules in plasma can be monitored. This methodology has not been reported before...... and will improve characterization of liposomal drugs during drug development and in studies on kinetics....

  3. A facile degradable linkage for timed drug delivery

    International Nuclear Information System (INIS)

    Kenawy, E.; Abdel-Hay, F.I.; El-Newehy, M.H.; Ottenbrite, R.M.

    2005-01-01

    New drug delivery systems based on hydroxamic acid polymers were evaluated. The system support was the poly acryloyl chloride which was synthesized via free radical polymerization of acryloyl chloride in 1,4-dioxane, initiated with 2,2-azobisisobutyronitrile. Poly(N-alkyl substituted acrylamide) were synthesized in Poly(acryloyl chloride) was modified in two steps, the first is with N-hydroxysuccinimide to give the imide ester of poly(acryloyl). In the second step, the imide ester of poly(acryloyl) was reacted either with hydroxylamine or with (N-methyl hydroxylamine), respectively. The hydroxamic polymers were reacted with, the model drug, ketoprofen, in the presence of dicyclohexylcarbodiimide at -5 degree C. All products were characterized by elemental analysis, FTIR and 1 HNMR spectra. In vitro drug release study was performed at various ph and temperature to elucidate the influence of temperature and ph on the hydrolysis rate of the amido-ester bond that links the drug to the macromolecule. The amount of drug released from N-methyl hydroxamic acid polymers was higher than from hydroxamic acid polymers. All polymers showed higher drug release at 37 degree C than at room temperature (25 degree C) and at higher ph

  4. Potential effect of cationic liposomes on interactions with oral bacterial cells and biofilms.

    Science.gov (United States)

    Sugano, Marika; Morisaki, Hirobumi; Negishi, Yoichi; Endo-Takahashi, Yoko; Kuwata, Hirotaka; Miyazaki, Takashi; Yamamoto, Matsuo

    2016-01-01

    Although oral infectious diseases have been attributed to bacteria, drug treatments remain ineffective because bacteria and their products exist as biofilms. Cationic liposomes have been suggested to electrostatically interact with the negative charge on the bacterial surface, thereby improving the effects of conventional drug therapies. However, the electrostatic interaction between oral bacteria and cationic liposomes has not yet been examined in detail. The aim of the present study was to examine the behavior of cationic liposomes and Streptococcus mutans in planktonic cells and biofilms. Liposomes with or without cationic lipid were prepared using a reverse-phase evaporation method. The zeta potentials of conventional liposomes (without cationic lipid) and cationic liposomes were -13 and 8 mV, respectively, and both had a mean particle size of approximately 180 nm. We first assessed the interaction between liposomes and planktonic bacterial cells with a flow cytometer. We then used a surface plasmon resonance method to examine the binding of liposomes to biofilms. We confirmed the binding behavior of liposomes with biofilms using confocal laser scanning microscopy. The interactions between cationic liposomes and S. mutans cells and biofilms were stronger than those of conventional liposomes. Microscopic observations revealed that many cationic liposomes interacted with the bacterial mass and penetrated the deep layers of biofilms. In this study, we demonstrated that cationic liposomes had higher affinity not only to oral bacterial cells, but also biofilms than conventional liposomes. This electrostatic interaction may be useful as a potential drug delivery system to biofilms.

  5. Molecular weight-dependent degradation and drug release of surface-eroding poly(ethylene carbonate)

    DEFF Research Database (Denmark)

    Bohr, Adam; Wang, Yingya; Harmankaya, Necati

    2017-01-01

    Poly(ethylene carbonate) (PEC) is a unique biomaterial showing significant potential for controlled drug delivery applications. The current study investigated the impact of the molecular weight on the biological performance of drug-loaded PEC films. Following the preparation and thorough...... physicochemical characterization of diverse PEC (molecular weights: 85, 110, 133, 174 and 196 kDa), the degradation and drug release behavior of rifampicin- and bovine serum albumin-loaded PEC films was investigated in vitro (in the presence and absence of cholesterol esterase), in cell culture (RAW264.......7 macrophages) and in vivo (subcutaneous implantation in rats). All investigated samples degraded by means of surface erosion (mass loss, but constant molecular weight), which was accompanied by a predictable, erosion-controlled drug release pattern. Accordingly, the obtained in vitro degradation half...

  6. Liposomal Formulations in Clinical Use: An Updated Review

    Directory of Open Access Journals (Sweden)

    Upendra Bulbake

    2017-03-01

    Full Text Available Liposomes are the first nano drug delivery systems that have been successfully translated into real-time clinical applications. These closed bilayer phospholipid vesicles have witnessed many technical advances in recent years since their first development in 1965. Delivery of therapeutics by liposomes alters their biodistribution profile, which further enhances the therapeutic index of various drugs. Extensive research is being carried out using these nano drug delivery systems in diverse areas including the delivery of anti-cancer, anti-fungal, anti-inflammatory drugs and therapeutic genes. The significant contribution of liposomes as drug delivery systems in the healthcare sector is known by many clinical products, e.g., Doxil®, Ambisome®, DepoDur™, etc. This review provides a detailed update on liposomal technologies e.g., DepoFoam™ Technology, Stealth technology, etc., the formulation aspects of clinically used products and ongoing clinical trials on liposomes.

  7. Spatial SPION Localization in Liposome Membranes

    OpenAIRE

    Bonnaud C{é}cile; Vanhecke Dimitri; Demurtas Davide; Rothen-Rutishauser Barbara M; Petri-Fink Alke

    2013-01-01

    Nanocarriers, including liposomes, offer great opportunities for targeted and controlled therapy. The development in this field has led to a large panel of drug delivery systems, which can be classified into 3 different nanovector generations. However, the success of such smart materials requires the control of a large variety of properties and parameters. Unfortunately, characterization at the nanoscale is often cumbersome and many methods are still being developed. Liposomes have been chara...

  8. Molecular weight-dependent degradation and drug release of surface-eroding poly(ethylene carbonate).

    Science.gov (United States)

    Bohr, Adam; Wang, Yingya; Harmankaya, Necati; Water, Jorrit J; Baldursdottír, Stefania; Almdal, Kristoffer; Beck-Broichsitter, Moritz

    2017-06-01

    Poly(ethylene carbonate) (PEC) is a unique biomaterial showing significant potential for controlled drug delivery applications. The current study investigated the impact of the molecular weight on the biological performance of drug-loaded PEC films. Following the preparation and thorough physicochemical characterization of diverse PEC (molecular weights: 85, 110, 133, 174 and 196kDa), the degradation and drug release behavior of rifampicin- and bovine serum albumin-loaded PEC films was investigated in vitro (in the presence and absence of cholesterol esterase), in cell culture (RAW264.7 macrophages) and in vivo (subcutaneous implantation in rats). All investigated samples degraded by means of surface erosion (mass loss, but constant molecular weight), which was accompanied by a predictable, erosion-controlled drug release pattern. Accordingly, the obtained in vitro degradation half-lives correlated well with the observed in vitro half-times of drug delivery (R 2 =0.96). Here, the PEC of the highest molecular weight resulted in the fastest degradation/drug release. When incubated with macrophages or implanted in animals, the degradation rate of PEC films superimposed the results of in vitro incubations with cholesterol esterase. Interestingly, SEM analysis indicated a distinct surface erosion process for enzyme-, macrophage- and in vivo-treated polymer films in a molecular weight-dependent manner. Overall, the molecular weight of surface-eroding PEC was identified as an essential parameter to control the spatial and temporal on-demand degradation and drug release from the employed delivery system. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. The use of PEGylated liposomes in the development of drug delivery applications for the treatment of hemophilia.

    Science.gov (United States)

    Yatuv, Rivka; Robinson, Micah; Dayan-Tarshish, Inbal; Baru, Moshe

    2010-09-07

    Hemophilia A is a rare X-linked bleeding disorder caused by lack or dysfunction of coagulation factor VIII (FVIII). Hemophilia A is treated with replacement therapy, but frequent injections of the missing FVIII often lead to the formation of inhibitory antibodies. Patients who develop high levels of inhibitors must be treated with bypassing agents such as activated FVII (FVIIa). Both FVIII and FVIIa have short half-lives and require multiple injections. Long-acting forms of these proteins would therefore reduce the frequency of injections, improve patient compliance and reduce complications. In this article we present a new platform technology that produces long-acting forms of FVIII and FVIIa and improves the efficacy of hemophilia treatment. This technology is based on the binding of proteins/peptides to the outer surface of PEGylated liposomes (PEGLip). Binding is dependent on an amino acid consensus sequence within the proteins and is highly specific. At the same time, binding is non-covalent and does not require any modification of the therapeutic agent or its production process. Association of proteins with PEGLip results in substantial enhancements in their pharmacodynamic properties following administration. These improvements seem to arise from the association of formulated proteins with platelets prior to induction of coagulation.

  10. Etoposide incorporated into camel milk phospholipids liposomes shows increased activity against fibrosarcoma in a mouse model.

    Science.gov (United States)

    Maswadeh, Hamzah M; Aljarbou, Ahmad N; Alorainy, Mohammed S; Alsharidah, Mansour S; Khan, Masood A

    2015-01-01

    Phospholipids were isolated from camel milk and identified by using high performance liquid chromatography and gas chromatography-mass spectrometry (GC/MS). Anticancer drug etoposide (ETP) was entrapped in liposomes, prepared from camel milk phospholipids, to determine its activity against fibrosarcoma in a murine model. Fibrosarcoma was induced in mice by injecting benzopyrene (BAP) and tumor-bearing mice were treated with various formulations of etoposide, including etoposide entrapped camel milk phospholipids liposomes (ETP-Cam-liposomes) and etoposide-loaded DPPC-liposomes (ETP-DPPC-liposomes). The tumor-bearing mice treated with ETP-Cam-liposomes showed slow progression of tumors and increased survival compared to free ETP or ETP-DPPC-liposomes. These results suggest that ETP-Cam-liposomes may prove to be a better drug delivery system for anticancer drugs.

  11. Etoposide Incorporated into Camel Milk Phospholipids Liposomes Shows Increased Activity against Fibrosarcoma in a Mouse Model

    Directory of Open Access Journals (Sweden)

    Hamzah M. Maswadeh

    2015-01-01

    Full Text Available Phospholipids were isolated from camel milk and identified by using high performance liquid chromatography and gas chromatography-mass spectrometry (GC/MS. Anticancer drug etoposide (ETP was entrapped in liposomes, prepared from camel milk phospholipids, to determine its activity against fibrosarcoma in a murine model. Fibrosarcoma was induced in mice by injecting benzopyrene (BAP and tumor-bearing mice were treated with various formulations of etoposide, including etoposide entrapped camel milk phospholipids liposomes (ETP-Cam-liposomes and etoposide-loaded DPPC-liposomes (ETP-DPPC-liposomes. The tumor-bearing mice treated with ETP-Cam-liposomes showed slow progression of tumors and increased survival compared to free ETP or ETP-DPPC-liposomes. These results suggest that ETP-Cam-liposomes may prove to be a better drug delivery system for anticancer drugs.

  12. Exploring the fate of liposomes in the intestine by dynamic in vitro lipolysis

    DEFF Research Database (Denmark)

    Parmentier, Johannes; Thomas, Nicky; Müllertz, Anette

    2012-01-01

    Liposomes are generally well tolerated drug delivery systems with a potential use for the oral route. However, little is known about the fate of liposomes during exposure to the conditions in the gastro-intestinal tract (GIT). To gain a better understanding of liposome stability in the intestine,...... to other lipid based delivery systems for the oral delivery of poorly soluble drugs......., a dynamic in vitro lipolysis model, which so far has only been used for the in vitro characterisation of other lipid-based drug delivery systems, was applied to different liposomal formulations. Liposome size and phospholipid (PL) digestion were determined as two markers for liposome stability. In addition...... lipolysis, the lipids exhibited a higher stability compared to SPC and only 30% of the PLs were digested. No direct correlation between liposome integrity assessed by vesicle size and PL digestion was observed. Danazol content in the liposomes was around 5% (mol/mol danazol/total lipid) and hardly any...

  13. Characterization and cytotoxicity of mixed polyethyleneglycol modified liposomes containing doxorubicin.

    Science.gov (United States)

    Sadzuka, Yasuyuki; Sugiyama, Ikumi; Tsuruda, Tomoko; Sonobe, Takashi

    2006-04-07

    Liposomes are recognized as one of the useful drug carriers, but have many problems to overcome before their clinical application. Liposomes, bonding peculiarly with serum protein (opsonization), are taken up by reticuloendothelial system (RES) cells in the liver and spleen. It is known that polyethyleneglycol (PEG) modification of the liposome surface induces the formation of a fixed aqueous layer around the liposomes due to the interaction between the PEG-polymer and water molecule, and thus prevents the attraction of opsonins. Namely, PEG-modified liposomes are able to escape trapping by the RES cells, and have a prolonged circulation time. In this study, the effects of different anchors with the same PEG molecular weight on the cell uptake and cytotoxicity of mixed PEG-modified liposomal doxorubicin (DOX) were examined. The fixed aqueous layer thickness (FALT) of liposomes covered with mixtures of PEG-molecules which differ in their chain length were increased, compared to that of the single PEG2000-modified liposome. Mixed PEG-modification of liposomes with different anchors (PEG2000-(1-monomethoxypolyethyleneglycol-2,3-distearoylglycerol (DSG): cholesterol (CHO)=1:1)-modified liposome) led to an increase in the FALT, compared to that of each single PEG-modification. The uptake of DOX into Ehrlich ascites carcinoma cells by the liposomes covered with PEG-CHO was higher than the other liposomes. Thus, liposomes covered with PEG-DSG and PEG-CHO have an enhanced cytotoxicity. In conclusion, it was confirmed that mix-modified liposomes using PEG-lipid with different anchors were superior.

  14. Superresolution and Fluorescence Dynamics Evidence Reveal That Intact Liposomes Do Not Cross the Human Skin Barrier

    DEFF Research Database (Denmark)

    Dreier, Jes; Sørensen, Jens A; Brewer, Jonathan R

    2016-01-01

    In this study we use the combination of super resolution optical microscopy and raster image correlation spectroscopy (RICS) to study the mechanism of action of liposomes as transdermal drug delivery systems in human skin. Two different compositions of liposomes were applied to newly excised human...... skin, a POPC liposome and a more flexible liposome containing the surfactant sodium cholate. Stimulated emission depletion microscopy (STED) images of intact skin and cryo-sections of skin treated with labeled liposomes were recorded displaying an optical resolution low enough to resolve the 100 nm...... liposomes in the skin. The images revealed that virtually none of the liposomes remained intact beneath the skin surface. RICS two color cross correlation diffusion measurements of double labeled liposomes confirmed these observations. Our results suggest that the liposomes do not act as carriers...

  15. Liposome Delivery Systems for Inhalation: A Critical Review Highlighting Formulation Issues and Anticancer Applications.

    Science.gov (United States)

    Rudokas, Mindaugas; Najlah, Mohammad; Alhnan, Mohamed Albed; Elhissi, Abdelbary

    2016-01-01

    This is a critical review on research conducted in the field of pulmonary delivery of liposomes. Issues relating to the mechanism of nebulisation and liposome composition were appraised and correlated with literature reports of liposome formulations used in clinical trials to understand the role of liposome size and composition on therapeutic outcome. A major highlight was liposome inhalation for the treatment of lung cancers. Many in vivo studies that explored the potential of liposomes as anticancer carrier systems were evaluated, including animal studies and clinical trials. Liposomes can entrap anticancer drugs and localise their action in the lung following pulmonary delivery. The safety of inhaled liposomes incorporating anticancer drugs depends on the anticancer agent used and the amount of drug delivered to the target cancer in the lung. The difficulty of efficient targeting of liposomal anticancer aerosols to the cancerous tissues within the lung may result in low doses reaching the target site. Overall, following the success of liposomes as inhalable carriers in the treatment of lung infections, it is expected that more focus from research and development will be given to designing inhalable liposome carriers for the treatment of other lung diseases, including pulmonary cancers. The successful development of anticancer liposomes for inhalation may depend on the future development of effective aerosolisation devices and better targeted liposomes to maximise the benefit of therapy and reduce the potential for local and systemic adverse effects. © 2016 S. Karger AG, Basel.

  16. Influence of the Encapsulation Efficiency and Size of Liposome on the Oral Bioavailability of Griseofulvin-Loaded Liposomes

    Directory of Open Access Journals (Sweden)

    Sandy Gim Ming Ong

    2016-08-01

    Full Text Available The objective of the present study was to investigate the influence of the encapsulation efficiency and size of liposome on the oral bioavailability of griseofulvin-loaded liposomes. Griseofulvin-loaded liposomes with desired characteristics were prepared from pro-liposome using various techniques. To study the effect of encapsulation efficiency, three preparations of griseofulvin, namely, griseofulvin aqueous suspension and two griseofulvin-loaded liposomes with different amounts of griseofulvin encapsulated [i.e., F1 (32% and F2(98%], were administered to rats. On the other hand, to study the effect of liposome size, the rats were given three different griseofulvin-loaded liposomes of various sizes, generated via different mechanical dispersion techniques [i.e., FTS (142 nm, MS (357 nm and NS (813 nm], but with essentially similar encapsulation efficiencies (about 93%. Results indicated that the extent of bioavailability of griseofulvin was improved 1.7–2.0 times when given in the form of liposomes (F1 compared to griseofulvin suspension. Besides that, there was an approximately two-fold enhancement of the extent of bioavailability following administration of griseofulvin-loaded liposomes with higher encapsulation efficiency (F2, compared to those of F1. Also, the results showed that the extent of bioavailability of liposomal formulations with smaller sizes were higher by approximately three times compared to liposomal formulation of a larger size. Nevertheless, a further size reduction of griseofulvin-loaded liposome (≤400 nm did not promote the uptake or bioavailability of griseofulvin. In conclusion, high drug encapsulation efficiency and small liposome size could enhance the oral bioavailability of griseofulvin-loaded liposomes and therefore these two parameters deserve careful consideration during formulation.

  17. Influence of the Encapsulation Efficiency and Size of Liposome on the Oral Bioavailability of Griseofulvin-Loaded Liposomes.

    Science.gov (United States)

    Ong, Sandy Gim Ming; Ming, Long Chiau; Lee, Kah Seng; Yuen, Kah Hay

    2016-08-26

    The objective of the present study was to investigate the influence of the encapsulation efficiency and size of liposome on the oral bioavailability of griseofulvin-loaded liposomes. Griseofulvin-loaded liposomes with desired characteristics were prepared from pro-liposome using various techniques. To study the effect of encapsulation efficiency, three preparations of griseofulvin, namely, griseofulvin aqueous suspension and two griseofulvin-loaded liposomes with different amounts of griseofulvin encapsulated [i.e., F1 (32%) and F2(98%)], were administered to rats. On the other hand, to study the effect of liposome size, the rats were given three different griseofulvin-loaded liposomes of various sizes, generated via different mechanical dispersion techniques [i.e., FTS (142 nm), MS (357 nm) and NS (813 nm)], but with essentially similar encapsulation efficiencies (about 93%). Results indicated that the extent of bioavailability of griseofulvin was improved 1.7-2.0 times when given in the form of liposomes (F1) compared to griseofulvin suspension. Besides that, there was an approximately two-fold enhancement of the extent of bioavailability following administration of griseofulvin-loaded liposomes with higher encapsulation efficiency (F2), compared to those of F1. Also, the results showed that the extent of bioavailability of liposomal formulations with smaller sizes were higher by approximately three times compared to liposomal formulation of a larger size. Nevertheless, a further size reduction of griseofulvin-loaded liposome (≤400 nm) did not promote the uptake or bioavailability of griseofulvin. In conclusion, high drug encapsulation efficiency and small liposome size could enhance the oral bioavailability of griseofulvin-loaded liposomes and therefore these two parameters deserve careful consideration during formulation.

  18. Liposomal cancer therapy: exploiting tumor characteristics

    DEFF Research Database (Denmark)

    Kaasgaard, Thomas; Andresen, Thomas Lars

    2010-01-01

    of cancer treatments. In the search for more effective cancer treatments, nanoparticle- based drug delivery systems, such as liposomes, that are capable of delivering their drug payload selectively to cancer cells are among the most promising approaches. Areas covered in this review: This review provides...... an overview of current strategies for improving the different stages of liposomal cancer therapy, which involve transporting drug-loaded liposomes through the bloodstream, increasing tumor accumulation, and improving drug release and cancer cell uptake after accumulation at the tumor target site. What......Importance of the field: More than 10 million people worldwide are diagnosed with cancer each year, and the development of effective cancer treatments is consequently of great significance. Cancer therapy is unfortunately hampered by severe dose-limiting side effects that reduce the efficacy...

  19. Drug-releasing shape-memory polymers - the role of morphology, processing effects, and matrix degradation.

    Science.gov (United States)

    Wischke, Christian; Behl, Marc; Lendlein, Andreas

    2013-09-01

    Shape-memory polymers (SMPs) have gained interest for temporary drug-release systems that should be anchored in the body by self-sufficient active movements of the polymeric matrix. Based on the so far published scientific literature, this review highlights three aspects that require particular attention when combining SMPs with drug molecules: i) the defined polymer morphology as required for the shape-memory function, ii) the strong effects that processing conditions such as drug-loading methodologies can have on the drug-release pattern from SMPs, and iii) the independent control of drug release and degradation by their timely separation. The combination of SMPs with a drug-release functionality leads to multifunctional carriers that are an interesting technology for pharmaceutical sciences and can be further expanded by new materials such as thermoplastic SMPs or temperature-memory polymers. Experimental studies should include relevant molecules as (model) drugs and provide a thermomechanical characterization also in an aqueous environment, report on the potential effect of drug type and loading levels on the shape-memory functionality, and explore the potential correlation of polymer degradation and drug release.

  20. Characterization and Degradation Behavior of Agar–Carbomer Based Hydrogels for Drug Delivery Applications: Solute Effect

    Directory of Open Access Journals (Sweden)

    Pietro Veglianese

    2011-05-01

    Full Text Available In this study hydrogels synthesized from agarose and carbomer 974P macromers were selected for their potential application in spinal cord injury (SCI repair strategies following their ability to carry cells and drugs. Indeed, in drug delivery applications, one of the most important issues to be addressed concerns hydrogel ability to provide a finely controlled delivery of loaded drugs, together with a coherent degradation kinetic. Nevertheless, solute effects on drug delivery system are often neglected in the large body of literature, focusing only on the characterization of unloaded matrices. For this reason, in this work, hydrogels were loaded with a chromophoric salt able to mimic, in terms of steric hindrance, many steroids commonly used in SCI repair, and its effects were investigated both from a structural and a rheological point of view, considering the pH-sensitivity of the material. Additionally, degradation chemistry was assessed by means of infrared bond response (FT-IR and mass loss.

  1. Engineering liposomal nanoparticles for targeted gene therapy.

    Science.gov (United States)

    Zylberberg, C; Gaskill, K; Pasley, S; Matosevic, S

    2017-08-01

    Recent mechanistic studies have attempted to deepen our understanding of the process by which liposome-mediated delivery of genetic material occurs. Understanding the interactions between lipid nanoparticles and cells is still largely elusive. Liposome-mediated delivery of genetic material faces systemic obstacles alongside entry into the cell, endosomal escape, lysosomal degradation and nuclear uptake. Rational design approaches for targeted delivery have been developed to reduce off-target effects and enhance transfection. These strategies, which have included the modification of lipid nanoparticles with target-specific ligands to enhance intracellular uptake, have shown significant promise at the proof-of-concept stage. Control of physical and chemical specifications of liposome composition, which includes lipid-to-DNA charge, size, presence of ester bonds, chain length and nature of ligand complexation, is integral to the performance of targeted liposomes as genetic delivery agents. Clinical advances are expected to rely on such systems in the therapeutic application of liposome nanoparticle-based gene therapy. Here, we discuss the latest breakthroughs in the development of targeted liposome-based agents for the delivery of genetic material, paying particular attention to new ligand and cationic lipid design as well as recent in vivo advances.

  2. OPTIMIZATION OF MIXING TEMPERATURE AND SONICATION DURATION IN LIPOSOME PREPARATION

    Directory of Open Access Journals (Sweden)

    Dina Christin Ayuning Putri

    2017-11-01

    Full Text Available Liposomes are a delivery system used in pharmaceutical products and cosmetics. Liposomes have many advantages such as increase stability and efficacy, can be targeted to reduce toxicity and increase accumulation at the target site and are biocompatible.  Preparation of liposomes can be done by conventional or new methods which are still being developed. Conventional methods often require a long time and organic solvents which may be toxic. Heating (Mozafari method is one of the new methods developed in the manufacture of liposomes without organic solvents. Mixing temperature can affect the physical properties of liposomes. The particle size has become one of the important physical properties because it affects the absorption of the drug. Sonication is an easy method of choice in reducing the size of liposomes. Optimization of mixing temperature and duration of sonication in liposomes’ preparation using new heating methods and sonication were performed by factorial design with 2 factors and 3-levels to obtain optimal liposome size. Data were analyzed with two-way ANOVA. The results showed that both mixing temperature and sonication duration significantly affect liposome size, but the interaction was not statistically significant. Data analysis also showed that mixing temperature, sonication, and their interaction do not affect the polydispersity index of liposome. Results showed the optimum mixing temperature and sonication duration that can produce liposomes with size below 100 nm is at 60°C for 30 minutes.

  3. A stimuli responsive liposome loaded hydrogel provides flexible on-demand release of therapeutic agents

    NARCIS (Netherlands)

    O'Neill, Hugh S.; Herron, Caroline C.; Hastings, Conn L.; Deckers, Roel; Lopez Noriega, Adolfo; Kelly, Helena M.; Hennink, Wim E.; McDonnell, Ciarán O.; O'Brien, Fergal J.; Ruiz-Hernández, Eduardo; Duffy, Garry P.

    2017-01-01

    Lysolipid-based thermosensitive liposomes (LTSL) embedded in a chitosan-based thermoresponsive hydrogel matrix (denoted Lipogel) represents a novel approach for the spatiotemporal release of therapeutic agents. The entrapment of drug-loaded liposomes in an injectable hydrogel permits local liposome

  4. Sustained distribution of aerosolized PEGylated liposomes in epithelial lining fluids on alveolar surfaces.

    Science.gov (United States)

    Kaneko, Keita; Togami, Kohei; Yamamoto, Eri; Wang, Shujun; Morimoto, Kazuhiro; Itagaki, Shirou; Chono, Sumio

    2016-10-01

    The distribution characteristics of aerosolized PEGylated liposomes in alveolar epithelial lining fluid (ELF) were examined in rats, and the ensuing mechanisms were investigated in the in vitro uptake and protein adsorption experiments. Nonmodified or PEGylated liposomes (particle size 100 nm) were aerosolized into rat lungs. PEGylated liposomes were distributed more sustainably in ELFs than nonmodified liposomes. Furthermore, the uptake of PEGylated liposomes by alveolar macrophages (AMs) was less than that of nonmodified liposomes. In further in vitro uptake experiments, nonmodified and PEGylated liposomes were opsonized with rat ELF components and then added to NR8383 cells as cultured rat AMs. The uptake of opsonized PEGylated liposomes by NR8383 cells was lower than that of opsonized nonmodified liposomes. Moreover, the protein absorption levels in opsonized PEGylated liposomes were lower than those in opsonized nonmodified liposomes. These findings suggest that sustained distributions of aerosolized PEGylated liposomes in ELFs reflect evasion of liposomal opsonization with surfactant proteins and consequent reductions in uptake by AMs. These data indicate the potential of PEGylated liposomes as aerosol-based drug delivery system that target ELF for the treatment of respiratory diseases.

  5. Temoporfin-loaded liposomes: physicochemical characterization.

    Science.gov (United States)

    Kuntsche, Judith; Freisleben, Ines; Steiniger, Frank; Fahr, Alfred

    2010-07-11

    Temoporfin (mTHPC) is a potent but highly hydrophobic second-generation photosensitizer and has been approved for the palliative treatment of patients with advanced head and neck cancer by photodynamic therapy. Liposome formulations have been evaluated as carrier system for this drug to overcome some problems associated with the commercial formulation Foscan where the drug is dissolved in a mixture of water-free ethanol and propylene glycol. The present study focuses on the physicochemical characterization of different liposome formulations with special emphasis on the influence of drug incorporation on the thermal phase behavior of the liposomes. In addition to conventional liposomes, pegylated lipids were used for the preparation of "stealth" liposomes. The dispersions as well as freeze-dried formulations were characterized by photon correlation spectroscopy, differential scanning calorimetry and cryo-electron microscopy. Incorporation of temoporfin resulted in a distinct concentration dependent decrease of the main phase transition of the liposomes. In case of liposomes based on dipalmitoylphosphatidylcholine/-glycerol, phase transition was close or even below body temperature. In contrast, if phospholipids with longer fatty acid chains (distearoylphosphatidylcholine/-glycerol) were used, phase transitions were well above body temperature even at high drug load. Size and thermal behavior were not distinctly influenced by the addition of pegylated lipids but cryo-electron microscopic investigations indicate the presence of micellar structures in addition to vesicles. Lyophilization and reconstitution led to an alteration in the morphology but had overall no distinct influence on the colloidal stability. 2010 Elsevier B.V. All rights reserved.

  6. Degradation of the chemotherapy drug 5-fluorouracil on medical-grade silver surfaces

    Science.gov (United States)

    Risinggård, Helene Kjær; Cooil, Simon; Mazzola, Federico; Hu, Di; Kjærvik, Marit; Østli, Elise Ramleth; Patil, Nilesh; Preobrajenski, Alexei; Andrew Evans, D.; Breiby, Dag W.; Trinh, Thuat T.; Wells, Justin W.

    2018-03-01

    The degradation of the chemotherapy drug 5-fluorouracil by a non-pristine metal surfaces is studied. Using density functional theory, X-ray photoelectron spectroscopy and X-ray absorption spectroscopy we show that the drug is entirely degraded by medical-grade silver surfaces, already at body temperature, and that all of the fluorine has left the molecule, presumably as HF. Remarkably, this degradation is even more severe than that reported previously for 5-fluorouracil on a pristine monocrystalline silver surface (in which case 80% of the drug reacted at body temperature) [1]. We conclude that the observed reaction is due to a reaction pathway, driven by H to F attraction between molecules on the surface, which results in the direct formation of HF; a pathway which is favoured when competing pathways involving reactive Ag surface sites are made unavailable by environmental contamination. Our measurements indicate that realistically cleaned, non-pristine silver alloys, which are typically used in medical applications, can result in severe degradation of 5-fluorouracil, with the release of HF - a finding which may have important implications for the handling of chemotherapy drugs.

  7. Development of irradiation technique on degradation residue of pesticide veterinary drugs and mycotoxins in food

    International Nuclear Information System (INIS)

    He Jiang; Huang Min; Chen Hao; Wu Ling; Gao Peng; Wang Yan; Lei Qing

    2012-01-01

    Irradiation technology is a new processing technology, It was widely used in food, medicines and medical supplies, chemical and other industries. In this paper, illustrated their applications in the degradation of pesticides, veterinary drugs and mycotoxins aspects residual pollution in food. Analysis of residual contaminants in food irradiation control study limitations and look forward to the prospect of food irradiation technology. (authors)

  8. Characterization of Diclofenac Liposomes Formulated with Palm Oil ...

    African Journals Online (AJOL)

    DS liposomes with good bioavailability. Keywords: Liposome, Drug delivery, Palm oil, Diclofenac. Tropical Journal of Pharmaceutical Research is indexed by Science Citation Index (SciSearch), Scopus,. International Pharmaceutical Abstract, Chemical Abstracts, Embase, Index Copernicus, EBSCO, African. Index Medicus ...

  9. The drug-induced degradation of oncoproteins: an unexpected Achilles' heel of cancer cells?

    Science.gov (United States)

    Ablain, Julien; Nasr, Rihab; Bazarbachi, Ali; de Thé, Hugues

    2011-07-01

    Many targeted therapies against cancer are aimed at inhibiting the enzymatic activity of kinases. Thus far, this approach has undoubtedly yielded significant clinical improvements, but has only rarely achieved cures. Other drugs, which selectively elicit proteasome-dependent degradation of oncoproteins, induce the loss of cancer cell self-renewal and promote cell differentiation and/or apoptosis. In acute promyelocytic leukemia, the cooperative degradation of PML/RARA by arsenic and retinoic acid cures most patients. In this condition and others, drug-induced proteolysis of oncoproteins is feasible and underlies improved clinical outcome. Several transcription factors, nuclear receptors, or fusion proteins driving cancer growth could be candidates for proteolysis-based drug-discovery programs.

  10. Liposomes, a promising strategy for clinical application of platinum derivatives.

    Science.gov (United States)

    Zalba, Sara; Garrido, María J

    2013-06-01

    Liposomes represent a versatile system for drug delivery in various pathologies. Platinum derivatives have been demonstrated to have therapeutic efficacy against several solid tumors. But their use is limited due to their side effects. Since liposomal formulations are known to reduce the toxicity of some conventional chemotherapeutic drugs, the encapsulation of platinum derivatives in these systems may be useful in reducing toxicity and maintaining an adequate therapeutic response. This review describes the strategies applied to platinum derivatives in order to improve their therapeutic activity, while reducing the incidence of side effects. It also reviews the results found in the literature for the different platinum-drugs liposomal formulations and their current status. The design of liposomes to achieve effectiveness in antitumor treatment is a goal for platinum derivatives. Liposomes can change the pharmacokinetic parameters of these encapsulated drugs, reducing their side effects. However, few liposomal formulations have demonstrated a significant advantage in therapeutic terms. Lipoplatin, a cisplatin formulation in Phase III, combines a reduction in the toxicity associated with an antitumor activity similar to the free drug. Thermosensitive or targeted liposomes for tumor therapy are also included in this review. Few articles about this strategy applied to platinum drugs can be found in the literature.

  11. A mixture model for water uptake, degradation, erosion and drug release from polydisperse polymeric networks.

    Science.gov (United States)

    Soares, João S; Zunino, Paolo

    2010-04-01

    We introduce a general class of mixture models suitable to describe water-dependent degradation and erosion of biodegradable polymers in conjunction with drug release. The ability to predict and quantify degradation and erosion has direct impact in a variety of biomedical applications and is a useful design tool for biodegradable implants and tissue engineering scaffolds. The model is based on a finite number of constituents describing the polydisperse polymeric system, each representing chains of an average size, and two additional constituents, water and drug. Hydrolytic degradation of individual chains occurs at the molecular level and mixture constituents diffuse individually accordingly to Fick's 1st law at the bulk level - such analysis confers a multi-scale aspect to the resulting reaction-diffusion system. A shift between two different types of behavior, each identified to surface or bulk erosion, is observed with the variation of a single non-dimensional parameter measuring the relative importance of the mechanisms of reaction and diffusion. Mass loss follows a sigmoid decrease in bulk eroding polymers, whereas decreases linearly in surface eroding polymers. Polydispersity influences degradation and erosion of bulk eroding polymers and drug release from unstable surface eroding matrices is dramatically enhanced in an erosion-controlled release. Copyright 2010 Elsevier Ltd. All rights reserved.

  12. Modelling drug degradation in a spray dried polymer dispersion using a modified Arrhenius equation.

    Science.gov (United States)

    Patterson, Adele; Ferreira, Ana P; Banks, Elizabeth; Skeene, Kirsty; Clarke, Graham; Nicholson, Sarah; Rawlinson-Malone, Clare

    2015-01-15

    The Pharmaceutical industry is increasingly utilizing amorphous technologies to overcome solubility challenges. A common approach is the use of drug in polymer dispersions to prevent recrystallization of the amorphous drug. Understanding the factors affecting chemical and physical degradation of the drug within these complex systems, e.g., temperature and relative humidity, is an important step in the selection of a lead formulation, and development of appropriate packaging/storage control strategies. The Arrhenius equation has been used as the basis of a number of models to predict the chemical stability of formulated product. In this work, we investigate the increase in chemical degradation seen for one particular spray dried dispersion formulation using hydroxypropyl methylcellulose acetate succinate (HPMC-AS). Samples, prepared using polymers with different substitution levels, were placed on storage for 6 months under a range of different temperature and relative humidity conditions and the degradant level monitored using high-performance liquid chromatography (HPLC). While the data clearly illustrates the impact of temperature and relative humidity on the degradant levels detected, it also highlighted that these terms do not account for all the variability in the data. An extension of the Arrhenius equation to include a term for the polymer chemistry, specifically the degree of succinoyl substitution on the polymer backbone, was shown to improve the fit of the model to the data. Copyright © 2014 Elsevier B.V. All rights reserved.

  13. Successful co-encapsulation of benzoyl peroxide and chloramphenicol in liposomes by a novel manufacturing method - dual asymmetric centrifugation.

    Science.gov (United States)

    Ingebrigtsen, Sveinung G; Škalko-Basnet, Nataša; de Albuquerque Cavalcanti Jacobsen, Cristiane; Holsæter, Ann Mari

    2017-01-15

    Encapsulation of more than one active pharmaceutical ingredient into nanocarriers such as liposomes is an attractive approach to achieve a synergic drug effect and less complicated dosing schedules in multi-drug treatment regimes. Liposomal drug delivery in acne treatment may improve drug efficiency by targeted delivery to pilosebaceous units, reduce adverse effects and improve patient compliance. We therefore aimed to co-encapsulate benzoyl peroxide (BPO) and chloramphenicol (CAM) into liposomes using the novel liposome processing method - dual asymmetric centrifugation (DAC). Liposomes were formed from soybean lecithin, propylene glycol and distilled water (2:1:2w/v/v ratio), forming a viscous liposome dispersion. Liposomes containing both drugs (BPO-CAM-Lip), single drug (BPO-Lip and CAM-Lip), and empty liposomes were prepared. Drug entrapment of BPO and CAM was determined by a newly developed HPLC method for simultaneous detection and quantification of both drugs. Encapsulation of around 50% for BPO and 60% for CAM respectively was obtained in both single-drug encapsulated formulations (BPO-Lip and CAM-Lip) and co-encapsulated formulations (BPO-CAM-Lip). Liposome sizes were comparable for all liposome formulations, ranging from 130 to 150nm mean diameter, with a polydispersity index <0.2 for all formulations. CAM exhibited a sustained release from all liposomal formulations, whereas BPO appeared retained within the liposomes. BPO retention could be attributed to its poor solubility. However, HaCaT cell toxicity was found dependent on BPO released from the liposomes. In the higher concentration range (4%v/v), liposomal formulations were less cytotoxic than the corresponding drug solutions used as reference. We have demonstrated that DAC is a fast, easy, suitable method for encapsulation of more than one drug within the same liposomes. Copyright © 2016 Elsevier B.V. All rights reserved.

  14. Identification, isolation and characterization of a new degradation product in sultamicillin drug substance.

    Science.gov (United States)

    Kumar, Vundavilli Jagadeesh; Gupta, P Badarinadh; Kumar, K S R Pavan; Ray, Uttam Kumar; Sreenivasulu, B; Kumar, G S Siva; Rao, K Ranga; Sharma, Hemant Kumar; Mukkanti, K

    2011-02-20

    A new degradant of sultamicillin drug substance was found during the gradient reverse phase HPLC analysis of stability storage samples. The level of this degradant impurity was observed up to 1.0%. The impurity (formaldehyde adduct with 5-oxo-4-phenylimidazolidin-1-yl moiety) was identified by LC/MS and was characterized by ((1)H NMR, (13)C NMR, 2D-NMR ((1)H-(1)H COSY, NOESY, HSQC and HMBC), LC/MS/MS, MS/TOF, elemental analysis and IR. This impurity was prepared by isolation and co-injected into HPLC system to confirm the retention time. Copyright © 2010 Elsevier B.V. All rights reserved.

  15. Preparation, characterization, and efficient transfection of cationic liposomes and nanomagnetic cationic liposomes

    Directory of Open Access Journals (Sweden)

    Samadikhah HR

    2011-10-01

    Full Text Available Hamid Reza Samadikhah1,*, Asia Majidi2,*, Maryam Nikkhah2, Saman Hosseinkhani11Department of Biochemistry, 2Department of Nanobiotechnology, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran *These authors contributed equally to this work Purpose: Cationic liposomes (CLs are composed of phospholipid bilayers. One of the most important applications of these particles is in drug and gene delivery. However, using CLs to deliver therapeutic nucleic acids and drugs to target organs has some problems, including low transfection efficiency in vivo. The aim of this study was to develop novel CLs containing magnetite to overcome the deficiencies. Patients and methods: CLs and magnetic cationic liposomes (MCLs were prepared using the freeze-dried empty liposome method. Luciferase-harboring vectors (pGL3 were transferred into liposomes and the transfection efficiencies were determined by luciferase assay. Firefly luciferase is one of most popular reporter genes often used to measure the efficiency of gene transfer in vivo and in vitro. Different formulations of liposomes have been used for delivery of different kinds of gene reporters. Lipoplex (liposome–plasmid DNA complexes formation was monitored by gel retardation assay. Size and charge of lipoplexes were determined using particle size analysis. Chinese hamster ovary cells were transfected by lipoplexes (liposome-pGL3; transfection efficiency and gene expression level was evaluated by luciferase assay. Results: High transfection efficiency of plasmid by CLs and novel nanomagnetic CLs was achieved. Moreover, lipoplexes showed less cytotoxicity than polyethyleneimine and Lipofectamine™. Conclusion: Novel liposome compositions (1,2-dipalmitoyl-sn-glycero-3-phosphocholine [DPPC]/dioctadecyldimethylammonium bromide [DOAB] and DPPC/cholesterol/DOAB with high transfection efficiency can be useful in gene delivery in vitro. MCLs can also be used for targeted gene delivery, due to

  16. Cyclic RGD peptide-modified liposomal drug delivery system for targeted oral apatinib administration: enhanced cellular uptake and improved therapeutic effects.

    Science.gov (United States)

    Song, Zhiwang; Lin, Yun; Zhang, Xia; Feng, Chan; Lu, Yonglin; Gao, Yong; Dong, Chunyan

    2017-01-01

    Apatinib is an oral tyrosine kinase inhibitor, which selectively targets vascular endothelial growth factor receptor 2 and has the potential to treat many tumors therapeutically. Cyclic arginylglycylaspartic acid (cRGD)- and polyethylene glycol (PEG)-modified liposomes (cRGD-Lipo-PEG) were constructed to act as a targeted delivery system for the delivery of apatinib to the human colonic cancer cell line, HCT116. These cRGD-modified liposomes specifically recognized integrin α v β 3 and exhibited greater uptake efficiency with respect to delivering liposomes into HCT116 cells when compared to nontargeted liposomes (Lipo-PEG), as well as greater death of tumor cells and apoptosis. The mechanism by which cRGD-Lipo-PEG targets cells was elucidated further with competition assays. To determine the anticancer efficacy in vivo, nude mice were implanted with HCT116 xenografts and treated with apatinib-loaded liposomes or free apatinib intravenously or via intragastric administration. The active and passive targeting of cRGD-Lipo-PEG led to significant tumor treatment targeting ability, better inhibition of tumor growth, and less toxicity when compared with treatments using uncombined apatinib. The results presented strongly support the case for cRGD-Lipo-PEG representing a targeted delivery system for apatinib in the treatment of colonic cancer.

  17. Recent advances on liposomal nanoparticles: synthesis, characterization and biomedical applications.

    Science.gov (United States)

    Panahi, Yunes; Farshbaf, Masoud; Mohammadhosseini, Majid; Mirahadi, Mozhdeh; Khalilov, Rovshan; Saghfi, Siamak; Akbarzadeh, Abolfazl

    2017-06-01

    Liposome is a new nanostructure for the encapsulation and delivery of bioactive agents. There are a lot of bioactive materials that could be incorporated into liposomes including cosmetics, food ingredients, and pharmaceuticals. Liposomes possess particular properties such as biocompatibility, biodegradability; accompanied by their nanosize they have potential applications in nanomedicine, cosmetics, and food industry. Nanoliposome technology offers thrilling chances for food technologists in fields including encapsulation and controlled release of food ingredients, also improved bioavailability and stability of sensitive materials. Amid numerous brilliant new drug and gene delivery systems, liposomes provide an advanced technology to carry active molecules to the specific site of action, and now days, various formulations are in clinical use. In this paper, we provide review of the main physicochemical properties of liposomes, current methods of the manufacturing and introduce some of their usage in food nanotechnology as carrier vehicles of nutrients, enzymes, and food antimicrobials and their applications as drug carriers and gene delivery agents in biomedicine.

  18. Targeting doxorubicin encapsulated in stealth liposomes to solid tumors by non thermal diode laser

    OpenAIRE

    Ghannam, Magdy M.; El Gebaly, Reem; Fadel, Maha

    2016-01-01

    Background The use of liposomes as drug delivery systems is the most promising technique for targeting drug especially for anticancer therapy. Methods In this study sterically stabilized liposomes was prepared from DPPC/Cholesterol/PEG-PE encapsulated doxorubicin. The effect of lyophilization on liposomal stability and hence expiration date were studied. Moreover, the effect of diode laser on the drug released from liposomesin vitro and in vivo in mice carrying implanted solid tumor were also...

  19. Improved Antitumor Efficacy and Pharmacokinetics of Bufalin via PEGylated Liposomes

    Science.gov (United States)

    Yuan, Jiani; Zhou, Xuanxuan; Cao, Wei; Bi, Linlin; Zhang, Yifang; Yang, Qian; Wang, Siwang

    2017-11-01

    Bufalin was reported to show strong pharmacological effects including cardiotonic, antiviral, immune-regulation, and especially antitumor effects. The objective of this study was to determine the characterization, antitumor efficacy, and pharmacokinetics of bufalin-loaded PEGylated liposomes compared with bufalin entity, which were prepared by FDA-approved pharmaceutical excipients. Bufalin-loaded PEGylated liposomes and bufalin-loaded liposomes were prepared reproducibly with homogeneous particle size by the combination of thin film evaporation method and high-pressure homogenization method. Their mean particle sizes were 127.6 and 155.0 nm, mean zeta potentials were 2.24 and - 18.5 mV, and entrapment efficiencies were 76.31 and 78.40%, respectively. In vitro release profile revealed that the release of bufalin in bufalin-loaded PEGylated liposomes was slower than that in bufalin-loaded liposomes. The cytotoxicity of blank liposomes has been found within acceptable range, whereas bufalin-loaded PEGylated liposomes showed enhanced cytotoxicity to U251 cells compared with bufalin entity. In vivo pharmacokinetics indicated that bufalin-loaded PEGylated liposomes could extend or eliminate the half-life time of bufalin in plasma in rats. The results suggested that bufalin-loaded PEGylated liposomes improved the solubility and increased the drug concentration in plasma.

  20. PLGA implants: How Poloxamer/PEO addition slows down or accelerates polymer degradation and drug release.

    Science.gov (United States)

    Hamoudi-Ben Yelles, M C; Tran Tan, V; Danede, F; Willart, J F; Siepmann, J

    2017-05-10

    The aim of this study was to evaluate the impact of the addition of small amounts of hydrophilic polymers (Poloxamer 188 and PEO 200kDa) to PLGA-based implants loaded with prilocaine. Special emphasis was placed on the importance of the type of preparation technique: direct compression of milled drug-polymer powder blends versus compression of drug loaded microparticles (prepared by spray-drying). The implants were thoroughly characterized before and upon exposure to phosphate buffer pH7.4, e.g. using optical and scanning electron microscopy, X-ray diffraction, DSC and GPC. Interestingly, the addition of Poloxamer/PEO to the PLGA implants had opposite effects on the resulting drug release kinetics, depending on the type of preparation method: in the case of implants prepared by compression of milled drug-polymer powder blends, drug release was accelerated, whereas it was slowed down when the implants were prepared by compression of drug loaded PLGA microparticles. These phenomena could be explained by the swelling/disintegration behavior of the implants upon exposure to the release medium. Systems consisting of compressed microparticles remained intact and autocatalytic effects were of major importance. The presence of a hydrophilic polymer facilitated water penetration into these devices, slowing down PLGA degradation and drug release. In contrast, implants consisting of compressed drug-polymer powder blends rapidly (at least partially) disintegrated and autocatalysis was much less important. In these cases, the addition of a hydrophilic polymer facilitated ester bond cleavage, leading to accelerated PLGA degradation and drug release. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. Development of a liposomal nanodelivery system for nevirapine

    Directory of Open Access Journals (Sweden)

    Krishnan Uma M

    2010-07-01

    Full Text Available Abstract Background The treatment of AIDS remains a serious challenge owing to high genetic variation of Human Immunodeficiency Virus type 1 (HIV-1. The use of different antiretroviral drugs (ARV is significantly limited by severe side-effects that further compromise the quality of life of the AIDS patient. In the present study, we have evaluated a liposome system for the delivery of nevirapine, a hydrophobic non-nucleoside reverse transcriptase inhibitor. Liposomes were prepared from egg phospholipids using thin film hydration. The parameters of the process were optimized to obtain spherical liposomes below 200 nm with a narrow polydispersity. The encapsulation efficiency of the liposomes was optimized at different ratios of egg phospholipid to cholesterol as well as drug to total lipid. The data demonstrate that encapsulation efficiency of 78.14% and 76.25% were obtained at egg phospholipid to cholesterol ratio of 9:1 and drug to lipid ratio of 1:5, respectively. We further observed that the size of the liposomes and the encapsulation efficiency of the drug increased concomitantly with the increasing ratio of drug and lipid and that maximum stability was observed at the physiological pH. Thermal analysis of the drug encapsulated liposomes indicated the formation of a homogenous drug-lipid system. The magnitude of drug release from the liposomes was examined under different experimental conditions including in phosphate buffered saline (PBS, Dulbecco's Modified Eagle's Medium (DMEM supplemented with 10% fetal bovine serum or in the presence of an external stimulus such as low frequency ultrasound. Within the first 20 minutes 40, 60 and 100% of the drug was released when placed in PBS, DMEM or when ultrasound was applied, respectively. We propose that nevirapine-loaded liposomal formulations reported here could improve targeted delivery of the anti-retroviral drugs to select compartments and cells and alleviate systemic toxic side effects as a

  2. Well-defined degradable brush polymer-drug conjugates for sustained delivery of Paclitaxel.

    Science.gov (United States)

    Yu, Yun; Chen, Chih-Kuang; Law, Wing-Cheung; Mok, Jorge; Zou, Jiong; Prasad, Paras N; Cheng, Chong

    2013-03-04

    To achieve a conjugated drug delivery system with high drug loading but minimal long-term side effects, a degradable brush polymer-drug conjugate (BPDC) was synthesized through azide-alkyne click reaction of acetylene-functionalized polylactide (PLA) with azide-functionalized paclitaxel (PTXL) and poly(ethylene glycol) (PEG). Well-controlled structures of the resulting BPDC and its precursors were verified by (1)H NMR and gel permeation chromatography (GPC) characterizations. With nearly quantitative click efficiency, drug loading amount of the BPDC reached 23.2 wt %. Both dynamic light scattering (DLS) analysis and transmission electron microscopy (TEM) imaging indicated that the BPDC had a nanoscopic size around 10-30 nm. The significant hydrolytic degradability of the PLA backbone of the BPDC was confirmed by GPC analysis of its incubated solution. Drug release study showed that PTXL moieties can be released through the cleavage of the hydrolyzable conjugation linkage in pH 7.4 at 37 °C, with 50% release in about 22 h. As illustrated by cytotoxicity study, while the polymeric scaffold of the BPDC is nontoxic, the BPDC exhibited higher therapeutic efficacy toward MCF-7 cancer cells than free PTXL at 0.1 and 1 μg/mL. Using Nile red as encapsulated fluorescence probe, cell uptake study showed effective internalization of the BPDC into the cells.

  3. Hydrogel Containing Nanoparticle-Stabilized Liposomes for Topical Antimicrobial Delivery

    Science.gov (United States)

    2015-01-01

    Adsorbing small charged nanoparticles onto the outer surfaces of liposomes has become an effective strategy to stabilize liposomes against fusion prior to “seeing” target bacteria, yet allow them to fuse with the bacteria upon arrival at the infection sites. As a result, nanoparticle-stabilized liposomes have become an emerging drug delivery platform for treatment of various bacterial infections. To facilitate the translation of this platform for clinical tests and uses, herein we integrate nanoparticle-stabilized liposomes with hydrogel technology for more effective and sustained topical drug delivery. The hydrogel formulation not only preserves the structural integrity of the nanoparticle-stabilized liposomes, but also allows for controllable viscoeleasticity and tunable liposome release rate. Using Staphylococcus aureus bacteria as a model pathogen, we demonstrate that the hydrogel formulation can effectively release nanoparticle-stabilized liposomes to the bacterial culture, which subsequently fuse with bacterial membrane in a pH-dependent manner. When topically applied onto mouse skin, the hydrogel formulation does not generate any observable skin toxicity within a 7-day treatment. Collectively, the hydrogel containing nanoparticle-stabilized liposomes hold great promise for topical applications against various microbial infections. PMID:24483239

  4. Recent advances in liposomal dry powder formulations: preparation and evaluation.

    Science.gov (United States)

    Misra, Ambikanandan; Jinturkar, Kaustubh; Patel, Deepa; Lalani, Jigar; Chougule, Mahavir

    2009-01-01

    Liposomal drug dry powder formulations have shown many promising features for pulmonary drug administration, such as selective localization of drug within the lung, controlled drug release, reduced local and systemic toxicities, propellant-free nature, patient compliance, high dose carrying capacity, stability and patent protection. Critical review of the recent developments will provide a balanced view on benefits of liposomal encapsulation while developing dry powder formulations and will help researchers to update themselves and focus their research in more relevant areas. In liposomal dry powder formulations (LDPF), drug encapsulated liposomes are homogenized, dispersed into the carrier and converted into dry powder form by using freeze drying, spray drying and spray freeze drying. Alternatively, LDPF can also be formulated by supercritical fluid technologies. On inhalation with a suitable inhalation device, drug encapsulated liposomes get rehydrated in the lung and release the drug over a period of time. The prepared LDPF are evaluated in vitro and in vivo for lung deposition behavior and drug disposition in the lung using a suitable inhaler device. The most commonly used liposomes are composed of lung surfactants and synthetic lipids. Delivery of anticancer agents for lung cancer, corticosteroids for asthma, immunosuppressants for avoiding lung transplantation rejection, antifungal drugs for lung fungal infections, antibiotics for local pulmonary infections and cystic fibrosis and opioid analgesics for pain management using liposome technology are a few examples. Many liposomal formulations have reached the stage of clinical trials for the treatment of pulmonary distress, cystic fibrosis, lung fungal infection and lung cancer. These formulations have given very promising results in both in vitro and in vivo studies. However, modifications to new therapies for respiratory diseases and systemic delivery will provide new challenges in conducting well

  5. System with embedded drug release and nanoparticle degradation sensor showing efficient rifampicin delivery into macrophages.

    Science.gov (United States)

    Trousil, Jiří; Filippov, Sergey K; Hrubý, Martin; Mazel, Tomáš; Syrová, Zdeňka; Cmarko, Dušan; Svidenská, Silvie; Matějková, Jana; Kováčik, Lubomír; Porsch, Bedřich; Konefał, Rafał; Lund, Reidar; Nyström, Bo; Raška, Ivan; Štěpánek, Petr

    2017-01-01

    We have developed a biodegradable, biocompatible system for the delivery of the antituberculotic antibiotic rifampicin with a built-in drug release and nanoparticle degradation fluorescence sensor. Polymer nanoparticles based on poly(ethylene oxide) monomethyl ether-block-poly(ε-caprolactone) were noncovalently loaded with rifampicin, a combination that, to best of our knowledge, was not previously described in the literature, which showed significant benefits. The nanoparticles contain a Förster resonance energy transfer (FRET) system that allows real-time assessment of drug release not only in vitro, but also in living macrophages where the mycobacteria typically reside as hard-to-kill intracellular parasites. The fluorophore also enables in situ monitoring of the enzymatic nanoparticle degradation in the macrophages. We show that the nanoparticles are efficiently taken up by macrophages, where they are very quickly associated with the lysosomal compartment. After drug release, the nanoparticles in the cmacrophages are enzymatically degraded, with half-life 88±11 min. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. Photocatalytic degradation of ciprofloxacin drug in water using ZnO nanoparticles

    Energy Technology Data Exchange (ETDEWEB)

    El-Kemary, Maged, E-mail: elkemary@yahoo.co [Photo- and Nanochemistry Laboratory, Chemistry Department, Faculty of Science, Kafrelsheikh University, 33516 Kafr ElSheikh (Egypt); El-Shamy, Hany; El-Mehasseb, Ibrahim [Photo- and Nanochemistry Laboratory, Chemistry Department, Faculty of Science, Kafrelsheikh University, 33516 Kafr ElSheikh (Egypt)

    2010-12-15

    We report the synthesis of nanostructure ZnO semiconductor with {approx}2.1 nm diameter using a chemical precipitation method. The resulting nanoparticles were characterized by X-ray diffraction analysis (XRD), Fourier-transform infrared (FT-IR) spectroscopy, scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The optical properties were investigated by UV-vis and fluorescence techniques. The absorption spectra exhibit a sharp absorption edge at {approx}334 nm corresponding to band gap of {approx}3.7 eV. The fluorescence spectra displayed a near-band-edge ultraviolet excitonic emission at {approx}410 nm and a green emission peak at {approx}525 nm, due to a transition of a photo-generated electron from the conduction band to a deeply trapped hole. The photocatalytic activity of the prepared ZnO nanoparticles has been investigated for the degradation of ciprofloxacin drug under UV light irradiation in aqueous solutions of different pH values. The results showed that the photocatalytic degradation process is effective at pH 7 and 10, but it is rather slow at pH 4. Higher degradation efficiency ({approx}50%) of the drug was observed at pH 10 after 60 min. Photodegradation of the drug follows a pseudo-first-order kinetics.

  7. Attenuation of dermal toxicity of doxorubicin by liposome encapsulation.

    Science.gov (United States)

    Forssen, E A; Tökes, Z A

    1983-05-01

    The severe tissue damage which occurs when doxorubicin (Dxn) is extravasated during infusion has been attenuated by encapsulating the drug in anionic liposomes. Mice were injected intradermally with either 0.05 or 0.10 mg of Dxn in the free or liposome-entrapped form. At both dose levels, the animals receiving free drug developed dermal lesions at a higher frequency and of a greater severity than did those animals receiving Dxn-liposomes. Determination of tissue-associated fluorescence indicated that free Dxn was removed from the area of the dermal injection more rapidly than was the liposome-entrapped drug. The data suggest that the dermal toxicity of Dxn may be determined more by its mode of disposition than by the absolute amount of drug in tissue. Similar observation was made earlier for the Dxn-induced chronic cardiotoxicity.

  8. Degradation behavior of theophylline/chitosan/β-cyclodextrin microspheres for pulmonary drug delivery

    Directory of Open Access Journals (Sweden)

    Li Wang

    2016-04-01

    Full Text Available To evaluate the degradation behavior of theophylline/chitosan/β-cyclo-dextrin microspheres, we performed both in vitro study by putting the microspheres in phosphate buffered saline or in phosphate buffer saline with enzyme and in vivo study by implanting the microspheres into the back of male Sprague-Dawley rats. The results showed that microspheres were degraded in enzymatic hydrolysis and phosphate buffer saline, which were degraded faster in 0.2 mg/mL lysozyme than in phosphate buffer saline. The morphology of microspheres in phosphate buffer saline and enzyme solution developed rough surfaces, and showed irregular shape and pores after 8 weeks. The microspheres were degraded in vivo within 8 weeks with irregular, sheet, porous morphology, and the diameters were smaller than 5 μm. These results indicated that the theophylline/chitosan/β-cyclodextrin microspheres had a good degradation both in vitro and in vivo which can be used as a pulmonary drug delivery carrier.

  9. Antibody-Hapten Recognition at the Surface of Functionalized Liposomes Studied by SPR: Steric Hindrance of Pegylated Phospholipids in Stealth Liposomes Prepared for Targeted Radionuclide Delivery

    Directory of Open Access Journals (Sweden)

    Eliot. P. Botosoa

    2011-01-01

    Full Text Available Targeted PEGylated liposomes could increase the amount of drugs or radionuclides delivered to tumor cells. They show favorable stability and pharmacokinetics, but steric hindrance of the PEG chains can block the binding of the targeting moiety. Here, specific interactions between an antihapten antibody (clone 734, specific for the DTPA-indium complex and DTPA-indium-tagged liposomes were characterized by surface plasmon resonance (SPR. Non-PEGylated liposomes fused on CM5 chips whereas PEGylated liposomes did not. By contrast, both PEGylated and non-PEGylated liposomes attached to L1 chips without fusion. SPR binding kinetics showed that, in the absence of PEG, the antibody binds the hapten at the surface of lipid bilayers with the affinity of the soluble hapten. The incorporation of PEGylated lipids hinders antibody binding to extents depending on PEGylated lipid fraction and PEG molecular weight. SPR on immobilized liposomes thus appears as a useful technique to optimize formulations of liposomes for targeted therapy.

  10. Kinetic Degradation and Controlled Drug Delivery System Studies for Sensitive Hydrogels Prepared by Gamma Irradiation

    International Nuclear Information System (INIS)

    Eid, M.; El-Arnaouty, M.B.

    2008-01-01

    Ternary mixtures of N-vinyle-2-pyrrolidone(NVP ), itaconic acid (IA) and gelatin (G) were gamma irradiated to prepared poly(NVP/IA/G) hydrogels. The equilibrium kinetic swelling, drug release behavior, Scan Electron Microscope (SEM) and the swelling-degradation kinetics were studied. Both the diffusion exponent and the diffusion coefficient increase with increasing content of (IA). Also, the swelling behavior of copolymer hydrogels in response to ph value of the external media was studied, it is noted that the highest swelling values at ph 4. The in vitro drug release behavior of these hydrogels was examined by quantification analysis with a UV/VIS spectrophotometers. Chlorpromazine hydrochloride was loaded into dried hydrogels to investigate the stimuli-sensitive property at the specific ph. The release studies show that the highest value of release was at ph 4 which can be used for drug delivery system

  11. Star Polymer-Drug Conjugates with pH-Controlled Drug Release and Carrier Degradation

    Directory of Open Access Journals (Sweden)

    H. Kostková

    2017-01-01

    Full Text Available In this study, we describe the design, synthesis, and physicochemical and preliminary biological characteristics of new biodegradable, high-molecular-weight (HMW drug delivery systems with star-like architectures bearing the cytotoxic drug doxorubicin (DOX attached by a hydrazone bond-containing spacer. The star polymers were synthesized by grafting semitelechelic N-(2-hydroxypropyl methacrylamide (HPMA copolymers on a 2,2-bis(hydroxymethylpropionic acid- (bis-MPA- based polyester dendritic core. The molecular weight of the star polymers ranged from 280 to 450 000 g/mol and could be adjusted by proper selection of the bis-MPA dendrimer generation and by considering the polymer to dendrimer molar ratio. The biodegradation of the polymer conjugates is based on the spontaneous slow hydrolysis of the dendritic core in neutral physiological conditions. Hydrazone spacers in the conjugates were fairly stable at neutral pH (7.4 mimicking blood stream conditions, and DOX was released from the conjugates under mild acidic conditions simulating the tumor cell microenvironment in endosomes and lysosomes (pH 5. Finally, we have shown the significant in vitro cytotoxicity of the star polymer-DOX conjugate on selected cancer cell lines with IC50 values almost comparable with that of the free drug and higher than that observed for a linear polymer-DOX conjugate with much lower molecular weight.

  12. MRI monitoring of nanocarrier accumulation and release using Gadolinium-SPIO co-labelled thermosensitive liposomes

    NARCIS (Netherlands)

    Lorenzato, Cyril; Oerlemans, Chris; van Elk, Merel; Geerts, Willie J C; Denis de Senneville, Baudouin; Moonen, Chrit; Bos, Clemens

    2016-01-01

    Encapsulation of anticancer drugs in triggerable nanocarriers can beneficially modify pharmacokinetics and biodistribution of chemotherapeutic drugs, and consequently increase tumor drug concentration and efficacy, while reducing side effects. Thermosensitive liposomes release their contents

  13. Characterisation and stability studies of a hydrophilic decapeptide in different adjuvant drug delivery systems: a comparative study of PLGA nanoparticles versus chitosan-dextran sulphate microparticles versus DOTAP-liposomes.

    Science.gov (United States)

    Wieber, Alena; Selzer, Torsten; Kreuter, Jörg

    2011-12-12

    Poly[lactic-co-glycolide] (PLGA) nanoparticles, chitosan-dextran sulphate microparticles, and DOTAP-liposomes were prepared as vaccine adjuvants and drug carriers for a small hydrophilic model peptide, and their different physico-chemical properties (size, PDI, zeta-potential, pH-value and peptide loading) were investigated. The model peptide's encapsulation efficiency (EE) in PLGA particles amounted to 15%, for DOTAP-liposomes to 20% and for chitosan particles up to 90%. The structural appearance of the particles was visualized by SEM and TEM. The stability of the aqueous formulations and the corresponding lyophilisates was monitored for 12 weeks (stored at T=2-8°C). The freeze-drying process and the addition of an appropriate cryoprotective agent (sucrose) proved to be essential for all carrier systems. As a result of this study, three different peptide-loaded drug delivery systems with different properties were successfully manufactured and showed sufficient product stability of their freeze-dried formulations over 12 weeks of storage. Copyright © 2011 Elsevier B.V. All rights reserved.

  14. Silica nanoparticle coated liposomes: a new type of hybrid nanocapsule for proteins.

    Science.gov (United States)

    Mohanraj, Vellore J; Barnes, Timothy J; Prestidge, Clive A

    2010-06-15

    A hybrid silica-liposome nanocapsule system containing insulin has been developed and the encapsulation, protection and release properties are evaluated. The formulation strategy is based on using insulin-loaded 1,2-dipalmitoyl-sn-glycero-3-phosphocholine and cholesterol liposomes as a template for the deposition of inert silica nanoparticles. The influence of formulation and process variables on particle size, zeta potential and liposome entrapment of insulin is reported. The ability to protect against lipolytic degradation and sustain insulin release in vitro in simulated GI conditions is also reported. Depending on the concentration and charge ratio of liposomes and silica nanoparticles, nanoparticle coated liposomes with varied size and zeta potential were obtained with an insulin entrapment efficiency of 70%. The silica nanoparticle coating protected liposomes against degradation by digestive enzymes in vitro; the release rate of insulin from silica coated liposomes was reduced in comparison to uncoated liposomes. Thus the liposomal release kinetics and stability can be controlled by including a specifically engineered nanoparticle layer. Silica nanoparticle-liposomes hybrid nanocapsules show promise as a delivery vehicle for proteins and peptides. Crown Copyright 2010. Published by Elsevier B.V. All rights reserved.

  15. Boron-Containing Compounds for Liposome-Mediated Tumor Localization and Application to Neutron Capture Therapy

    International Nuclear Information System (INIS)

    Hawthorne, M. Frederick

    2005-01-01

    Medical application of boron neutron capture therapy (BNCT) has been significantly hindered by the slow development of boron drug-targeting methodologies for the selective delivery of high boron concentration sto malignant cells. We have successfully sought to fill this need by creating liposomes suitable as in vivo boron delivery vehicles for BNCT. Delivery of therapeutic quantities of boron to tumors in murine models has been achieved with small unilamellar boron-rich liposomes. Subsequently, attempts have been made to improve delivery efficiency of liposomes encapsulating boron-containing water-soluble species into their hollow core by incorporating lipophilic boron compounds as addenda to the liposome bilayer, incorporating boron compounds as structural components of the bilayer (which however, poses the risk of sacrificing some stability), and combinations thereof. Regardless of the method, approximately 90% of the total liposome mass remains therapeutically inactive and comprised of the vehicle's construction materials, while less than 5% is boron for neutron targeting. Following this laboratory's intensive study, the observed tumor specificity of certain liposomes has been attributed to their diminutive size of these liposomes (30-150 nm), which enables these small vesicles to pass through the porous, immature vasculature of rapidly growing tumor tissue. We surmised that any amphiphilic nanoparticle of suitable size could possess some tumor selectivity. Consequently, the discovery of a very boron-rich nanoparticle delivery agent with biodistribution performance similar to unilamellar liposomes became one of our goals. Closomers, a new class of polyhedral borane derivatives, attracted us as an alternative BNCT drug-delivery system. We specifically envisioned dodeca (nido-carboranyl)-substituted closomers as possibly having a great potential role in BNCT drug delivery. They could function as extraordinarily boron-rich BNCT drugs since they are amphiphilic

  16. Boron-Containing Compounds for Liposome-Mediated Tumor Localization and Application to Neutron Capture Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Hawthorne, M. Frederick [Univ. of California, Los Angeles, CA (United States)

    2005-04-07

    Medical application of boron neutron capture therapy (BNCT) has been significantly hindered by the slow development of boron drug-targeting methodologies for the selective delivery of high boron concentration sto malignant cells. We have successfully sought to fill this need by creating liposomes suitable as in vivo boron delivery vehicles for BNCT. Delivery of therapeutic quantities of boron to tumors in murine models has been achieved with small unilamellar boron-rich liposomes. Subsequently, attempts have been made to improve delivery efficiency of liposomes encapsulating boron-containing water-soluble species into their hollow core by incorporating lipophilic boron compounds as addenda to the liposome bilayer, incorporating boron compounds as structural components of the bilayer (which however, poses the risk of sacrificing some stability), and combinations thereof. Regardless of the method, approximately 90% of the total liposome mass remains therapeutically inactive and comprised of the vehicle's construction materials, while less than 5% is boron for neutron targeting. Following this laboratory's intensive study, the observed tumor specificity of certain liposomes has been attributed to their diminutive size of these liposomes (30-150 nm), which enables these small vesicles to pass through the porous, immature vasculature of rapidly growing tumor tissue. We surmised that any amphiphilic nanoparticle of suitable size could possess some tumor selectivity. Consequently, the discovery of a very boron-rich nanoparticle delivery agent with biodistribution performance similar to unilamellar liposomes became one of our goals. Closomers, a new class of polyhedral borane derivatives, attracted us as an alternative BNCT drug-delivery system. We specifically envisioned dodeca (nido-carboranyl)-substituted closomers as possibly having a great potential role in BNCT drug delivery. They could function as extraordinarily boron-rich BNCT drugs since they are

  17. Investigation of polymeric scaffold degradation for drug delivery and neovascularization applications

    Science.gov (United States)

    Bulusu, Kartik V.; Alibouzar, Mitra; Castro, Nathan J.; Zhang, Lijie G.; Sarkar, Kausik; Plesniak, Michael W.

    2016-11-01

    Degradable polymer-based prosthetics for the treatment of osseous tissue defects, maxillo-/cranio-facial trauma and brain injury face two common clinical obstacles impeding efficient tissue engraftment i.e., controlled material release and neovascularization. Ascertaining the time scales of polymer degradation for controlled delivery of drugs and nutrients is critical to treatment efficacy and strategy. We incorporated multiple experimental methodologies to understand the driving forces of transport mechanisms in polyvinyl alcohol-based (PVA) 3D-printed scaffolds of different porosity. Scaffold degradation was monitored various pulsatile flow conditions using MEMS-based pressure catheters and an ultrasonic flow rate sensor. Ultrasonic properties (bulk attenuation and sound velocity) were measured to monitor the degradation process in a static, alkaline medium. Viscosity and the absorption spectra variations with PVA-solute concentrations were measured using a rheometer and a spectrophotometer, respectively. A simple mathematical model based on Fick's law of diffusion provides the fundamental description of solute transport from the scaffold matrices. However, macroscopic material release could become anomalous or non-Fickian in complex polymeric scaffold matrices. Supported by the GW Center for Biomimetics and Bioinspired Engineering and NIH Director's New Innovator Award 1DP2EB020549-01.

  18. Liposome formation in microgravity

    Science.gov (United States)

    Claassen, D. E.; Spooner, B. S.

    Liposomes are artificial vesicles with a phospholipid bilayer membrane. The formation of liposomes is a self-assembly process that is driven by the amphipathic nature of phospholipid molecules and can be observed during the removal of detergent from phospholipids dissolved in detergent micelles. As detergent concentration in the mixed micelles decreases, the non-polar tail regions of phospholipids produce a hydrophobic effect that drives the micelles to fuse and form planar bilayers in which phospholipids orient with tail regions to the center of the bilayer and polar head regions to the external surface. Remaining detergent molecules shield exposed edges of the bilayer sheet from the aqueous environment. Further removal of detergent leads to intramembrane folding and membrane vesiculation, forming liposomes. We have observed that the formation of liposomes is altered in microgravity. Liposomes that were formed at 1-g did not exceed 150 nm in diameter, whereas liposomes that were formed during spaceflight exhibited diameters up to 2000 nm. Using detergent-stabilized planar bilayers, we determined that the stage of liposome formation most influenced by gravity is membrane vesiculation. In addition, we found that small, equipment-induced fluid disturbances increased vesiculation and negated the size-enhancing effects of microgravity. However, these small disturbances had no effect on liposome size at 1-g, likely due to the presence of gravity-induced buoyancy-driven fluid flows (e.g., convection currents). Our results indicate that fluid disturbances, induced by gravity, influence the vesiculation of membranes and limit the diameter of forming liposomes.

  19. Bleomycin-Loaded pH-Sensitive Polymer–Lipid-Incorporated Liposomes for Cancer Chemotherapy

    Directory of Open Access Journals (Sweden)

    Eiji Yuba

    2018-01-01

    Full Text Available Cancer chemotherapeutic systems with high antitumor effects and less adverse effects are eagerly desired. Here, a pH-sensitive delivery system for bleomycin (BLM was developed using egg yolk phosphatidylcholine liposomes modified with poly(ethylene glycol-lipid (PEG-PE for long circulation in the bloodstream and 2-carboxycyclohexane-1-carboxylated polyglycidol-having distearoyl phosphatidylethanolamine (CHexPG-PE for pH sensitization. The PEG-PE/CHexPG-PE-introduced liposomes showed content release responding to pH decrease and were taken up by tumor cells at a rate 2.5 times higher than that of liposomes without CHexPG-PE. BLM-loaded PEG-PE/CHexPG-PE-introduced liposomes exhibited comparable cytotoxicity with that of the free drug. Intravenous administration of these liposomes suppressed tumor growth more effectively in tumor-bearing mice than did the free drug and liposomes without CHexPG-PE. However, at a high dosage of BLM, these liposomes showed severe toxicity to the spleen, liver, and lungs, indicating the trapping of liposomes by mononuclear phagocyte systems, probably because of recognition of the carboxylates on the liposomes. An increase in PEG molecular weight on the liposome surface significantly decreased toxicity to the liver and spleen, although toxicity to the lungs remained. Further improvements such as the optimization of PEG density and lipid composition and the introduction of targeting ligands to the liposomes are required to increase therapeutic effects and to reduce adverse effects.

  20. Radiolabeling, biodistribution and tumor imaging of stealth liposomes containing methotrexate

    International Nuclear Information System (INIS)

    Subramanian, N; Arulsudar, N; Chuttani, K; Mishra, P; Sharma, R.K; Murthy, R.S.R

    2003-01-01

    To study the utility of sterically stabilized liposomes (stealth liposomes) in tumor scintigraphy by studying its biodistribution and accumulation in target tissue after radiolabeling with Technetium-99m (99mTC). Conventional and Stealth liposomes were prepared by lipid film hydration method using methotrexate as model anticancer drug. Radiolabeling of the liposomes was carried out by direct labeling using reduced 99mTc. Experimental conditions for maximum labeling yield were optimized. The stability studies were carried out to check binding strength of the radiolabeled complexes. The blood kinetic study was carried out in rabbits after giving the labeled complex by intravenous administration through ear vein. The biodistribution studies were carried out in the Ehrlich ascites tumor (EAT) bearing mice after intravenous administration through tail vein, showed prolonged circulation in blood and significant increase in the accumulation in tumor for the sterically stabilized liposomes compared to the conventional liposomes. The gamma scintigraphic image shows the distribution of the stealth liposomes in liver, spleen, kidney and tumor. The study gives precise idea about the use of stealth liposomes in tumor scintigraphy and organ distribution studies (Au)

  1. Biodegradable polyesters for veterinary drug delivery systems: Characterization, in vitro degradation and release behavior of Oligolactides and Polytartrate

    OpenAIRE

    Schliecker, Gesine

    2004-01-01

    This thesis deals with the degradation and release behavior of aliphatic polyesters with special respect to the influence of oligomers on the degradation rate and the potential use of these biomaterials for the development of veterinary drug delivery systems. In Chapter 1 the animal health care market is introduced with regard to opportunities and challenges of veterinary drug delivery systems. . In the second part of this chapter...

  2. Hybrid Mesoporous Silica-Based Drug Carrier Nanostructures with Improved Degradability by Hydroxyapatite.

    Science.gov (United States)

    Hao, Xiaohong; Hu, Xixue; Zhang, Cuimiao; Chen, Shizhu; Li, Zhenhua; Yang, Xinjian; Liu, Huifang; Jia, Guang; Liu, Dandan; Ge, Kun; Liang, Xing-Jie; Zhang, Jinchao

    2015-10-27

    Potential bioaccumulation is one of the biggest limitations for silica nanodrug delivery systems in cancer therapy. In this study, a mesoporous silica nanoparticles/hydroxyapatite (MSNs/HAP) hybrid drug carrier, which enhanced the biodegradability of silica, was developed by a one-step method. The morphology and structure of the nanoparticles were characterized by TEM, DLS, FT-IR, XRD, N2 adsorption-desorption isotherms, and XPS, and the drug loading and release behaviors were tested. TEM and ICP-OES results indicate that the degradability of the nanoparticles has been significantly improved by Ca(2+) escape from the skeleton in an acid environment. The MSNs/HAP sample exhibits a higher drug loading content of about 5 times that of MSNs. The biological experiment results show that the MSNs/HAP not only exhibits good biocompatibility and antitumor effect but also greatly reduces the side effects of free DOX. The as-synthesized hybrid nanoparticles may act as a promising drug delivery system due to their good biocompatibility, high drug loading efficiency, pH sensitivity, and excellent biodegradability.

  3. Liposomes equipped with cell penetrating peptide BR2 enhances chemotherapeutic effects of cantharidin against hepatocellular carcinoma.

    Science.gov (United States)

    Zhang, Xue; Lin, Congcong; Lu, Aiping; Lin, Ge; Chen, Huoji; Liu, Qiang; Yang, Zhijun; Zhang, Hongqi

    2017-11-01

    A main hurdle for the success of tumor-specific liposomes is their inability to penetrate tumors efficiently. In this study, we incorporated a cell-penetrating peptide BR2 onto the surface of a liposome loaded with the anticancer drug cantharidin (CTD) to create a system targeting hepatocellular carcinoma (HCC) cells more efficiently and effectively. The in vitro cytotoxicity assay comparing the loaded liposomes' effects on hepatocellular cancer HepG2 and the control Miha cells showed that CTD-loaded liposomes had a stronger anticancer effect after BR2 modification. The cellular uptake results of HepG2 and Miha cells further confirmed the superior ability of BR2-modified liposomes to penetrate cancer cells. The colocalization study revealed that BR2-modified liposomes could enter tumor cells and subsequently release drugs. A higher efficiency of delivery by BR2 liposomes as compared to unmodified liposomes was evident by evaluation of the HepG2 tumor spheroids penetration and inhibition. The biodistribution studies and anticancer efficacy results in vivo showed the significant accumulation of BR2-modified liposomes into tumor sites and an enhanced tumor inhibition. In conclusion, BR2-modified liposomes improve the anticancer potency of drugs for HCC.

  4. Optimization of liposomal topotecan for use in treating neuroblastoma.

    Science.gov (United States)

    Chernov, Lina; Deyell, Rebecca J; Anantha, Malathi; Dos Santos, Nancy; Gilabert-Oriol, Roger; Bally, Marcel B

    2017-06-01

    The purpose of this work was to develop an optimized liposomal formulation of topotecan for use in the treatment of patients with neuroblastoma. Drug exposure time studies were used to determine that topotecan (Hycamtin) exhibited great cytotoxic activity against SK-N-SH, IMR-32 and LAN-1 neuroblastoma human cell lines. Sphingomyelin (SM)/cholesterol (Chol) and 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC)/Chol liposomes were prepared using extrusion methods and then loaded with topotecan by pH gradient and copper-drug complexation. In vitro studies showed that SM/Chol liposomes retained topotecan significantly better than DSPC/Chol liposomes. Decreasing the drug-to-lipid ratio engendered significant increases in drug retention. Dose-range finding studies on NRG mice indicated that an optimized SM/Chol liposomal formulation of topotecan prepared with a final drug-to-lipid ratio of 0.025 (mol: mol) was better tolerated than the previously described DSPC/Chol topotecan formulation. Pharmacokinetic studies showed that the optimized SM/Chol liposomal topotecan exhibited a 10-fold increase in plasma half-life and a 1000-fold increase in AUC 0-24 h when compared with Hycamtin administered at equivalent doses (5 mg/kg). In contrast to the great extension in exposure time, SM/Chol liposomal topotecan increased the life span of mice with established LAN-1 neuroblastoma tumors only modestly in a subcutaneous and systemic model. The extension in exposure time may still not be sufficient and the formulation may require further optimization. In the future, liposomal topotecan will be assessed in combination with high-dose radiotherapy such as 131 I-metaiodobenzylguanidine, and immunotherapy treatment modalities currently used in neuroblastoma therapy. © 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

  5. Calcipotriol delivery into the skin with PEGylated liposomes

    DEFF Research Database (Denmark)

    Knudsen, Nina Østergaard; Rønholt, Stine; Salte, Ragnhild Djønne

    2012-01-01

    The d-vitamin analogue calcipotriol is commonly used for topical treatment of psoriasis, but skin penetration is required for calcipotriol to reach its pharmacological target: the keratinocytes in the lower epidermis. Liposomes can enhance the delivery of drugs into the skin, but a major challenge...... of the liposomes and the ability to deliver membrane-intercalated calcipotriol into the skin. Inclusion of 0.5, l and 5mol% PEG-DSPE in the membrane enhanced the colloidal stability of the liposomes without compromising the delivery of calcipotriol from the vehicle into excised pig skin. Calcipotriol...

  6. Gold nanoparticles decorated liposomes and their SERS performance in tumor cells

    Science.gov (United States)

    Zhu, D.; Wang, Z. Y.; Zong, S. F.; Chen, H.; Chen, P.; Li, M. Y.; Wu, L.; Cui, Y. P.

    2015-05-01

    Due to their unique properties, liposomes have been widely used as drug nanocarriers. Herein a liposome-Au nanohybrid has been demonstrated as a SERS active intracellular drug nanocarrier. In this study, cationic Raman reporter tagged gold nanoparticles (Au@4MBA@PAH) were anchored onto the surfaces of anionic liposomes via electrostatic interactions. Using SKBR3 cells as model cells, we revealed that the hybrid formulation can be effectively taken up by tumor cells and tracked by the SERS signals. Collectively, the liposome-Au nanohybrids hold great promise in biomedical applications.

  7. Degradation of the anti-inflammatory drug ibuprofen by electro-peroxone process.

    Science.gov (United States)

    Li, Xiang; Wang, Yujue; Yuan, Shi; Li, Zhaoxin; Wang, Bin; Huang, Jun; Deng, Shubo; Yu, Gang

    2014-10-15

    Electro-peroxone (E-peroxone) treatment of the anti-inflammatory drug ibuprofen aqueous solution was investigated in this study. The E-peroxone process combined conventional ozonation with electrolysis processes, and used a carbon-polytetrafluorethylene cathode to electrochemically generate H2O2 from O2 in the sparged ozone generator effluent (O2 and O3 mixture). The in-situ generated H2O2 then reacted with the sparged O3 to produce aqueous •OH, which can in turn oxidize pollutants effectively in the bulk solution. The E-peroxone process overcomes several intrinsic limitations of conventional ozonation and electrolysis processes for pollutant degradation such as the selective oxidation with O3 and mass transfer limitations of pollutants to the electrodes, and thus significantly enhanced both ibuprofen degradation and total organic carbon (TOC) mineralization. Results show that ibuprofen could be completely degraded much more rapidly in the E-peroxone process (e.g., 5-15 min under all tested reaction conditions) than in ozonation (≥30 min) and electrolysis (several hours) processes. In addition, thanks to the powerful and non-selective oxidation capacity of •OH, toxic intermediates formed during ibuprofen degradation could be completely mineralized in the E-peroxone process. The E-peroxone effluent (2 h) thus exhibited much lower toxicity (5% inhibition of bioluminescence of Vibrio fisheri) than the ozonation and electrolysis effluents (22% and 88% inhibition, respectively). The results of this study indicate that the E-peroxone process may provide a promising technology for pharmaceutical wastewater treatment. Copyright © 2014 Elsevier Ltd. All rights reserved.

  8. Oral delivery of vancomycin by tetraether lipid liposomes.

    Science.gov (United States)

    Uhl, Philipp; Pantze, Silvia; Storck, Philip; Parmentier, Johannes; Witzigmann, Dominik; Hofhaus, Götz; Huwyler, Jörg; Mier, Walter; Fricker, Gert

    2017-10-15

    Despite the outstanding progress in modern medicine, the oral delivery of peptide drugs is limited until today due to their instability in the gastrointestinal tract and low mucosa penetration. To overcome these hurdles, liposomes containing the specific tetraether lipid GCTE (glycerylcaldityltetraether lipid) were examined. For this purpose, the glycopeptide antibiotic vancomycin was used as model substance and liposomes were prepared by DAC (dual assymetric centrifugation). These liposomes showed a size and polydispersity index comparable to standard liposomes. A high encapsulation efficiency of 58.53±1.76% of the peptide drug vancomycin could be obtained as detected by HPLC. FCS analysis showed that in average each liposome contains 30 molecules of vancomycin. TEM and Cryo-EM micrographs verified the size and lamellarity of the liposomal formulations. Cytotoxicity tests in Caco-2 cells showed no significant cytotoxicity for all liposomal concentrations tested, indicating the good tolerability of these formulations. Furthermore, the use of sucrose as lyoprotector enabled the long term storage of the liposomal formulation for at least three months. The potency of this drug delivery system could be proven in an animal model using Wistar rats. One hour after oral application, 4.82±0.56% of the administered dose of vancomycin could be found in the blood as detected by immunoassay measurements. This transport did also not affect the integrity of the peptide as verified by immunoassay measurements. In combination with long term storage stability, this formulation appears to be a promising delivery system for oral application of peptide drugs. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. High-Throughput Quantification of Nanoparticle Degradation Using Computational Microscopy and Its Application to Drug Delivery Nanocapsules

    KAUST Repository

    Ray, Aniruddha

    2017-04-25

    Design and synthesis of degradable nanoparticles are very important in drug delivery and biosensing fields. Although accurate assessment of nanoparticle degradation rate would improve the characterization and optimization of drug delivery vehicles, current methods rely on estimating the size of the particles at discrete points over time using, for example, electron microscopy or dynamic light scattering (DLS), among other techniques, all of which have drawbacks and practical limitations. There is a significant need for a high-throughput and cost-effective technology to accurately monitor nanoparticle degradation as a function of time and using small amounts of sample. To address this need, here we present two different computational imaging-based methods for monitoring and quantification of nanoparticle degradation. The first method is suitable for discrete testing, where a computational holographic microscope is designed to track the size changes of protease-sensitive protein-core nanoparticles following degradation, by periodically sampling a subset of particles mixed with proteases. In the second method, a sandwich structure was utilized to observe, in real-time, the change in the properties of liquid nanolenses that were self-assembled around degrading nanoparticles, permitting continuous monitoring and quantification of the degradation process. These cost-effective holographic imaging based techniques enable high-throughput monitoring of the degradation of any type of nanoparticle, using an extremely small amount of sample volume that is at least 3 orders of magnitude smaller than what is required by, for example, DLS-based techniques.

  10. Multimodality imaging demonstrates trafficking of liposomes preferentially to ischemic myocardium

    Energy Technology Data Exchange (ETDEWEB)

    Lipinski, Michael J., E-mail: mjlipinski12@gmail.com [MedStar Heart and Vascular Institute, MedStar Washington Hospital Center, Washington, DC (United States); Albelda, M. Teresa [GIBI2" 3" 0, Grupo de Investigación Biomédica en Imagen, IIS La Fe, Valencia (Spain); Frias, Juan C. [Departamento de Ciencias Biomédicas, Universidad CEU Cardenal Herrera, Valencia (Spain); Anderson, Stasia A. [Advanced Cardiovascular Imaging Laboratory, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (United States); Luger, Dror; Westman, Peter C.; Escarcega, Ricardo O.; Hellinga, David G.; Waksman, Ron [MedStar Heart and Vascular Institute, MedStar Washington Hospital Center, Washington, DC (United States); Arai, Andrew E. [Advanced Cardiovascular Imaging Laboratory, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (United States); Epstein, Stephen E. [MedStar Heart and Vascular Institute, MedStar Washington Hospital Center, Washington, DC (United States)

    2016-03-15

    Introduction: Nanoparticles may serve as a promising means to deliver novel therapeutics to the myocardium following myocardial infarction. We sought to determine whether lipid-based liposomal nanoparticles can be shown through different imaging modalities to specifically target injured myocardium following intravenous injection in an ischemia–reperfusion murine myocardial infarction model. Methods: Mice underwent ischemia–reperfusion surgery and then either received tail-vein injection with gadolinium- and fluorescent-labeled liposomes or no injection (control). The hearts were harvested 24 h later and underwent T1 and T2-weighted ex vivo imaging using a 7 Tesla Bruker magnet. The hearts were then sectioned for immunohistochemistry and optical fluorescent imaging. Results: The mean size of the liposomes was 100 nm. T1-weighted signal intensity was significantly increased in the ischemic vs. the non-ischemic myocardium for mice that received liposomes compared with control. Optical imaging demonstrated significant fluorescence within the infarct area for the liposome group compared with control (163 ± 31% vs. 13 ± 14%, p = 0.001) and fluorescent microscopy confirmed the presence of liposomes within the ischemic myocardium. Conclusions: Liposomes traffic to the heart and preferentially home to regions of myocardial injury, enabling improved diagnosis of myocardial injury and could serve as a vehicle for drug delivery.

  11. Tissue distribution of radiolabeled phosphatidylserine-containing liposome in mice

    Energy Technology Data Exchange (ETDEWEB)

    Borborema, Samanta E.T.; Nascimento, Nanci do [Instituto de Pesquisas Energeticas e Nucleares (IPEN/CNEN-SP), Sao Paulo, SP (Brazil). Centro de Biotecnologia], e-mail: samanta@usp.br, e-mail: nnascime@ipen.br; Andrade Junior, Heitor F. de [Instituto de Medicina Tropical de Sao Paulo (IMTSP), Sao Paulo, SP (Brazil)], e-mail: hfandrad@usp.br; Osso Junior, Joao A. [Instituto de Pesquisas Energeticas e Nucleares (IPEN/CNEN-SP), Sao Paulo, SP (Brazil). Centro de Radiofarmacia], e-mail: jaosso@ipen.br

    2009-07-01

    Liposomes are used as drug delivery systems to modify pharmacokinetic of drugs and also to improve their action in target cells. Liposomes containing phosphatidylserine are efficiently eliminated from the blood by cells of the mononuclear phagocytic system (MPS), predominantly Kupffer cells in the liver. In this way, this is a valuable approach to treat infectious diseases involving MPS, especially leishmaniasis. Leishmaniasis is a severe parasitic disease, caused by intramacrophage protozoa Leishmania sp., and is fatal if left untreated. Leishmania resides mainly in the liver and the spleen. Antileishmanial agents containing-liposomes showed more effective therapies with reduction of toxicity and adverse side effects. The purpose of this study was to investigate the tissue distribution of radioactive meglumine antimoniate encapsulated in phosphatidylserine-containing liposome. Meglumine antimoniate was neutron irradiated inside the IEA-R1 nuclear reactor to produce antimony radiotracers, {sup 122}Sb and {sup 124}Sb, and encapsulated in liposome. Healthy mice received a single intraperitoneal dose of the radiolabeled drug. Analysis of the mean radioactive tissue concentration-time data curves showed that liver and spleen had the highest levels of radioactivity. In addition these levels of drug remained for more than 48 hours. The dominant route of elimination was via biliary excretion with slow rate. Small fraction of the drug was found in the kidneys with very fast elimination. In conclusion, the phosphatidylserine-containing liposome showed to be a very useful tool to target antileishmanial agents to MPS and to sustain the drug levels for longer times. Besides, radiolabeled liposome is the easiest approach to perform biodistribution evaluation. (author)

  12. Characterization of a new degradation product of nifedipine formed on catalysis by atenolol: A typical case of alteration of degradation pathway of one drug by another.

    Science.gov (United States)

    Handa, Tarun; Singh, Saranjit; Singh, Inder Pal

    2014-02-01

    An increasing interest is being shown throughout the world on the use of fixed-dose combinations of drugs in the therapy of select diseases, like cardiovascular diseases, due to their multiple advantages. Though the main criterion for combining drugs in a single dosage form is the rationale, but consideration like stability of formulation is equally important, due to an added aspect of drug-drug interaction. The objective of this study was to evaluate interaction among the drugs in an antihypertensive combination of nifedipine and atenolol. Nifedipine is a known light sensitive drug, which degrades via intra-molecular mechanisms to nitro- and nitroso-pyridine analogs, along with a few minor secondary products that are formed through inter-molecular interactions amongst primary degradation products and their intermediates. Atenolol is reasonably stable weakly basic drug that is mainly hydrolyzed at acetamide terminal amide moiety to its corresponding carboxylic acid. To the best of our knowledge, there is no known information on chemical compatibility among the two drugs. The present study involved subjecting of nifedipine, atenolol and their combination to a variety of accelerated and stress conditions. HPLC studies revealed formation of a new product in the mixture of two drugs (∼2%), which was also generated from nifedipine alone, but at trace levels (product was isolated by preparative chromatography and subjected to indepth studies for its characterization. Ultra-violet, FT-IR, mass spectrometric and nuclear magnetic resonance spectroscopic studies highlighted that the principal photo-degradation pathway of nifedipine was modified and diverted in the presence of atenolol. To verify the same, a study was conducted employing two other β-blockers with similar structures to atenolol, and the same product was formed in relatively higher quantity therein also. The new product is postulated to be produced as a result of rearrangement of hydroxylamine intermediate

  13. Plasticized drug-loaded melt electrospun polymer mats: characterization, thermal degradation, and release kinetics.

    Science.gov (United States)

    Balogh, Attila; Drávavölgyi, Gábor; Faragó, Kornél; Farkas, Attila; Vigh, Tamás; Sóti, Péter Lajos; Wagner, István; Madarász, János; Pataki, Hajnalka; Marosi, György; Nagy, Zsombor Kristóf

    2014-04-01

    Melt electrospinning (MES) was used to prepare fast dissolving fibrous drug delivery systems in the presence of plasticizers. This new method was found promising in the field of pharmaceutical formulation because it combines the advantages of melt extrusion and solvent-based electrospinning. Lowering of the process temperature was performed using plasticizers in order to avoid undesired thermal degradation. Carvedilol (CAR), a poorly water-soluble and thermal-sensitive model drug, was introduced into an amorphous methacrylate terpolymer matrix, Eudragit® E, suitable for fiber formation. Three plasticizers (triacetin, Tween® 80, and polyethylene glycol 1500) were tested, all of which lowered the process temperature effectively. Scanning electron microscopy, X-ray diffraction, differential scanning calorimetry, and Raman microspectrometry investigations showed that crystalline CAR turned into an amorphous form during processing and preserved it for longer time. In vitro dissolution studies revealed ultrafast drug dissolution of the fibrous samples. According to the HPLC impurity tests, the reduced stability of CAR under conditions applied without plasticizer could be avoided using plasticizers, whereas storage tests also indicated the importance of optimizing the process parameters during MES. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

  14. Photocatalytic degradation kinetics and mechanism of antivirus drug-lamivudine in TiO{sub 2} dispersion

    Energy Technology Data Exchange (ETDEWEB)

    An, Taicheng, E-mail: antc99@gig.ac.cn [State Key Laboratory of Organic Geochemistry and Guangdong Key Laboratory of Environmental Resources Utilization and Protection, Guangzhou Institute of Geochemistry, Chinese Academy of Sciences, Guangzhou 510640 (China); An, Jibin [State Key Laboratory of Organic Geochemistry and Guangdong Key Laboratory of Environmental Resources Utilization and Protection, Guangzhou Institute of Geochemistry, Chinese Academy of Sciences, Guangzhou 510640 (China); College of Petrochemical Technology, Lanzhou University of Technology, Lanzhou 730050 (China); Graduate School of Chinese Academy of Sciences, Beijing 100049 (China); Yang, Hai [State Key Laboratory of Organic Geochemistry and Guangdong Key Laboratory of Environmental Resources Utilization and Protection, Guangzhou Institute of Geochemistry, Chinese Academy of Sciences, Guangzhou 510640 (China); Graduate School of Chinese Academy of Sciences, Beijing 100049 (China); Li, Guiying [State Key Laboratory of Organic Geochemistry and Guangdong Key Laboratory of Environmental Resources Utilization and Protection, Guangzhou Institute of Geochemistry, Chinese Academy of Sciences, Guangzhou 510640 (China); Feng, Huixia [College of Petrochemical Technology, Lanzhou University of Technology, Lanzhou 730050 (China); Nie, Xiangping [Institute of Hydrobiology, Jinan University, Guangzhou 510632 (China)

    2011-12-15

    Highlights: Black-Right-Pointing-Pointer Photocatalytic degradation kinetics of antivirus drug lamivudine. Black-Right-Pointing-Pointer The degradation kinetics was optimized by the single-variable-at-a-time. Black-Right-Pointing-Pointer The degradation kinetics was optimized by central composite design. Black-Right-Pointing-Pointer The contribution of reactive species was investigated with addition of scavengers. Black-Right-Pointing-Pointer Six intermediates were identified and a degradation mechanism was proposed. - Abstract: Photocatalytic degradation kinetics of antivirus drug-lamivudine in aqueous TiO{sub 2} dispersions was systematically optimized by both single-variable-at-a-time and central composite design based on the response surface methodology. Three variables, TiO{sub 2} content, initial pH and lamivudine concentration, were selected to determine the dependence of degradation efficiencies of lamivudine on independent variables. Response surface methodology modeling results indicated that degradation efficiencies of lamivudine were highly affected by TiO{sub 2} content and initial lamivudine concentration. The highest degradation efficiency was achieved at suitable amount of TiO{sub 2} and with maintaining initial lamivudine concentration to a minimum. In addition, the contribution experiments of various primary reactive species produced during the photocatalysis were investigated with the addition of different scavengers and found that hydroxyl radicals was the major reactive species involved in lamivudine degradation in aqueous TiO{sub 2}. Six degradation intermediates were identified using HPLC/MS/MS, and photocatalytic degradation mechanism of lamivudine was proposed by utilizing collective information from both experimental results of HPLC/MS/MS, ion chromatography as well as total organic carbon and theoretical data of frontier electron densities and point charges.

  15. Innovations in Liposomal DDS Technology and Its Application for the Treatment of Various Diseases.

    Science.gov (United States)

    Oku, Naoto

    2017-01-01

    Liposomes have been widely used as drug carriers in the field of drug delivery systems (DDS), and they are thought to be ideal nano-capsules for targeting DDS after being injected into the bloodstream. In general, DDS drugs meet the needs of aged and super-aged societies, since the administration route of drugs can be changed, the medication frequency reduced, the adverse effects of drugs suppressed, and so on. In fact, a number of liposomal drugs have been launched and used worldwide including liposomal anticancer drugs, and these drugs have appeared on the market owing to various innovations in liposomal DDS technologies. The accumulation of long-circulating liposomes in cancer tissue is driven by the enhanced permeability and retention (EPR) effect. In this review, liposome-based targeting DDS for cancer therapy is briefly discussed. Since cancer angiogenic vessels are the ideal target of drug carriers after their injection and are critical for cancer growth, damaging of these neovessels has been an approach for eradicating cancer cells. Also, the usage of liposomal DDS for the treatment of ischemic stroke is possible, since we observed that PEGylated liposomes accumulate in the site of cerebral ischemia in transient middle cerebral artery occlusion (t-MCAO) model rats. Interestingly, liposomes carrying neuroprotectants partly suppress ischemia/reperfusion injury of these model rats, suggesting that the EPR effect also works in ischemic diseases by causing an increase in the permeability of the blood vessel endothelium. The potential of liposomal DDS against life-threatening diseases might thus be attractive for supporting long-lived societies.

  16. Stabilization of liophilized liposomal products

    Directory of Open Access Journals (Sweden)

    2001-08-01

    Full Text Available Liposomes as a drug carrier have numerous dominancy. Liophilization is the most propr form of these products for long-term maintenance, but this procedure is affected by unstabilizing agent that results in destruction of membrane, release of content and change in size and microbial contamination; hence for prevention of the adverse effects, the protective role of sugars such as: Maltose, Fructose, Glucose, Galactose, Saccharose and Lactose were studied. For this purpose, after preparation of liposomal suspention, categorized in for duplicate groups and concentrations of 25, 50, 100 percent of these sugars were added to those. On the basis of color and consistency of products, the best method of freezing is as application of absolute alcohol and then chilling in-70 oc for 16 h. In survey of protective substances concentrations 0.7, 1.4, 2.8, and 5.6 percent of the mentioned sugars were used for calculating of leakage percent (Upon on the ratio of optical density of treated samples to untreated. In this study, released maltose had highest effect. Level of fusion and aggregation had any significant difference between pre and post lyophilized samples in centrifugation with 10000 rpm. Microbial state of recent samples were studied by culturing in SCD and SCDA media that indicated microbial growth in both samples.     

  17. PROTACs: An Emerging Targeting Technique for Protein Degradation in Drug Discovery.

    Science.gov (United States)

    Gu, Shanshan; Cui, Danrui; Chen, Xiaoyu; Xiong, Xiufang; Zhao, Yongchao

    2018-04-01

    Proteolysis-targeting chimeric molecules (PROTACs) represent an emerging technique that is receiving much attention for therapeutic intervention. The mechanism is based on the inhibition of protein function by hijacking a ubiquitin E3 ligase for protein degradation. The hetero-bifunctional PROTACs contain a ligand for recruiting an E3 ligase, a linker, and another ligand to bind with the protein targeted for degradation. Thus, PROTACs have profound potential to eliminate "undruggable" protein targets, such as transcription factors and non-enzymatic proteins, which are not limited to physiological substrates of the ubiquitin-proteasome system. These findings indicate great prospects for PROTACs in the development of therapeutics. However, there are several limitations related to poor stability, biodistribution, and penetrability in vivo. This review provides an overview of the main PROTAC-based approaches that have been developed and discusses the promising opportunities and considerations for the application of this technology in therapies and drug discovery. © 2018 The Authors. BioEssays Published by Wiley Periodicals, Inc.

  18. Cdt1 is differentially targeted for degradation by anticancer chemotherapeutic drugs.

    Directory of Open Access Journals (Sweden)

    Athanasia Stathopoulou

    Full Text Available BACKGROUND: Maintenance of genome integrity is crucial for the propagation of the genetic information. Cdt1 is a major component of the pre-replicative complex, which controls once per cell cycle DNA replication. Upon DNA damage, Cdt1 is rapidly targeted for degradation. This targeting has been suggested to safeguard genomic integrity and prevent re-replication while DNA repair is in progress. Cdt1 is deregulated in tumor specimens, while its aberrant expression is linked with aneuploidy and promotes tumorigenesis in animal models. The induction of lesions in DNA is a common mechanism by which many cytotoxic anticancer agents operate, leading to cell cycle arrest and apoptosis. METHODOLOGY/PRINCIPAL FINDING: In the present study we examine the ability of several anticancer drugs to target Cdt1 for degradation. We show that treatment of HeLa and HepG2 cells with MMS, Cisplatin and Doxorubicin lead to rapid proteolysis of Cdt1, whereas treatment with 5-Fluorouracil and Tamoxifen leave Cdt1 expression unaffected. Etoposide affects Cdt1 stability in HepG2 cells and not in HeLa cells. RNAi experiments suggest that Cdt1 proteolysis in response to MMS depends on the presence of the sliding clamp PCNA. CONCLUSION/SIGNIFICANCE: Our data suggest that treatment of tumor cells with commonly used chemotherapeutic agents induces differential responses with respect to Cdt1 proteolysis. Information on specific cellular targets in response to distinct anticancer chemotherapeutic drugs in different cancer cell types may contribute to the optimization of the efficacy of chemotherapy.

  19. Targeting doxorubicin encapsulated in stealth liposomes to solid tumors by non thermal diode laser.

    Science.gov (United States)

    Ghannam, Magdy M; El Gebaly, Reem; Fadel, Maha

    2016-04-05

    The use of liposomes as drug delivery systems is the most promising technique for targeting drug especially for anticancer therapy. In this study sterically stabilized liposomes was prepared from DPPC/Cholesterol/PEG-PE encapsulated doxorubicin. The effect of lyophilization on liposomal stability and hence expiration date were studied. Moreover, the effect of diode laser on the drug released from liposomesin vitro and in vivo in mice carrying implanted solid tumor were also studied. The results indicated that lyophilization of the prepared liposomes encapsulating doxorubicin led to marked stability when stored at 5 °C and it is possible to use the re-hydrated lyophilized liposomes within 12 days post reconstitution. Moreover, the use of low energy diode laser for targeting anticancer drug to the tumor cells is a promising method in cancer therapy. We can conclude that lyophilization of the liposomes encapsulating doxorubicin lead to marked stability for the liposomes when stored at 5 °C. Moreover, the use of low energy diode laser for targeting anticancer drug to the tumor cells through the use of photosensitive sterically stabilized liposomes loaded with doxorubicin is a promising method. It proved to be applicable and successful for treatment of Ehrlich solid tumors implanted in mice and eliminated toxic side effects of doxorubicin.

  20. Photocatalytic and photoelectrocatalytic degradation of the drug omeprazole on nanocrystalline titania films in alkaline media: Effect of applied electrical bias on degradation and transformation products.

    Science.gov (United States)

    Tantis, Iosif; Bousiakou, Leda; Frontistis, Zacharias; Mantzavinos, Dionissios; Konstantinou, Ioannis; Antonopoulou, Maria; Karikas, George-Albert; Lianos, Panagiotis

    2015-08-30

    Photocatalytic and photoelectrocatalytic degradation of the drug omeprazole has been studied in the presence of nanocrystalline titania films supported on glass slides or transparent FTO electrodes in alkaline environment. Its photocatalytic degradation rate was assessed by its UV absorbance and by HPLC, while its transformation products were analyzed by HR-LC-MS. Based on UV absorbance, omeprazole can be photocatalytically degraded at an average rate of 6.7×10(-4)min(-1) under low intensity UVA irradiation of 1.5mWcm(-2) in the presence of a nanoparticulate titania film. This corresponds to degradation of 1.4mg of omeprazole per gram of the photocatalyst per liter of solution per hour. The photodegradation rate can be accelerated in a photoelectrochemical cell by applying a forward bias. In this case, the maximum rate reached under the present conditions was 11.6×10(-4)min(-1) by applying a forward bias of +0.6V vs. Ag/AgCl. Four major transformation products were successfully identified and their profiles were followed by HR-LC-MS. The major degradation path includes the scission of the sulfoxide bridge into the corresponding pyridine and benzimidazole ring derivates and this is accompanied by the release of sulfate anions in the reaction mixture. Copyright © 2015 Elsevier B.V. All rights reserved.

  1. Development and pharmacokinetic of antimony encapsulated in liposomes of phosphatidylserine using radioisotopes in experimental leishmaniasis

    International Nuclear Information System (INIS)

    Borborema, Samanta Etel Treiger

    2010-01-01

    Leishmaniasis are a complex of parasitic diseases caused by intra macrophage protozoa of the genus Leishmania, and is fatal if left untreated. Pentavalent antimonials, though toxic and their mechanism of action being unclear, remain the first-line drugs for treatment. Effective therapy could be achieved by delivering antileishmanial drugs to these sites of infection. Liposomes are phospholipid vesicles that promote improvement in the efficacy and action of drugs in target cell. Liposomes are taken up by the cells of mononuclear phagocytic system (MPS). The purpose of this study was to develop a preparation of meglumine antimonate encapsulated in liposomes of phosphatidylserine and to study its pharmacokinetic in healthy mice to establish its metabolism and distribution. Quantitative analysis of antimony from liposomes demonstrated that Neutron Activation Analysis was the most sensitive technique with almost 100 % of accuracy. All liposome formulations presented a mean diameter size of 150 nm. The determination of IC 50 in infected macrophage showed that liposome formulations were between 10 - 63 fold more effective than the free drug, indicating higher selectivity index. By fluorescence microscopy, an increased uptake of fluorescent-liposomes was seen in infected macrophages during short times of incubation compared with non-infected macrophages. Biodistribution studies showed that meglumine antimonate irradiated encapsulated in liposomes of phosphatidylserine promoted a targeting of antimony for MPS tissues and maintained high doses in organs for a prolonged period. In conclusion, these data suggest that meglumine antimonate encapsulated in liposomes showed higher effectiveness than the non-liposomal drug against Leishmania infection. The development of liposome formulations should be a new alternative for the chemotherapy of infection diseases, especially Leishmaniasis, as they are used to sustain and target pharmaceuticals to the local of infection. (author)

  2. Technological and Theoretical Aspects for Testing Electroporation on Liposomes

    Directory of Open Access Journals (Sweden)

    Agnese Denzi

    2017-01-01

    Full Text Available Recently, the use of nanometer liposomes as nanocarriers in drug delivery systems mediated by nanoelectroporation has been proposed. This technique takes advantage of the possibility of simultaneously electroporating liposomes and cell membrane with 10-nanosecond pulsed electric fields (nsPEF facilitating the release of the drug from the liposomes and at the same time its uptake by the cells. In this paper the design and characterization of a 10 nsPEF exposure system is presented, for liposomes electroporation purposes. The design and the characterization of the applicator have been carried out choosing an electroporation cuvette with 1 mm gap between the electrodes. The structure efficiency has been evaluated at different experimental conditions by changing the solution conductivity from 0.25 to 1.6 S/m. With the aim to analyze the influence of device performances on the liposomes electroporation, microdosimetric simulations have been performed considering liposomes of 200 and 400 nm of dimension with different inner and outer conductivity (from 0.05 to 1.6 S/m in order to identify the voltage needed for their poration.

  3. Interaction of dipalmitoyl phosphatidylcholine (DPPC) liposomes and insulin

    Science.gov (United States)

    Mady, Mohsen M.; Elshemey, Wael M.

    2011-06-01

    Insulin, a peptide that has been used for decades in the treatment of diabetes, has well-defined properties and delivery requirements. Liposomes, which are lipid bilayer vesicles, have gained increasing attention as drug carriers which reduce the toxicity and increase the pharmacological activity of various drugs. The molecular interaction between (uncharged lipid) dipalmitoyl phosphatidylcholine (DPPC) liposomes and insulin has been characterized by using Fourier transform infrared spectroscopy (FTIR) and X-ray diffraction. The characteristic protein absorption band peaks, Amide I (at about 1660 cm-1) and Amide II band (at about 1546 cm-1) are potentially reduced in the liposome insulin complex. Wide-angle x-ray scattering measurements showed that the association of insulin with DPPC lipid of liposomes still maintains the characteristic DPPC diffraction peaks with almost no change in relative intensities or change in peak positions. The absence of any shift in protein peak positions after insulin being associated with DPPC liposomes indicates that insulin is successfully forming complex with DPPC liposomes with possibly no pronounced alterations in the structure of insulin molecule.

  4. An evaluation of anti-tumor effect and toxicity of PEGylated ursolic acid liposomes

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Qianqian; Zhao, Tingting; Liu, Yanping; Xing, Shanshan; Li, Lei; Gao, Dawei, E-mail: dwgao@ysu.edu.cn [Yanshan University, Applying Chemistry Key Lab of Hebei Province, Department of Bioengineer (China)

    2016-02-15

    Therapy of solid tumors mediated by nano-drug delivery has attracted considerable interest. In our previous study, ursolic acid (UA) was successfully encapsulated into PEGylated liposomes. The study aimed to evaluate the tumor inhibition effect and cytotoxicity of the PEGylated UA liposomes by U14 cervical carcinoma-bearing mice. The liposomes were spherical particles with mean particle diameters of 127.2 nm. The tumor inhibition rate of PEGylated UA liposomes was 53.60 % on U14 cervical carcinoma-bearing mice, which was greater than those of the UA solution (18.25 %) and traditional UA liposome groups (40.75 %). The tumor cells apoptosis rate of PEGylated UA liposomes was 25.81 %, which was significantly higher than that of the traditional UA liposomes (13.37 %). Moreover, the kidney and liver did not emerge the pathological changes in UA therapeutic mice by histopathological analysis, while there were significant differences on tumor tissues among three UA formulation groups. The PEGylated UA liposomes exhibited higher anti-tumor activity and lower cytotoxicity, and the main reason was that the coating PEG layer improved UA liposome properties, such as enhancing the stability of liposomes, promoting the effect of slow release, and prolonging the time of blood circulation. This may shed light on the development of PEGylated nano-vehicles.

  5. Binding and uptake of transferrin-bound liposomes targeted to transferrin receptors of endothelial cells.

    Science.gov (United States)

    Voinea, Manuela; Dragomir, Elena; Manduteanu, Ileana; Simionescu, Maya

    2002-07-01

    The use of liposomes as carriers for site-specific delivery is an attractive strategy, especially for the vascular endothelium that by position is an accessible target for drug and gene delivery via the blood circulation. The aim of this study was to detect whether liposomes coupled to transferrin (Tf)-bound and are taken up by aortic endothelial cells (EC) following the pathway of Tf interaction with transferrin receptors, reportedly expressed on their cell membrane. To this purpose, small unilamellar liposomes of different compositions, either classical (C) or sterically stabilized (SS), have been prepared, characterized and coupled with transferrin (Tf-liposomes). To assess the binding and uptake, cultured EC were incubated with fluorescently labelled Tf-liposomes for various times intervals (from 5 min to 24 h) at 4 and 37 degrees C, and further investigated by flow cytometry, fluorimetry and fluorescence microscopy. The results showed that: (i) binding of Tf-liposomes to EC was specific; (ii) the EC binding of SS-Tf-liposomes was lower than that of C-Tf-liposomes; and (iii) after 30 min of incubation, both C- and SS-Tf-liposomes appeared localized in the acidic compartments of the cells. Together, the data indicate that transferrin-bound liposomes are specifically taken up by EC by a receptor-mediated mechanism employing the pathway of surface-exposed Tf receptors.

  6. Superresolution and Fluorescence Dynamics Evidence Reveal That Intact Liposomes Do Not Cross the Human Skin Barrier.

    Directory of Open Access Journals (Sweden)

    Jes Dreier

    Full Text Available In this study we use the combination of super resolution optical microscopy and raster image correlation spectroscopy (RICS to study the mechanism of action of liposomes as transdermal drug delivery systems in human skin. Two different compositions of liposomes were applied to newly excised human skin, a POPC liposome and a more flexible liposome containing the surfactant sodium cholate. Stimulated emission depletion microscopy (STED images of intact skin and cryo-sections of skin treated with labeled liposomes were recorded displaying an optical resolution low enough to resolve the 100 nm liposomes in the skin. The images revealed that virtually none of the liposomes remained intact beneath the skin surface. RICS two color cross correlation diffusion measurements of double labeled liposomes confirmed these observations. Our results suggest that the liposomes do not act as carriers that transport their cargo directly through the skin barrier, but mainly burst and fuse with the outer lipid layers of the stratum corneum. It was also found that the flexible liposomes showed a greater delivery of the fluorophore into the stratum corneum, indicating that they functioned as chemical permeability enhancers.

  7. A generic 89Zr labeling method to quantify the in vivo pharmacokinetics of liposomal nanoparticles with positron emission tomography.

    Science.gov (United States)

    Li, Nan; Yu, Zilin; Pham, Truc Thuy; Blower, Philip J; Yan, Ran

    2017-01-01

    Liposomal nanoparticles are versatile drug delivery vehicles that show great promise in cancer therapy. In an effort to quantitatively measure their in vivo pharmacokinetics, we developed a highly efficient 89 Zr liposome-labeling method based on a rapid ligand exchange reaction between the membrane-permeable 89 Zr(8-hydroxyquinolinate) 4 complex and the hydrophilic liposomal cavity-encapsulated deferoxamine (DFO). This novel 89 Zr-labeling strategy allowed us to prepare radiolabeled forms of a folic acid (FA)-decorated active targeting 89 Zr-FA-DFO-liposome, a thermosensitive 89 Zr-DFO-liposome, and a renal avid 89 Zr-PEG-DFO-liposome at room temperature with near-quantitative isolated radiochemical yields of 98%±1% (n=6), 98%±2% (n=5), and 97%±1% (n=3), respectively. These 89 Zr-labeled liposomal nanoparticles showed remarkable stability in phosphate-buffered saline and serum at 37°C without leakage of radioactivity for 48 h. The uptake of 89 Zr-FA-DFO-liposome by the folate receptor-overexpressing KB cells was almost 15-fold higher than the 89 Zr-DFO-liposome in vitro. Positron emission tomography imaging and ex vivo biodistribution studies enabled us to observe the heterogeneous distribution of the 89 Zr-FA-DFO-liposome and 89 Zr-DFO-liposome in the KB tumor xenografts, the extensive kidney accumulation of the 89 Zr-FA-DFO-liposome and 89 Zr-PEG-DFO-liposome, and the different metabolic fate of the free and liposome-encapsulated 89 Zr-DFO. It also unveiled the poor resistance of all three liposomes against endothelial uptake resulting in their catabolism and high uptake of free 89 Zr in the skeleton. Thus, this technically simple 89 Zr-labeling method would find widespread use to guide the development and clinical applications of novel liposomal nanomedicines.

  8. Observation of inhomogeneity in the lipid composition of individual nanoscale liposomes

    DEFF Research Database (Denmark)

    Larsen, Jannik; Hatzakis, Nikos; Stamou, Dimitrios

    2011-01-01

    Liposomes, or vesicles, have been studied extensively both as models of biological membranes and as drug delivery vehicles. Typically it is assumed that all liposomes within the same preparation are identical. Here by employing pairs of fluorescently labeled lipids we demonstrated an up to 10-fold...... variation in the relative lipid composition of individual liposomes with diameters between 50 nm and 15 µm. Since the physicochemical properties of liposomes are directly linked to their composition, a direct consequence of compositional inhomogeneities is a polydispersity in the properties...

  9. Improved therapeutic benefits of doxorubicin by entrapment in anionic liposomes.

    Science.gov (United States)

    Forssen, E A; Tökés, Z A

    1983-02-01

    When used as drug carriers, anionic liposomes can reduce the chronic cardiac toxicity and increase the antileukemic activity of doxorubicin (DXN; Adriamycin). Continuing investigations, reported here, have now established the therapeutic benefits of this mode of drug delivery. Liposome encapsulation caused a prolonged elevation in DXN plasma levels and a 2-fold reduction in the exposure of cardiac tissue to the drug. This reduction, however, was not proportional to the substantial decrease in chronic heart toxicity observed in the earlier study. In vivo studies have demonstrated that the entrapped drug retains its full activity against Sarcoma 180 and significantly increases its action against Lewis lung carcinoma, as measured by reduced tumor volume. The increased antineoplastic activity was again not proportional to the increased association of drug with tumor tissue. The effect of liposome entrapment on the immune-suppressive activity of DXN was also examined to determine if factors other than the direct delivery of drug to tumor tissue might improve the therapeutic response. The suppression of the humoral immune response and peripheral leukocyte counts by free DXN was nearly abolished when the drug was administered in the liposome form. These experiments suggest that the improved therapeutic effect of encapsulation may be the outcome of three different mechanisms: (a) altered disposition into subcellular compartments, which reduces cardiotoxicity; (b) increased plasma drug exposure to tumor cells; and (c) significant reduction in the immune suppressive activity of DXN.

  10. Enzyme sensitive liposomes in chemotherapy and potentiation of immunotherapy

    DEFF Research Database (Denmark)

    Østrem, Ragnhild Garborg

    efficacy and induction of severe adverse effects. Interestingly, the pharmacokinetics and biodistribution of drugs can be substantially altered by encapsulation in liposomal drug delivery vehicles. The first chapter of this thesis gives a brief introduction to cancer followed by a discussion...

  11. Role of liposome in treatment of overactive bladder and interstitial cystitis

    Directory of Open Access Journals (Sweden)

    Shih-Ya Hung

    2015-03-01

    Full Text Available Intravesical (local therapy of agents has been effective in delaying or preventing recurrence of superficial bladder cancer. This route of drug administration has also shown tremendous promise in the treatment of interstitial cystitis/painful bladder syndrome (IC/PBS and overactive bladder without systemic side effects. Liposomes are lipid vesicles composed of phospholipid bilayers surrounding an aqueous core. They can incorporate drug molecules, both hydrophilic and hydrophobic, and show greater uptake into cells via endocytosis. Intravesical liposomes have therapeutic effects on IC/PBS patients, mainly because of their ability to form a protective lipid film on the urothelial surface. Recent studies have shown the sustained efficacy and safety of intravesical instillation of botulinum toxin formulated with liposomes (lipo-BoNT for the treatment of refractory overactive bladder This review considers the current status of intravesical liposomes or liposomal mediated drug delivery for the treatment of IC/PBS and overactive bladder.

  12. Encapsulation of a Lactic Acid Bacteria Cell-Free Extract in Liposomes and Use in Cheddar Cheese Ripening

    Science.gov (United States)

    Nongonierma, Alice Beebyaanda; Abrlova, Magdalena; Kilcawley, Kieran Noel

    2013-01-01

    A concentrated form of cell free extract (CFE) derived from attenuated Lactococcus lactis supsb. lactis 303 CFE was encapsulated in liposomes prepared from two different proliposome preparations (Prolipo Duo and Prolipo S) using microfluidization. Entrapment efficiencies of 19.7 % (Prolipo S) and 14.0 % (Prolipo Duo) were achieved and the preparations mixed in the ratio 4 (Prolipo Duo):1 (Prolipo S). Cheddar cheese trials were undertaken evaluating the performance of CFE entrapped in liposomes, empty liposomes and free CFE in comparison to a control cheese without any CFE or liposomes. Identical volumes of liposome and amounts of CFE were used in triplicate trials. The inclusion of liposomes did not adversely impact on cheese composition water activity, or microbiology. Entrapment of CFE in liposomes reduced loss of CFE to the whey. No significant differences were evident in proteolysis or expressed PepX activity during ripening in comparison to the cheeses containing free CFE, empty liposomes or the control, as the liposomes did not degrade during ripening. This result highlights the potential of liposomes to minimize losses of encapsulated enzymes into the whey during cheese production but also highlights the need to optimize the hydrophobicity, zeta potential, size and composition of the liposomes to maximize their use as vectors for enzyme addition in cheese to augment ripening. PMID:28239101

  13. Sustained release of hydrophilic drug from polyphosphazenes/poly(methyl methacrylate) based microspheres and their degradation study.

    Science.gov (United States)

    Akram, Muhammad; Yu, Haojie; Wang, Li; Khalid, Hamad; Abbasi, Nasir M; Zain-ul-Abdin; Chen, Yongsheng; Ren, Fujie; Saleem, Muhammad

    2016-01-01

    Drug delivery system is referred as an approach to deliver the therapeutic agents to the target site safely in order to achieve the maximum therapeutic effects. In this perspective, synthesis of three new polyphosphazenes and their blend fabrication system with poly(methyl methacrylate) is described and characterized with (1)H NMR, (31)P NMR, GPC and DSC. Furthermore, these novel blends were used to fabricate microspheres and evaluated for sustain release of hydrophilic drug (aspirin as model drug). Microspheres of the two blends showed excellent encapsulation efficacy (about 93%), controlled burst release (2.3% to 7.93%) and exhibited sustain in vitro drug release (13.44% to 32.77%) up to 218 h. At physiological conditions, the surface degradation of microspheres and diffusion process controlled the drug release sustainability. Furthermore, it was found that the degree of porosity was increased with degradation and the resulting porous network was responsible for water retention inside the microspheres. The percentage water retention was found to be interrelated with degradation time and percentage drug release. Copyright © 2015 Elsevier B.V. All rights reserved.

  14. On the interaction of fluorophore-encapsulating PEGylated lecithin liposomes with hamster and human platelets

    NARCIS (Netherlands)

    Heger, M.; Salles, I.I.; van Vuure, W.; Deckmyn, H.; Beek, J.F.

    2009-01-01

    Polyethylene glycol (PEG)-grafted phosphatidylcholine liposomes are used as drug carriers due to their low immunogenicity and prolonged circulation time. The interaction between sterically stabilized lecithin liposomes and platelets has not been investigated before, and deserves to be subjected to

  15. Protein-liposome conjugates using cysteine-lipids and native chemical ligation

    NARCIS (Netherlands)

    Reulen, Sanne W. A.; Brusselaars, Wilco W. T.; Langereis, Sander; Mulder, Willem J. M.; Breurken, Monica; Merkx, Maarten

    2007-01-01

    Liposomes have become popular drug delivery vehicles and have more recently also been applied as contrast agents for molecular imaging. Most current methods for functionalization of liposomes with targeting proteins rely on reactions of amine or thiol groups at the protein exterior, which generally

  16. Mathematical modeling of degradation for bulk-erosive polymers: applications in tissue engineering scaffolds and drug delivery systems.

    Science.gov (United States)

    Chen, Yuhang; Zhou, Shiwei; Li, Qing

    2011-03-01

    The degradation of polymeric biomaterials, which are widely exploited in tissue engineering and drug delivery systems, has drawn significant attention in recent years. This paper aims to develop a mathematical model that combines stochastic hydrolysis and mass transport to simulate the polymeric degradation and erosion process. The hydrolysis reaction is modeled in a discrete fashion by a fundamental stochastic process and an additional autocatalytic effect induced by the local carboxylic acid concentration in terms of the continuous diffusion equation. Illustrative examples of microparticles and tissue scaffolds demonstrate the applicability of the model. It is found that diffusive transport plays a critical role in determining the degradation pathway, whilst autocatalysis makes the degradation size dependent. The modeling results show good agreement with experimental data in the literature, in which the hydrolysis rate, polymer architecture and matrix size actually work together to determine the characteristics of the degradation and erosion processes of bulk-erosive polymer devices. The proposed degradation model exhibits great potential for the design optimization of drug carriers and tissue scaffolds. Copyright © 2010 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

  17. Photocatalytic and photoelectrocatalytic degradation of the drug omeprazole on nanocrystalline titania films in alkaline media: Effect of applied electrical bias on degradation and transformation products

    Energy Technology Data Exchange (ETDEWEB)

    Tantis, Iosif [Department of Chemical Engineering, University of Patras, Caratheodory 1, University Campus, GR-26504 Patras (Greece); Bousiakou, Leda [Department of Physics and Astronomy, King Saud University, Riyadh (Saudi Arabia); Department of Automation Engineering, Technological Educational Institute of Pireaus, GR-12244 Athens (Greece); Frontistis, Zacharias; Mantzavinos, Dionissios [Department of Chemical Engineering, University of Patras, Caratheodory 1, University Campus, GR-26504 Patras (Greece); Konstantinou, Ioannis; Antonopoulou, Maria [Department of Environmental and Natural Resources Management, University of Patras, GR-30100 Agrinio (Greece); Karikas, George-Albert [Department of Medical Laboratories Technology, Technological Educational Institute of Athens, 12210 Athens (Greece); Lianos, Panagiotis, E-mail: lianos@upatras.gr [Department of Chemical Engineering, University of Patras, Caratheodory 1, University Campus, GR-26504 Patras (Greece); FORTH/ICE-HT, P.O. Box 1414, GR-26504 Patras (Greece)

    2015-08-30

    Highlights: • Photocatalytic and photoelectrocatalytic degradation of the proton pump omeprazole. • Improvement of photocatalysis rate by applying a moderate forward bias. • Highlighting of the advantages of photoelectrocatalysis in a straightforward manner. • HPLC and HR-LC–MS analysis of transformation products. - Abstract: Photocatalytic and photoelectrocatalytic degradation of the drug omeprazole has been studied in the presence of nanocrystalline titania films supported on glass slides or transparent FTO electrodes in alkaline environment. Its photocatalytic degradation rate was assessed by its UV absorbance and by HPLC, while its transformation products were analyzed by HR-LC–MS. Based on UV absorbance, omeprazole can be photocatalytically degraded at an average rate of 6.7 × 10{sup −4} min{sup −1} under low intensity UVA irradiation of 1.5 mW cm{sup −2} in the presence of a nanoparticulate titania film. This corresponds to degradation of 1.4 mg of omeprazole per gram of the photocatalyst per liter of solution per hour. The photodegradation rate can be accelerated in a photoelectrochemical cell by applying a forward bias. In this case, the maximum rate reached under the present conditions was 11.6 × 10{sup −4} min{sup −1} by applying a forward bias of +0.6 V vs. Ag/AgCl. Four major transformation products were successfully identified and their profiles were followed by HR-LC–MS. The major degradation path includes the scission of the sulfoxide bridge into the corresponding pyridine and benzimidazole ring derivates and this is accompanied by the release of sulfate anions in the reaction mixture.

  18. Photocatalytic and photoelectrocatalytic degradation of the drug omeprazole on nanocrystalline titania films in alkaline media: Effect of applied electrical bias on degradation and transformation products

    International Nuclear Information System (INIS)

    Tantis, Iosif; Bousiakou, Leda; Frontistis, Zacharias; Mantzavinos, Dionissios; Konstantinou, Ioannis; Antonopoulou, Maria; Karikas, George-Albert; Lianos, Panagiotis

    2015-01-01

    Highlights: • Photocatalytic and photoelectrocatalytic degradation of the proton pump omeprazole. • Improvement of photocatalysis rate by applying a moderate forward bias. • Highlighting of the advantages of photoelectrocatalysis in a straightforward manner. • HPLC and HR-LC–MS analysis of transformation products. - Abstract: Photocatalytic and photoelectrocatalytic degradation of the drug omeprazole has been studied in the presence of nanocrystalline titania films supported on glass slides or transparent FTO electrodes in alkaline environment. Its photocatalytic degradation rate was assessed by its UV absorbance and by HPLC, while its transformation products were analyzed by HR-LC–MS. Based on UV absorbance, omeprazole can be photocatalytically degraded at an average rate of 6.7 × 10 −4 min −1 under low intensity UVA irradiation of 1.5 mW cm −2 in the presence of a nanoparticulate titania film. This corresponds to degradation of 1.4 mg of omeprazole per gram of the photocatalyst per liter of solution per hour. The photodegradation rate can be accelerated in a photoelectrochemical cell by applying a forward bias. In this case, the maximum rate reached under the present conditions was 11.6 × 10 −4 min −1 by applying a forward bias of +0.6 V vs. Ag/AgCl. Four major transformation products were successfully identified and their profiles were followed by HR-LC–MS. The major degradation path includes the scission of the sulfoxide bridge into the corresponding pyridine and benzimidazole ring derivates and this is accompanied by the release of sulfate anions in the reaction mixture

  19. Effect of cisplatin containing liposomes formulated by unsaturated chain-containing lipids on gynecological tumor cells.

    Science.gov (United States)

    Ringhieri, Paola; Pannunzio, Alessandra; Boccarelli, Angelina; Morelli, Giancarlo; Coluccia, Mauro; Tesauro, Diego

    2016-12-01

    Gynecological tumors are major therapeutic areas of platinum-based anticancer drugs. Here, we report the characterization and in vitro biological assays of cisplatin-containing Egg L-α-phosphatidylcholine liposomes with different amounts of cholesterol. Dynamic light scattering estimated sizes of all obtained liposomes in the 100 nm range that are suitable for in vivo use. On the basis of these data and of the drug loading values, the best formulation has been selected. Stability and drug release properties of platinum-containing liposomes have been verified in serum. The growth inhibitory effects of both liposomal and free drug in a panel of ovarian and breast human cancer cell lines, characterized by a different drug sensitivity, give comparable or better results with respect to free cisplatin drug.

  20. Vitamin C-driven epirubicin loading into liposomes

    Directory of Open Access Journals (Sweden)

    Lipka D

    2013-09-01

    Full Text Available Dominik Lipka,1 Jerzy Gubernator,1 Nina Filipczak,1 Sabine Barnert,2 Regine Süss,2 Mateusz Legut,1 Arkadiusz Kozubek1 1Department of Lipids and Liposomes, University of Wroclaw, Wroclaw, Poland; 2Department of Pharmaceutical Technology, Albert Ludwigs University, Freiburg, Germany Abstract: The encapsulation of anticancer drugs in a liposome structure protects the drug during circulation and increases drug accumulation in the cancer tissue and antitumor activity while decreasing drug toxicity. This paper presents a new method of active drug loading based on a vitamin C pH/ion gradient. Formulations were characterized in terms of the following parameters: optimal external pH, time and drug-to-lipid ratio for the purpose of remote loading, and in vitro stability. In the case of the selected drug, epirubicin (EPI, its coencapsulation increases its anticancer activity through a possibly synergistic effect previously reported by other groups for a free nonencapsulated drug/vitamin C cocktail. The method also has another advantage over other remote-loading methods: it allows faster drug release through liposome destabilization at the tumor site, thanks to the very good solubility of the EPI vitamin C salt, as seen on cryogenic transmission electron microscopy images. This influences the drug-release process and increases the anticancer activity of the liposome formulation. The liposomes are characterized as stable, with very good pharmacokinetics (half-life 18.6 hours. The antitumor activity toward MCF-7 and 4T-1 breast cancer cells was higher in the case of EPI loaded via our gradient than via an ammonium sulfate gradient. Finally, the EPI liposomal formulation and the free drug were tested using the murine 4T-1 breast cancer model. The antitumor activity of the encapsulated drug was confirmed (tumor-growth inhibition over 40% from day 16 until the end of the experiment, and the free drug was shown to have no anticancer activity at the tested dose

  1. Linear type azo-containing polyurethane as drug-coating material for colon-specific delivery: its properties, degradation behavior, and utilization for drug formulation.

    Science.gov (United States)

    Yamaoka, T; Makita, Y; Sasatani, H; Kim, S I; Kimura, Y

    2000-05-15

    A segmented polyurethane containing azo aromatic groups in the main chain was synthesized by reaction of isophorone diisocyanate with a mixture of m,m'-di(hydroxymethyl)azobenzene, poly(ethylene glycol) (Mn = 2000), and 1,2-propanediol. This polyurethane was soluble in various solvents and showed a good coating and film-forming property. A solution-cast film of this polyurethane was found to be degraded in a culture of intestinal flora with the azo group reduction to hydrazo groups, not to amino groups. The film degradation, therefore, was attributed to the decreased cohesive energy in the hydrazo polymer compared with that in the original azo polymer. Then, the drug pellets containing water-soluble drugs (ONO-3708 and OKY-046) were undercoated with (carboxymethyl)(ethyl)-cellulose and overcoated with the azo polymer in order to examine the drug-releasing profiles in the culture of intestinal flora. The releasing rate of drugs from these double-coating pellets was found to depend on the molecular weight and the composition of the polyurethane used as the overcoat as well as the hydrophilicity of the incorporated drugs. Since the polyurethane was glassy and its segment motion or conformational change is frozen, the structure change should be retarded even after partial reduction of the azo groups, resulting in the effective prevention of the drug leakage. These data suggested that the present azo-containing polyurethanes are applicable as coating material of drug pellets in a colon-targeting delivery system.

  2. The antimicrobial activity of liposomal lauric acids against Propionibacterium acnes.

    Science.gov (United States)

    Yang, Darren; Pornpattananangkul, Dissaya; Nakatsuji, Teruaki; Chan, Michael; Carson, Dennis; Huang, Chun-Ming; Zhang, Liangfang

    2009-10-01

    This study evaluated the antimicrobial activity of lauric acid (LA) and its liposomal derivatives against Propionibacterium acnes (P. acnes), the bacterium that promotes inflammatory acne. First, the antimicrobial study of three free fatty acids (lauric acid, palmitic acid and oleic acid) demonstrated that LA gives the strongest bactericidal activity against P. acnes. However, a setback of using LA as a potential treatment for inflammatory acne is its poor water solubility. Then the LA was incorporated into a liposome formulation to aid its delivery to P. acnes. It was demonstrated that the antimicrobial activity of LA was not only well maintained in its liposomal derivatives but also enhanced at low LA concentration. In addition, the antimicrobial activity of LA-loaded liposomes (LipoLA) mainly depended on the LA loading concentration per single liposomes. Further study found that the LipoLA could fuse with the membranes of P. acnes and release the carried LA directly into the bacterial membranes, thereby killing the bacteria effectively. Since LA is a natural compound that is the main acid in coconut oil and also resides in human breast milk and liposomes have been successfully and widely applied as a drug delivery vehicle in the clinic, the LipoLA developed in this work holds great potential of becoming an innate, safe and effective therapeutic medication for acne vulgaris and other P. acnes associated diseases.

  3. Development of risperidone liposomes for brain targeting through intranasal route.

    Science.gov (United States)

    Narayan, Reema; Singh, Mohan; Ranjan, OmPrakash; Nayak, Yogendra; Garg, Sanjay; Shavi, Gopal V; Nayak, Usha Y

    2016-10-15

    The present paper is aimed at development of functionalized risperidone liposomes for brain targeting through nasal route for effective therapeutic management of schizophrenia. The risperidone liposomes were prepared by thin film hydration method. Various parameters such as lipid ratio and lipid to drug ratio were optimized by using Design-Expert(®) Software to obtain high entrapment with minimum vesicle size. The surface of the optimized liposomes was modified by coating stearylamine and MPEG-DSPE for enhanced penetration to the brain. The formulations were evaluated for vesicle size, zeta potential, and entrapment efficiency. The morphology was studied by Transmission Electron Microscopy (TEM). In vivo efficacy was assessed by performing pharmacokinetic study in Wistar albino rats following intranasal administration of the formulations in comparison to intravenous bolus administration of pure drug. The mean vesicle size of optimized liposomes ranged from 90 to 100nm with low polydispersity index (risperidone into the brain than plasma. High brain targeting efficiency index for LP-16 indicating preferential transport of the drug to brain. The study demonstrated successful formulation of surface modified risperidone liposomes for nasal delivery with brain targeting potential. Copyright © 2016 Elsevier Inc. All rights reserved.

  4. Improved Efficacy of Liposomal Doxorubicin Treatment of Superficial Tumors by Thermotherapy.

    Science.gov (United States)

    Ping, Xiong; Angang, Ding; Xia, Gong; Yinzhu, Zhao; Jia, Li; Guofeng, Shen; Yazhu, Chen

    2016-04-01

    Our study aimed to investigate the effect of ultrasonic thermotherapy on the targeted delivery of liposomal doxorubicin to superficial tumors, local drug concentrations in tumor tissue, and the curative effect of chemotherapy. Twenty rabbits with VX2 tumors transplanted into the superficial muscle of the hind limb were randomly assigned to the following 4 treatment groups: (1) free doxorubicin, (2) liposomal doxorubicin hydrochloride, (3) liposomal doxorubicin hydrochloride plus 41 °C thermotherapy, and (4) liposomal doxorubicin hydrochloride plus 43 °C thermotherapy. Ultrasonic thermotherapy was delivered at 41 °C to 43 °C. Plasma, tumor, and organ/tissue homogenates were analyzed by high-pressure liquid chromatography to determine doxorubicin concentrations. The drug concentration in plasma and tumor tissue was significantly higher in the liposomal doxorubicin hydrochloride plus thermotherapy group than in the liposomal doxorubicin hydrochloride and free doxorubicin groups, but there were no significant differences among the 4 groups in the concentration in heart or kidney tissue. Combining thermotherapy with liposomal doxorubicin hydrochloride chemotherapy significantly increased the concentration of the drug in tumor tissue. The doxorubicin concentration was significantly higher in the liposomal doxorubicin hydrochloride plus 41 °C thermotherapy group. © The Author(s) 2015.

  5. Boronated liposome development and evaluation

    International Nuclear Information System (INIS)

    Hawthorne, M.F.

    1995-01-01

    The boronated liposome development and evaluation effort consists of two separate tasks. The first is the development of new boron compounds and the synthesis of known boron species with BNCT potential. These compounds are then encapsulated within liposomes for the second task, biodistribution testing in tumor-bearing mice, which examines the potential for the liposomes and their contents to concentrate boron in cancerous tissues

  6. Distinct solubility and cytotoxicity regimes of paclitaxel-loaded cationic liposomes at low and high drug content revealed by kinetic phase behavior and cancer cell viability studies.

    Science.gov (United States)

    Steffes, Victoria M; Murali, Meena M; Park, Yoonsang; Fletcher, Bretton J; Ewert, Kai K; Safinya, Cyrus R

    2017-11-01

    Lipid-based particles are used worldwide in clinical trials as carriers of hydrophobic paclitaxel (PTXL) for cancer chemotherapy, albeit with little improvement over the standard-of-care. Improving efficacy requires an understanding of intramembrane interactions between PTXL and lipids to enhance PTXL solubilization and suppress PTXL phase separation into crystals. We studied the solubility of PTXL in cationic liposomes (CLs) composed of positively charged 2,3-dioleyloxypropyltrimethylammonium chloride (DOTAP) and neutral 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC) as a function of PTXL membrane content and its relation to efficacy. Time-dependent kinetic phase diagrams were generated from observations of PTXL crystal formation by differential-interference-contrast microscopy. Furthermore, a new synchrotron small-angle x-ray scattering in situ methodology applied to DOTAP/DOPC/PTXL membranes condensed with DNA enabled us to detect the incorporation and time-dependent depletion of PTXL from membranes by measurements of variations in the membrane interlayer and DNA interaxial spacings. Our results revealed three regimes with distinct time scales for PTXL membrane solubility: hours for >3 mol% PTXL (low), days for ≈ 3 mol% PTXL (moderate), and ≥20 days for Cell viability experiments on human cancer cell lines using CL PTXL nanoparticles (NPs) in the distinct CL PTXL solubility regimes reveal an unexpected dependence of efficacy on PTXL content in NPs. Remarkably, formulations with lower PTXL content and thus higher stability show higher efficacy than those formulated at the membrane solubility limit of ≈3 mol% PTXL (which has been the focus of most previous physicochemical studies and clinical trials of PTXL-loaded CLs). Furthermore, an additional high-efficacy regime is seen on occasion for liposome compositions with PTXL ≥9 mol% applied to cells at short time scales (hours) after formation. At longer time scales (days), CL PTXL NPs with ≥3

  7. Novel salicylazo polymers for colon drug delivery: dissolving polymers by means of bacterial degradation.

    Science.gov (United States)

    Saphier, Sigal; Karton, Yishai

    2010-02-01

    Novel azo polymers were prepared for colonic drug delivery with a release mechanism based on structural features of azo derivatives designed for rapid bacterial degradation leading to soluble polymers. Two Salicylazo derivatives were prepared and conjugated as side chains at different ratios to methacrylic acid-methyl methacrylate copolymers (Eudragits). The azo compounds were designed to have a hydrophilic and a hydrophobic part on opposite sides of the azo bond. Upon reduction of the azo bonds, the hydrophobic part is released, resulting in a more water soluble polymer. The solubility of the polymeric films was studied relative to Eudragit S known to dissolve toward the end of the small intestine. One of the two azo derivatives prepared gave rise to polymers, which showed reduced solubility relative to Eudragit S. These polymers were subjected to reduction tests in anaerobic rat cecal suspensions by following the release of the hydrophobic product. Reduction rate was found to be rapid, comparable to that of Sulfasalazine. Studies on the azopolymeric films in anaerobic rat cecal suspensions, showed that these polymers dissolve faster than in sterilized suspensions. Solid dosage forms may be coated with these polymers to provide an efficient delivery system to the colon with a rapid release mechanism. (c) 2009 Wiley-Liss, Inc. and the American Pharmacists Association.

  8. Thermoresponsive pegylated bubble liposome nanovectors for efficient siRNA delivery via endosomal escape

    KAUST Repository

    Alamoudi, Kholod

    2017-05-19

    Improving the delivery of siRNA into cancer cells via bubble liposomes. Designing a thermoresponsive pegylated liposome through the introduction of ammonium bicarbonate salt into liposomes so as to control their endosomal escape for gene therapy.A sub-200 nm nanovector was fully characterized and examined for cellular uptake, cytotoxicity, endosomal escape and gene silencing.The siRNA-liposomes were internalized into cancer cells within 5 min and then released siRNAs in the cytosol prior to lysosomal degradation upon external temperature elevation. This was confirmed by confocal bioimaging and gene silencing reaching up to 90% and further demonstrated by the protein inhibition of both target genes.The thermoresponsiveness of ammonium bicarbonate containing liposomes enabled the rapid endosomal escape of the particles and resulted in an efficient gene silencing.

  9. Real-time potentiometric sensor; an innovative tool for monitoring hydrolysis of chemo/bio-degradable drugs in pharmaceutical sciences.

    Science.gov (United States)

    Ma'mun, Ahmed; Abd El-Rahman, Mohamed K; Abd El-Kawy, Mohamed

    2018-05-30

    In recent years, the whole field of ion-selective electrodes(ISEs) in pharmaceutical sciences has expanded far beyond its original roots. The diverse range of opportunities offered by ISEs was broadly used in a number of pharmaceutical applications, with topics presented ranging from bioanalysis of drugs and metabolites, to protein binding studies, green analytical chemistry, impurity profiling, and drug dissolution in biorelevant media. Inspired from these advances and with the aim of extending the functional capabilities of ISEs, the primary focus of the present paper is the utilization of ISE as a tool in personalized medicine. Given the opportunity to explore biological events in real-time (such as drug metabolism) could be central to personalized medicine. (ATR) is a chemo-degradable and bio-degradable pharmaceutically active drug. Laudanosine (LDS) is the major degradation product and metabolite of ATR and is potentially toxic and reported to possess epileptogenic activity which increases the risk of convulsive effects. In this work, ATR have been subjected to both chemical and biological hydrolysis, and the course of the reactions is monitored by means of a ISE. In this study, we have designed an efficient real-time tracking strategy which substantially resolve the challenges of the ATR chemical and biological degradation kinetics. By utilizing a potentiometric sensor, tracking of ATR chemical and biological degradation kinetics can be performed in a very short time with excellent accuracy. The LOD was calculated to be 0.23 μmol L -1 , the potential drift was investigated over a period of 60 min and the value was 0.25 mV h -1 . Real serum samples for measurement the rate of in vitro metabolism of ATR was performed. Furthermore, a full description of the fabricated screen-printed sensor was presented. Copyright © 2018 Elsevier B.V. All rights reserved.

  10. Influence of Physicochemical Properties and PEG Modification of Magnetic Liposomes on Their Interaction with Intestinal Epithelial Caco-2 Cells.

    Science.gov (United States)

    Kono, Yusuke; Jinzai, Hitomi; Kotera, Yota; Fujita, Takuya

    2017-12-01

    The present study aimed to investigate the effect of particle size (100, 500 nm), surface charge (cationic, neutral and anionic) and polyethylene glycol (PEG) modification of magnetic liposomes on their interaction with the human intestinal epithelial cell line, Caco-2. The cellular associated amount of all the magnetic liposomes was significantly increased by the presence of a magnetic field. The highest association and internalization into Caco-2 cells was observed with magnetic cationic liposomes. Moreover, small magnetic liposomes were more efficiently associated and taken up into the cells, than large ones. In contrast, PEG modification significantly attenuated the enhancing effect of the magnetic field on the cellular association of magnetic liposomes. We also found that magnetic cationic liposomes had the highest retention properties to Caco-2 cells. Moreover, the retention of large magnetic liposomes to the cells was much longer than that of small ones. In addition, magnetic cationic and neutral liposomes had relatively high stability in Caco-2 cells, whereas magnetic anionic liposomes rapidly degraded. These results indicate that the physicochemical properties and PEG modification of magnetic liposomes greatly influences their intestinal epithelial transport.

  11. Process optimization by use of design of experiments: Application for liposomalization of FK506.

    Science.gov (United States)

    Toyota, Hiroyasu; Asai, Tomohiro; Oku, Naoto

    2017-05-01

    Design of experiments (DoE) can accelerate the optimization of drug formulations, especially complexed formulas such as those of drugs, using delivery systems. Administration of FK506 encapsulated in liposomes (FK506 liposomes) is an effective approach to treat acute stroke in animal studies. To provide FK506 liposomes as a brain protective agent, it is necessary to manufacture these liposomes with good reproducibility. The objective of this study was to confirm the usefulness of DoE for the process-optimization study of FK506 liposomes. The Box-Behnken design was used to evaluate the effect of the process parameters on the properties of FK506 liposomes. The results of multiple regression analysis showed that there was interaction between the hydration temperature and the freeze-thaw cycle on both the particle size and encapsulation efficiency. An increase in the PBS hydration volume resulted in an increase in encapsulation efficiency. Process parameters had no effect on the ζ-potential. The multiple regression equation showed good predictability of the particle size and the encapsulation efficiency. These results indicated that manufacturing conditions must be taken into consideration to prepare liposomes with desirable properties. DoE would thus be promising approach to optimize the conditions for the manufacturing of liposomes. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Noninvasive control of the transport function of fluorescent coloured liposomal nanoparticles

    Science.gov (United States)

    Stelmashchuk, O.; Zherebtsov, E.; Zherebtsova, A.; Kuznetsova, E.; Vinokurov, A.; Dunaev, A.; Mamoshin, A.; Snimshchikova, I.; Borsukov, A.; Bykov, A.; Meglinski, I.

    2017-06-01

    The use of liposomal nanoparticles with an incorporated active substance is an innovative and promising approach to diagnostics and therapy. The application of liposomal nanoparticle-based drugs allows for targeted localized delivery, overcomes the natural barriers within the body effectively, and minimizes possible side effects. Liposomes are able to contain a variety of ingredients with practically no limitations to their chemical composition, chemical properties, or size of constituent molecules. This study evaluated the ability to control the passage of fluorescent dye-filled liposomes through the intestinal mucosal barrier after oral administration. For this purpose, the increase in transcutaneous registered fluorescence from tetrabromofluorescein dye was recorded and analysed. Fluorescence intensity was measured at the proximal end of the tail of an animal model after oral administration of the liposomes. Measurements were taken at the excitation wavelengths of 365 and 450 nm. The fluorescence intensity in the group treated with the fluorescent contrast agent encapsulated in liposomal particles increased 140% of the initial level, but in the group treated with pure contrast agent, the increase in detected fluorescence intensity did not exceed 110%. Mice that received empty liposomes as well as the control group did not demonstrate statistically significant changes in fluorescence intensity. A potential application of our results is an express laser optical method of monitoring the transport of orally administered liposomal particles. The results can be used to help create new optical tools for use in the development of new drugs and in high-throughput screening used during their testing.

  13. Influence of Quil A on liposomal membranes.

    Science.gov (United States)

    Paepenmüller, T; Müller-Goymann, C C

    2014-11-20

    Quil A is the purified saponin fraction extracted from the bark of Quillaja saponaria Molina. Besides its utilisation as a surfactant, it is commonly used in a pseudo-ternary system with cholesterol and phospholipid to form colloidal structures known as ISCOMs (immunostimulating complexes). Their appropriateness as immune stimulating drug carriers has been widely demonstrated, albeit the evaluation of physico-chemical properties of the ISCOM matrix still draws a heterogeneous picture. The aim of our study was to elucidate the effects of Quil A on liposomal phosphatidylcholine/cholesterol dispersions as this interaction is regarded as the major step for the formation of the ISCOM matrix. Transmission electron microscopy was applied to observe structural changes of liposomal dispersions upon addition of Quil A. A formation of ISCOM matrices readily out of the liposomal membrane was proven. The entrapment efficiency (EE) of Arsenazo III as well as differential thermal analysis (DSC) also demonstrated an interaction between the components above a critical concentration of Quil A. To further clarify the effects of interaction, Langmuir trough experiments of insoluble monolayers of both cholesterol and PC and their interaction with Quil A were performed. Measurable effects even below the critical concentration of Quil A (derived from DSC and EE) were shown. Cholesterol had a major impact on the formation and stabilisation of the ISCOM matrix. Copyright © 2014 Elsevier B.V. All rights reserved.

  14. Preparation and physicochemical characterization of topical chitosan-based film containing griseofulvin-loaded liposomes

    Directory of Open Access Journals (Sweden)

    Neda Bavarsad

    2016-01-01

    Full Text Available Griseofulvin is an antifungal drug and is available as oral dosage forms. Development of topical treatment could be advantageous for superficial fungal infections of the skin. In this study, films prepared from the incorporation of griseofulvin-loaded liposomes in chitosan film for topical drug delivery in superficial fungal infections. The properties of the films were characterized regarding mechanical properties, swelling, ability to transmit vapor, drug release, thermal behavior, and antifungal efficacy against Microsporum gypseum and Epidermophyton floccosum. The presence of liposomes led to decreased mechanical properties but lower swelling ratio. Higher amount of drug permeation and rate of flux were obtained by liposomes incorporated in films compared to liposomal formulations. Antifungal efficacy of formulations was confirmed against two species of dermatophytes in vitro. Therefore, two concepts of using vesicular carrier systems and biopolymeric films have been combined and this topical novel composite film has the potential for griseofulvin delivery to superficial fungal infections.

  15. A Mechanistic Model for Drug Release in PLGA Biodegradable Stent Coatings Coupled with Polymer Degradation and Erosion

    Science.gov (United States)

    Zhu, Xiaoxiang; Braatz, Richard D.

    2015-01-01

    Biodegradable poly(D,L-lactic-co-glycolic acid) (PLGA) coating for applications in drug-eluting stents has been receiving increasing interest as a result of its unique properties compared with biodurable polymers in delivering drug for reducing stents-related side effects. In this work, a mathematical model for describing the PLGA degradation and erosion and coupled drug release from PLGA stent coating is developed and validated. An analytical expression is derived for PLGA mass loss that predicts multiple experimental studies in the literature. An analytical model for the change of the number-average degree of polymerization (or molecular weight) is also derived. The drug transport model incorporates simultaneous drug diffusion through both the polymer solid and the liquid-filled pores in the coating, where an effective drug diffusivity model is derived taking into account factors including polymer molecular weight change, stent coating porosity change, and drug partitioning between solid and aqueous phases. The model is used to describe in vitro sirolimus release from PLGA stent coating, and demonstrates the significance of simultaneous sirolimus release via diffusion through both polymer solid and pore space. The proposed model is compared to existing drug transport models, and the impact of model parameters, limitations and possible extensions of the model are also discussed. PMID:25345656

  16. Preparation of liposomes containing zedoary turmeric oil using freeze-drying of liposomes via TBA/water cosolvent systems and evaluation of the bioavailability of the oil.

    Science.gov (United States)

    Yang, Zhiwen; Yu, Songlin; Fu, Dahua

    2010-02-01

    The purpose of this study was to enhance the absorption of zedoary turmeric oil (ZTO) in vivo and develop new formulations of a water-insoluble oily drug. This study described a method for preparing ZTO liposomes, which involved freeze-drying (FD) of liposomes with TBA/water cosolvent systems. The TBA/water cosolvent systems were used to investigate a feasible method of liposomes manufacture; the two factors, sugar/lipid mass ratio and TBA content (concentration), of the preparation process were evaluated in this study. The results showed that the addition of TBA content could significantly enhance the sublimation of ice resulting in short FD cycles time, and reduce the entrapment efficiency of liposomes. In addition, the residual TBA solvents levels were determined to be less than 0.37% under all optimum formulations and processing conditions. Several physical properties of liposomes were examined by H-600 transmission electron microscope (TEM) and zetamaster analyser system. The results revealed that the liposomes were smooth and spherical with an average particle size of 457 +/- 7.8 nm and the zeta potential was more than 3.65 Mv. The bioavailability of the liposomes was evaluated in rabbits, compared with the conventional self-emulsifying formulation for oral administration. Compared with the conventional self-emulsifying formulation, the plasma concentration-time profiles with improved sustained-release characteristics were achieved after oral administration of the liposomes with a bioavailability of 257.7% (a good strategy for improving the bioavailability of an oily drug). In conclusion, the present experimental findings clearly demonstrated the usefulness of ZTO liposome vesicles in improving therapeutic efficacy by enhancing oral bioavailability. Our study offered an alternative method for designing sustained-release preparations of oily drugs.

  17. Mechanism of Enhanced Activity of Liposome-Entrapped Aminoglycosides against Resistant Strains of Pseudomonas aeruginosa

    Science.gov (United States)

    Mugabe, Clement; Halwani, Majed; Azghani, Ali O.; Lafrenie, Robert M.; Omri, Abdelwahab

    2006-01-01

    Pseudomonas aeruginosa is inherently resistant to most conventional antibiotics. The mechanism of resistance of this bacterium is mainly associated with the low permeability of its outer membrane to these agents. We sought to assess the bactericidal efficacy of liposome-entrapped aminoglycosides against resistant clinical strains of P. aeruginosa and to define the mechanism of liposome-bacterium interactions. Aminoglycosides were incorporated into liposomes, and the bactericidal efficacies of both free and liposomal drugs were evaluated. To define the mechanism of liposome-bacterium interactions, transmission electron microscopy (TEM), flow cytometry, lipid mixing assay, and immunocytochemistry were employed. Encapsulation of aminoglycosides into liposomes significantly increased their antibacterial activity against the resistant strains used in this study (MICs of ≥32 versus ≤8 μg/ml). TEM observations showed that liposomes interact intimately with the outer membrane of P. aeruginosa, leading to the membrane deformation. The flow cytometry and lipid mixing assays confirmed liposome-bacterial membrane fusion, which increased as a function of incubation time. The maximum fusion rate was 54.3% ± 1.5% for an antibiotic-sensitive strain of P. aeruginosa and 57.8% ± 1.9% for a drug-resistant strain. The fusion between liposomes and P. aeruginosa significantly enhanced the antibiotics' penetration into the bacterial cells (3.2 ± 2.3 versus 24.2 ± 6.2 gold particles/bacterium, P ≤ 0.001). Our data suggest that liposome-entrapped antibiotics could successfully resolve infections caused by antibiotic-resistant P. aeruginosa through an enhanced mechanism of drug entry into the bacterial cells. PMID:16723560

  18. Effective mucoadhesive liposomal delivery system for risedronate: preparation and in vitro/in vivo characterization

    Directory of Open Access Journals (Sweden)

    Jung IW

    2014-05-01

    Full Text Available Il-Woo Jung, Hyo-Kyung HanCollege of Pharmacy, Dongguk University-Seoul, Ilsan-Donggu, Goyang, Republic of KoreaAbstract: In this work, we aimed to develop chitosan-coated mucoadhesive liposomes ­containing risedronate to improve intestinal drug absorption. Liposomes containing risedronate were prepared with 1,2-distearoryl-sn-glycero-3-phosphocholine and distearoryl-sn-glycero-3-[phospho-rac-(1-glycerol] using the freeze-drying method, with subsequent coating of the anionic surfaces of the liposomes with chitosan. The in vitro characteristics of the chitosan-coated liposomes were investigated, including their stability, mucoadhesiveness, and Caco-2 cell permeability. This formulation was stable in simulated gastric and intestinal fluids, with the percentage of drug remaining in the liposomes being more than 90% after 24 hours of incubation. Chitosan-coated liposomes also showed strong mucoadhesive properties, implying potential electrostatic interaction with the mucous layer in the gastrointestinal tract. Compared with the untreated drug, chitosan-coated liposomes significantly enhanced the cellular uptake of risedronate, resulting in an approximately 2.1–2.6-fold increase in Caco-2 cells. Further, the chitosan-coated liposomes increased the oral exposure of risedronate by three-fold in rats. Taken together, the results of this study suggest that chitosan-coated liposomes containing risedronate should be effective for improving the bioavailability of risedronate.Keywords: cellular uptake, bioavailability, mucoadhesiveness, liposome, chitosan

  19. On the use of liposome controls in studies investigating the clinical potential of extracellular vesicle-based drug delivery systems - A commentary

    DEFF Research Database (Denmark)

    Johnsen, Kasper Bendix; Gudbergsson, Johann Mar; Duroux, Meg

    2018-01-01

    The field of extracellular vesicle (EV)-based drug delivery systems has evolved significantly through the recent years, and numerous studies suggest that these endogenous nanoparticles can function as efficient drug delivery vehicles in a variety of diseases. Many characteristics of these EV...

  20. Long-term stability study of L-adrenaline injections: Kinetics of sulfonation and racemization pathways of drug degradation.

    Science.gov (United States)

    Stepensky, David; Chorny, Michael; Dabour, Ziad; Schumacher, Ilana

    2004-04-01

    Injectable formulations of L-adrenaline are commonly used in emergency medicine. Despite numerous studies, the comparative contribution and kinetics of the L-adrenaline inactivation pathways during storage have not been conclusively evaluated. We examined the kinetics of L-adrenaline degradation in a prospective study and determined the extent of drug inactivation by different pathways during and beyond the stipulated product shelf-life in 42 batches of adrenaline ampules stored under controlled conditions. The content of L-adrenaline and degradation products was determined with a chiral high-performance liquid chromatography (HPLC) assay, and the degradation products were identified by mass spectrometric detection as D-adrenaline and L- and D-adrenaline sulfonate. The kinetics of the content change with storage was analyzed simultaneously for L-adrenaline and the degradation products using kinetic modeling. The lower acceptable level of adrenaline content in the formulation stated by US Pharmacopoeia (90% as a sum of L- and D-isomers) was attained after 2.0 years of storage, at which time the content of the therapeutically active L-isomer amounted to as low as 85%. The modeling revealed significant differences in the degradation kinetics in the formulations produced before and after 1997, whose cause remained unidentified in this study. Copyright 2004 Wiley-Liss, Inc. and the American Pharmacists Association.

  1. Activatable photodynamic destruction of cancer cells by NIR dye/photosensitizer loaded liposomes.

    Science.gov (United States)

    Yuan, Ahu; Tang, Xiaolei; Qiu, Xuefeng; Jiang, Ke; Wu, Jinhui; Hu, Yiqiao

    2015-02-25

    The phototoxicity of Chlorin e6 (Ce6) for photodynamic therapy (PDT) was found to be effectively suppressed by indocyanine green (ICG), a near infrared (NIR) dye. Upon NIR laser irradiation at 808 nm, ICG in the liposomes containing ICG and Ce6 could be degraded, while the phototoxicity of Ce6 could be recovered. In addition, we demonstrate that this newly developed liposomal component can be successfully used for activatable PDT to destroy cancer cells in vitro.

  2. In vivo toxicity of cationic micelles and liposomes

    DEFF Research Database (Denmark)

    Knudsen, Kristina Bram; Northeved, Helle; Ek, Pramod Kumar

    2015-01-01

    This study investigated toxicity of nanocarriers comprised of cationic polymer and lipid components often used in gene and drug delivery, formulated as cationic micelles and liposomes. Rats were injected intravenously with 10, 25 or 100 mg/kg and sacrificed after 24 or 48 h, or 24 h after the las...

  3. Effect of Cytotoxicity of Pegylated Liposomal Recombinant Human ...

    African Journals Online (AJOL)

    Purpose: To evaluate the cytotoxic effect of pegylated liposomal Recombinant Human Erythropoietin- alfa (rHuEPO) nanoparticles synthesized by reverse phase evaporation technique on SH-SY5Y cell line. Methods: To prepare the nanoparticles of the drug, rHuEPO, PEG3000, cholesterol and phosphatidylcholine were ...

  4. Propulsion of liposomes using bacterial motors

    International Nuclear Information System (INIS)

    Zhang Zhenhai; Li Kejie; Li Zhifei; Yu Wei; Xie Zhihong; Shi Zhiguo

    2013-01-01

    Here we describe the utilization of flagellated bacteria as actuators to propel spherical liposomes by attaching bacteria to the liposome surface. Bacteria were stably attached to liposomes using a cross-linking antibody. The effect of the number of attached bacteria on propulsion speed was experimentally determined. The effects of bacterial propulsion on the bacteria–antibody–liposome complex were stochastic. We demonstrated that liposomal mobility increased when bacteria were attached, and the propulsion speed correlated with the number of bacteria. (paper)

  5. Comparison of conventional chemotherapy, stealth liposomes and temperature-sensitive liposomes in a mathematical model.

    Science.gov (United States)

    Gasselhuber, Astrid; Dreher, Matthew R; Rattay, Frank; Wood, Bradford J; Haemmerich, Dieter

    2012-01-01

    Various liposomal drug carriers have been developed to overcome short plasma half-life and toxicity related side effects of chemotherapeutic agents. We developed a mathematical model to compare different liposome formulations of doxorubicin (DOX): conventional chemotherapy (Free-DOX), Stealth liposomes (Stealth-DOX), temperature sensitive liposomes (TSL) with intra-vascular triggered release (TSL-i), and TSL with extra-vascular triggered release (TSL-e). All formulations were administered as bolus at a dose of 9 mg/kg. For TSL, we assumed locally triggered release due to hyperthermia for 30 min. Drug concentrations were determined in systemic plasma, aggregate body tissue, cardiac tissue, tumor plasma, tumor interstitial space, and tumor cells. All compartments were assumed perfectly mixed, and represented by ordinary differential equations. Contribution of liposomal extravasation was negligible in the case of TSL-i, but was the major delivery mechanism for Stealth-DOX and for TSL-e. The dominant delivery mechanism for TSL-i was release within the tumor plasma compartment with subsequent tissue- and cell uptake of released DOX. Maximum intracellular tumor drug concentrations for Free-DOX, Stealth-DOX, TSL-i, and TSL-e were 3.4, 0.4, 100.6, and 15.9 µg/g, respectively. TSL-i and TSL-e allowed for high local tumor drug concentrations with reduced systemic exposure compared to Free-DOX. While Stealth-DOX resulted in high tumor tissue concentrations compared to Free-DOX, only a small fraction was bioavailable, resulting in little cellular uptake. Consistent with clinical data, Stealth-DOX resulted in similar tumor intracellular concentrations as Free-DOX, but with reduced systemic exposure. Optimal release time constants for maximum cellular uptake for Stealth-DOX, TSL-e, and TSL-i were 45 min, 11 min, and constants were shorter for MDR cells, with ∼4 min for Stealth-DOX and for TSL-e. Tissue concentrations correlated well quantitatively with a prior in-vivo study

  6. Comparison of conventional chemotherapy, stealth liposomes and temperature-sensitive liposomes in a mathematical model.

    Directory of Open Access Journals (Sweden)

    Astrid Gasselhuber

    Full Text Available Various liposomal drug carriers have been developed to overcome short plasma half-life and toxicity related side effects of chemotherapeutic agents. We developed a mathematical model to compare different liposome formulations of doxorubicin (DOX: conventional chemotherapy (Free-DOX, Stealth liposomes (Stealth-DOX, temperature sensitive liposomes (TSL with intra-vascular triggered release (TSL-i, and TSL with extra-vascular triggered release (TSL-e. All formulations were administered as bolus at a dose of 9 mg/kg. For TSL, we assumed locally triggered release due to hyperthermia for 30 min. Drug concentrations were determined in systemic plasma, aggregate body tissue, cardiac tissue, tumor plasma, tumor interstitial space, and tumor cells. All compartments were assumed perfectly mixed, and represented by ordinary differential equations. Contribution of liposomal extravasation was negligible in the case of TSL-i, but was the major delivery mechanism for Stealth-DOX and for TSL-e. The dominant delivery mechanism for TSL-i was release within the tumor plasma compartment with subsequent tissue- and cell uptake of released DOX. Maximum intracellular tumor drug concentrations for Free-DOX, Stealth-DOX, TSL-i, and TSL-e were 3.4, 0.4, 100.6, and 15.9 µg/g, respectively. TSL-i and TSL-e allowed for high local tumor drug concentrations with reduced systemic exposure compared to Free-DOX. While Stealth-DOX resulted in high tumor tissue concentrations compared to Free-DOX, only a small fraction was bioavailable, resulting in little cellular uptake. Consistent with clinical data, Stealth-DOX resulted in similar tumor intracellular concentrations as Free-DOX, but with reduced systemic exposure. Optimal release time constants for maximum cellular uptake for Stealth-DOX, TSL-e, and TSL-i were 45 min, 11 min, and <3 s, respectively. Optimal release time constants were shorter for MDR cells, with ∼4 min for Stealth-DOX and for TSL-e. Tissue concentrations

  7. Trifluralin liposomal formulations active against Leishmania donovani infections.

    Science.gov (United States)

    Carvalheiro, Manuela; Jorge, João; Eleutério, Carla; Pinhal, Ana F; Sousa, Ana C; Morais, José G; Cruz, M Eugénia M

    2009-02-01

    The purpose of this study was to increase the therapeutic index of the antiparasitic drug, trifluralin (TFL), to allow its parenteral administration without the need of toxic solvents. This was achieved by incorporating TFL in liposomes with high loading capacity. These formulations were stable in freeze-dried form during at least one year and in frozen form during at least three months. Therapeutic activity, assessed on a visceral model of infection, showed that TFL liposomes reduced the number of parasites by up to one third or one half as compared to negative control and to free TFL, respectively.

  8. Thiol-Triggered Release of Intraliposomal Content from Liposomes Made of Extremophile-Inspired Tetraether Lipids.

    Science.gov (United States)

    Koyanagi, Takaoki; Cifelli, Jessica L; Leriche, Geoffray; Onofrei, David; Holland, Gregory P; Yang, Jerry

    2017-08-16

    Liposomal drug-delivery systems have been used for delivery of drugs to targeted tissues while reducing unwanted side effects. DOXIL, for instance, is a liposomal formulation of the anticancer agent doxorubicin (DOX) that has been used to address problems associated with nonspecific toxicity of free DOX. However, while this liposomal formulation allows for a more-stable circulation of doxorubicin in the body compared to free drug, the efficacy for cancer therapy is reduced in comparison with systemic injections of free drug. A robust liposomal system that can be triggered to release DOX in cancer cells could mitigate problems associated with reduced drug efficacy. In this work, we present a serum-stable, cholesterol-integrated tetraether lipid comprising of a cleavable disulfide bond, {GcGT(S-S)PC-CH}, that is designed to respond to the reducing environment of the cell to trigger the release intraliposomal content upon cellular uptake by cancer cells. A cell viability assay revealed that DOX- loaded liposomes composed of pure GcGT(S-S)PC-CH lipids were ∼20 times more toxic than DOXIL, with an IC 50 value comparable to that of free DOX. The low inherent membrane-leakage properties of GcGT(S-S)PC-CH liposomes in the presence of serum, combined with an intracellular triggered release of encapsulated cargo, represents a promising approach for developing improved drug-delivery formulations for the treatment of cancer and possibly other diseases.

  9. Towards clinical translation of ligand-functionalized liposomes in targeted cancer therapy: Challenges and opportunities.

    Science.gov (United States)

    Belfiore, Lisa; Saunders, Darren N; Ranson, Marie; Thurecht, Kristofer J; Storm, Gert; Vine, Kara L

    2018-03-01

    The development of therapeutic resistance to targeted anticancer therapies remains a significant clinical problem, with intratumoral heterogeneity playing a key role. In this context, improving the therapeutic outcome through simultaneous targeting of multiple tumor cell subtypes within a heterogeneous tumor is a promising approach. Liposomes have emerged as useful drug carriers that can reduce systemic toxicity and increase drug delivery to the tumor site. While clinically used liposomal drug formulations show marked therapeutic advantages over free drug formulations, ligand-functionalized liposomes that can target multiple tumor cell subtypes may further improve the therapeutic efficacy by facilitating drug delivery to a broader population of tumor cells making up the heterogeneous tumor tissue. Ligand-directed liposomes enable the so-called active targeting of cell receptors via surface-attached ligands that direct drug uptake into tumor cells or tumor-associated stromal cells, and so can increase the selectivity of drug delivery. Despite promising preclinical results demonstrating improved targeting and anti-tumor effects of ligand-directed liposomes, there has been limited translation of this approach to the clinic. Key challenges for translation include the lack of established methods to scale up production and comprehensively characterize ligand-functionalized liposome formulations, as well as the inadequate recapitulation of in vivo tumors in the preclinical models currently used to evaluate their performance. Herein, we discuss the utility of recent ligand-directed liposome approaches, with a focus on dual-ligand liposomes, for the treatment of solid tumors and examine the drawbacks limiting their progression to clinical adoption. Copyright © 2018 Elsevier B.V. All rights reserved.

  10. Biological activity of liposomal vanillin.

    Science.gov (United States)

    Castan, Leniher; Del Toro, Grisel; Fernández, Adolfo A; González, Manuel; Ortíz, Emilia; Lobo, Daliana

    2013-06-01

    This article presents a study of vanillin encapsulation inside multilamellar liposomes, with emphasis on the evaluation of antioxidant activity, the hemolytic effect, and the antisickling properties of these products. Egg phosphatidylcholine-cholesterol and egg phosphatidylcholine-cholesterol-1-O-decylglycerol liposomes were prepared by mechanical dispersion, all with vanillin included. Vesicles were characterized by determination of encapsulation efficiency and vanillin retention capacity. Antioxidant activity was determined by the 2,2-diphenyl-1-picrylhydrazyl (DPPH) method. The hemolytic effect of liposomes was also evaluated by spectrophotometry, as well as the antisickling activity by the Huck test using optical microscopy. Results showed that the lipid composition of liposomes did not significantly affect the encapsulation efficiency. Stable vesicles were obtained with a high retention percentage of vanillin. Liposomes exhibited a high capture of the DPPH radical compared to free vanillin and 1-O-decylglycerol (C10) in solution. Vesicles caused no significant hemolisys in normal erythrocytes, nor in those coming from patients with sickle cell anemia. Vanillin encapsulated in liposomes retained its antisickling activity, with a greater effect for C10-containing vesicles. Our results show that vanillin encapsulation in liposomes is a way to enhance the pharmacologic properties of this molecule using a suitable vehicle.

  11. Liposomal bupivacaine: a review of a new bupivacaine formulation

    Directory of Open Access Journals (Sweden)

    Chahar P

    2012-08-01

    Full Text Available Praveen Chahar, Kenneth C Cummings IIIAnesthesiology Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USAAbstract: Many attempts have been made to increase the duration of local anesthetic action. One avenue of investigation has focused on encapsulating local anesthetics within carrier molecules to increase their residence time at the site of action. This article aims to review the literature surrounding the recently approved formulation of bupivacaine, which consists of bupivacaine loaded in multivesicular liposomes. This preparation increases the duration of local anesthetic action by slow release from the liposome and delays the peak plasma concentration when compared to plain bupivacaine administration. Liposomal bupivacaine has been approved by the US Food and Drug Administration for local infiltration for pain relief after bunionectomy and hemorrhoidectomy. Studies have shown it to be an effective tool for postoperative pain relief with opioid sparing effects and it has also been found to have an acceptable adverse effect profile. Its kinetics are favorable even in patients with moderate hepatic impairment, and it has been found not to delay wound healing after orthopedic surgery. More studies are needed to establish its safety and efficacy for use via intrathecal, epidural, or perineural routes. In conclusion, liposomal bupivacaine is effective for treating postoperative pain when used via local infiltration when compared to placebo with a prolonged duration of action, predictable kinetics, and an acceptable side effect profile. However, more adequately powered trials are needed to establish its superiority over plain bupivacaine.Keywords: liposomal bupivacaine, postoperative pain, pharmacokinetics, pharmacodynamics, efficacy, safety

  12. Radiolabeling and Quantitative In Vivo SPECT/CT Imaging Study of Liposomes Using the Novel Iminothiolane-99mTc-Tricarbonyl Complex

    Directory of Open Access Journals (Sweden)

    Zoltán Varga

    2017-01-01

    Full Text Available The in vivo biodistribution of liposomal formulations greatly influences the pharmacokinetics of these novel drugs; therefore the radioisotope labeling of liposomes and the use of nuclear imaging methods for in vivo studies are of great interest. In the present work, a new procedure for the surface labeling of liposomes is presented using the novel 99mTc-tricarbonyl complex. Liposomes mimicking the composition of two FDA approved liposomal drugs were used. In the first step of the labeling, thiol-groups were formed on the surface of the liposomes using Traut’s reagent, which were subsequently used to bind 99mTc-tricarbonyl complex to the liposomal surface. The labeling efficiency determined by size exclusion chromatography was 95%, and the stability of the labeled liposomes in bovine serum was found to be 94% over 2 hours. The obtained specific activity was 50 MBq per 1 μmol lipid which falls among the highest values reported for 99mTc labeling of liposomes. Quantitative in vivo SPECT/CT biodistribution studies revealed distinct differences between the labeled liposomes and the free 99mTc-tricarbonyl, which indicates the in vivo stability of the labeling. As the studied liposomes were non-PEGylated, fast clearance from the blood vessels and high uptake in the liver and spleen were observed.

  13. The modulation of physicochemical characterization of innovative liposomal platforms: the role of the grafted thermoresponsive polymers.

    Science.gov (United States)

    Chountoulesi, Maria; Kyrili, Aimilia; Pippa, Natassa; Meristoudi, Anastasia; Pispas, Stergios; Demetzos, Costas

    2017-05-01

    This study is focused on chimeric advanced drug delivery systems and specifically on thermosensitive liposomes, combining lipids and thermoresponsive polymers. In this investigation, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) chimeric liposomal systems were prepared, incorporating the homopolymer C 12 H 25 -poly(N-isopropylacrylamide)-COOH (C 12 H 25 -PNIPAM-COOH) and the block copolymer poly(n-butylacrylate-b-N-isoropylacrylamide) (PnBA-PNIPAM), at six different molar ratios. Both of these polymers contain the thermoresponsive PNIPAM block, which exhibits lower critical solution temperature (LCST) at 32 °C in aqueous solutions, changing its nature from hydrophilic to hydrophobic above LCST. During the preparation of liposomes, the dispersions were observed visually, while after the preparation we studied the alterations of the physicochemical characteristics, by measuring the size, size distribution and ζ-potential of prepared liposomes. The presence of polymer, either C 12 H 25 -PNIPAM-COOH or PnBA-PNIPAM, resulted in liposomes exhibiting different physicochemical characteristics in comparison to conventional DPPC liposomes. At the highest percentage of the polymeric guest, chimeric liposomes were found to retain their size during the stability studies. The incorporation of the appropriate amount of these novel thermoresponsive polymers yields liposomal stabilization and imparts thermoresponsiveness, due to the functional PNIPAM block.

  14. Highly penetrative liposome nanomedicine generated by a biomimetic strategy for enhanced cancer chemotherapy.

    Science.gov (United States)

    Jia, Yali; Sheng, Zonghai; Hu, Dehong; Yan, Fei; Zhu, Mingting; Gao, Guanhui; Wang, Pan; Liu, Xin; Wang, Xiaobing; Zheng, Hairong

    2018-04-25

    Liposome nanomedicine has been successfully applied for cancer chemotherapy in patients. However, in general, the therapeutic efficacy is confined by its limited accumulation and penetration in solid tumors. Here, we established a biomimetic strategy for the preparation of highly penetrative liposome nanomedicine for enhanced chemotherapeutic efficacy. By applying this unique type of nanomedicine, membrane proteins on the cancer cells are used as highly penetrative targeting ligands. Biomimetic liposomes are highly stable, exhibiting a superior in vitro homologous targeting ability, and a 2.25-fold deeper penetration in 3D tumor spheroids when compared to conventional liposome nanomedicine. The fluorescence/photoacoustic dual-modal imaging approach demonstrated enhanced tumor accumulation and improved tumor penetration of the biomimetic liposome in C6 glioma tumor-bearing nude mice. Following the intravenous administration of biomimetic liposome nanomedicine, the tumor inhibition rate reached up to 93.3%, which was significantly higher when compared to that of conventional liposome nanomedicine (69.3%). Moreover, histopathological analyses demonstrated that biomimetic liposome nanomedicine has limited side effects. Therefore, these results suggested that a cancer cell membrane-based biomimetic strategy may provide a breakthrough approach for enhancing drug penetration and improving treatment efficacy, holding a great promise for further clinical studies.

  15. Degradation of the drug sodium diclofenac by Trametes versicolor pellets and identification of some intermediates by NMR

    International Nuclear Information System (INIS)

    Marco-Urrea, Ernest; Perez-Trujillo, Miriam; Cruz-Morato, Carles; Caminal, Gloria; Vicent, Teresa

    2010-01-01

    Degradation of diclofenac sodium, a nonsteroidal anti-inflammatory drug widely found in the aquatic environment, was assessed using the white-rot fungus Trametes versicolor. Almost complete diclofenac removal (≥94%) occurred the first hour with T. versicolor pellets when the drug was added at relatively high (10 mg L -1 ) and environmentally relevant low (45 μg L -1 ) concentrations in a defined liquid medium. In vivo and in vitro experiments using the cytochrome P450 inhibitor 1-aminobenzotriazole and purified laccase, respectively, suggested at least two different mechanisms employed by T. versicolor to initiate diclofenac degradation. Two hydroxylated metabolites, 4'-hydroxydiclofenac and 5-hydroxydiclofenac, were structurally elucidated by nuclear magnetic resonance as degradation intermediates in fungal cultures spiked with diclofenac. Both parent compound and intermediates disappeared after 24 h leading to a decrease in ecotoxicity calculated by the Microtox test. Laccase-catalyzed transformation of diclofenac led to the formation of 4-(2,6-dichlorophenylamino)-1,3-benzenedimethanol, which was not detected in in vivo experiments probably due to the low laccase activity levels observed through the first hours of incubation.

  16. Degradation of the drug sodium diclofenac by Trametes versicolor pellets and identification of some intermediates by NMR

    Energy Technology Data Exchange (ETDEWEB)

    Marco-Urrea, Ernest [Departament d' Enginyeria Quimica and Institut de Ciencia i Tecnologia Ambiental, Escola d' Enginyeria (Estonia), Universitat Autonoma de Barcelona (UAB), 08193 Bellaterra (Spain); Perez-Trujillo, Miriam [Servei de Ressonancia Magnetica Nuclear, UAB, 08193 Bellaterra (Spain); Cruz-Morato, Carles [Departament d' Enginyeria Quimica and Institut de Ciencia i Tecnologia Ambiental, Escola d' Enginyeria (Estonia), Universitat Autonoma de Barcelona (UAB), 08193 Bellaterra (Spain); Caminal, Gloria, E-mail: gloria.caminal@uab.es [Unitat de Biocatalisis Aplicada associada al IQAC (CSIC-UAB), EE, UAB, 08193 Bellaterra (Spain); Vicent, Teresa [Departament d' Enginyeria Quimica and Institut de Ciencia i Tecnologia Ambiental, Escola d' Enginyeria (Estonia), Universitat Autonoma de Barcelona (UAB), 08193 Bellaterra (Spain)

    2010-04-15

    Degradation of diclofenac sodium, a nonsteroidal anti-inflammatory drug widely found in the aquatic environment, was assessed using the white-rot fungus Trametes versicolor. Almost complete diclofenac removal ({>=}94%) occurred the first hour with T. versicolor pellets when the drug was added at relatively high (10 mg L{sup -1}) and environmentally relevant low (45 {mu}g L{sup -1}) concentrations in a defined liquid medium. In vivo and in vitro experiments using the cytochrome P450 inhibitor 1-aminobenzotriazole and purified laccase, respectively, suggested at least two different mechanisms employed by T. versicolor to initiate diclofenac degradation. Two hydroxylated metabolites, 4'-hydroxydiclofenac and 5-hydroxydiclofenac, were structurally elucidated by nuclear magnetic resonance as degradation intermediates in fungal cultures spiked with diclofenac. Both parent compound and intermediates disappeared after 24 h leading to a decrease in ecotoxicity calculated by the Microtox test. Laccase-catalyzed transformation of diclofenac led to the formation of 4-(2,6-dichlorophenylamino)-1,3-benzenedimethanol, which was not detected in in vivo experiments probably due to the low laccase activity levels observed through the first hours of incubation.

  17. Liposomal photosensitizers: potential platforms for anticancer photodynamic therapy

    Directory of Open Access Journals (Sweden)

    L.A. Muehlmann

    2011-08-01

    Full Text Available Photodynamic therapy is a well-established and clinically approved treatment for several types of cancer. Antineoplastic photodynamic therapy is based on photosensitizers, i.e., drugs that absorb photons translating light energy into a chemical potential that damages tumor tissues. Despite the encouraging clinical results with the approved photosensitizers available today, the prolonged skin phototoxicity, poor selectivity for diseased tissues, hydrophobic nature, and extended retention in the host organism shown by these drugs have stimulated researchers to develop new formulations for photodynamic therapy. In this context, due to their amphiphilic characteristic (compatibility with both hydrophobic and hydrophilic substances, liposomes have proven to be suitable carriers for photosensitizers, improving the photophysical properties of the photosensitizers. Moreover, as nanostructured drug delivery systems, liposomes improve the efficiency and safety of antineoplastic photodynamic therapy, mainly by the classical phenomenon of extended permeation and retention. Therefore, the association of photosensitizers with liposomes has been extensively studied. In this review, both current knowledge and future perspectives on liposomal carriers for antineoplastic photodynamic therapy are critically discussed.

  18. Topical liposomal azithromycin in the treatment of acute cutaneous leishmaniasis.

    Science.gov (United States)

    Rajabi, Omid; Layegh, Pouran; Hashemzadeh, Sara; Khoddami, Mohsen

    2016-09-01

    Cutaneous leishmaniasis (CL) treatment is based on pentavalant antimony (sbv) drugs which are accompanied by many side effects and are facing ever-increasing resistance. Topical treatment of CL is an attractive alternative avoiding toxicities of parenteral therapy while being administered through a simple painless route. The liposomal formulations of different drugs have recently been increasingly used in the treatment of several types of leishmaniasis. The efficacy of a topical liposomal azithromycin formulation was compared with intralesional meglumine antimoniate (glucantime) in the treatment of CL. Sixty-six patients with 97 lesions who met our inclusion criteria were randomly divided into two groups. One group was administered with the topical liposomal form of azithromycin twice daily. The other group was treated by weekly intralesional injections of glucantime with a volume of 0.5-2 cm3 into each lesion till complete blanching of the lesion occurred. Clinical evaluations were performed weekly during the treatment course (8 weeks) by a single dermatologist for both groups. Per-protocol analysis showed no statistically significant difference between the two groups (p = 0.84, 95% confidence interval (CI) = 0.764 (0.714-0.821). Serious drug side effects were not observed in either group. Topical liposomal azithromycin has the same efficacy as intralesional glucantime in the treatment of CL. © 2016 Wiley Periodicals, Inc.

  19. Thrombin-Inhibiting Anticoagulant Liposomes: Development and Characterization.

    Science.gov (United States)

    Endreas, Wegderes; Brüßler, Jana; Vornicescu, Doru; Keusgen, Michael; Bakowsky, Udo; Steinmetzer, Torsten

    2016-02-04

    Many peptides and peptidomimetic drugs suffer from rapid clearance in vivo; this can be reduced by increasing their size through oligomerization or covalent conjugation with polymers. As proof of principle, an alternative strategy for drug oligomerization is described, in which peptidomimetic thrombin inhibitors are incorporated into the liposome surface. For this purpose, the inhibitor moieties were covalently coupled to a palmitic acid residue through a short bifunctionalized ethylene glycol spacer. These molecules were directly added to the lipid mixture used for liposome preparation. The obtained liposomes possess strong thrombin inhibitory potency in enzyme kinetic measurements and anticoagulant activity in plasma. Their strong potency and positive ζ potential indicate that large amounts of the benzamidine-derived inhibitors are located on the surface of the liposomes. This concept should be applicable to other drug molecules that suffer from rapid elimination and allow covalent modification with a suitable fatty acid residue. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  20. Encapsulating contact allergens in liposomes, ethosomes, and polycaprolactone may affect their sensitizing properties.

    Science.gov (United States)

    Madsen, Jakob Torp; Vogel, Stefan; Johansen, Jeanne Duus; Andersen, Klaus Ejner

    2011-06-01

    Attempts to improve formulation of topical products are a continuing process and the development of micro- and nanovesicular systems as well as polymeric microparticles has led to marketing of topical drugs and cosmetics using these technologies. Encapsulation of some well-known contact allergens in ethanolic liposomes have been reported to enhance allergenicity compared with the allergens in similar vehicles without liposomes. The present report includes data on more sensitization studies using the mouse local lymph node assay with three contact allergens encapsulated in different dermal drug-delivery systems: liposomes, ethosomes, and polycaprolactone particles. The results show that the drug-delivery systems are not sensitizers in themselves. Encapsulating the hydrophilic contact allergen potassium dichromate in all three drug-delivery systems did not affect the sensitizing capacity of potassium dichromate compared with control solutions. However, encapsulating the lipophilic contact allergen dinitrochlorobenzene (DNCB) in polycaprolactone reduced the sensitizing capacity to 1211 ± 449 compared with liposomes (7602 ± 2658) and in acetone:olive oil (4:1) (5633 ± 666). The same trend was observed for encapsulating isoeugenol in polycaprolactone (1100 ± 406) compared with a formulation in acetone:olive oil (4491 ± 819) and in liposomes (3668 ± 950). Further, the size of DNCB-loaded liposomes did not affect the sensitizing properties. These results suggest that modern dermal drug-delivery systems may in some cases magnify or decrease the sensitizing capacity of the encapsulated contact allergen.

  1. Liposome preparation using a hollow fiber membrane contactor--application to spironolactone encapsulation.

    Science.gov (United States)

    Laouini, A; Jaafar-Maalej, C; Sfar, S; Charcosset, C; Fessi, H

    2011-08-30

    In this study, we present a novel liposome preparation technique suitable for the entrapment of pharmaceutical and cosmetic agents. This new method uses a membrane contactor in a hollow fiber configuration. In order to investigate the process, key parameters influence on the liposome characteristics was studied. It has been established that the vesicle size distribution decreased with the organic phase pressure decrease, the phospholipid concentration decreases and the aqueous to organic phase volume ratio increases. Liposomes were filled with a hydrophobic drug model, spironolactone that could be used for a paediatric medication. The mean size of drug-free and drug-loaded liposomes was, respectively, 113 ± 4 nm and 123 ± 3 nm. The zeta potential of drug-free and drug-loaded liposomes was, respectively, -43 ± 0.7 mV and -23 ± 0.6 mV. High entrapment efficiency values were successfully achieved (93 ± 1.12%). Transmission electron microscopy images revealed nanometric sized and spherical shaped oligo-lamellar vesicles. The release profile showed a rapid and complete release within about 5h. Additionally, special attention was paid on process reproducibility and long term lipid vesicles stability. Results confirmed the robustness of the hollow fiber module based technique. Moreover, the technique is simple, fast and has a potential for continuous production of nanosized liposome suspensions at large scale. Copyright © 2011 Elsevier B.V. All rights reserved.

  2. Innovative bionanocomposite films of edible proteins containing liposome-encapsulated nisin and halloysite nanoclay.

    Science.gov (United States)

    Boelter, Juliana Ferreira; Brandelli, Adriano

    2016-09-01

    Films and coatings based on natural polymers have gained increased interest for food packaging applications. In this work, halloysite and phosphatidylcholine liposomes encapsulating nisin were used to develop nanocomposite films of gelatin and casein. Liposomes prepared with either soybean lecithin or Phospholipon(®) showed particle size ranging from 124 to 178nm and high entrapment efficiency (94-100%). Considering their stability, Phospholipon(®) liposomes with 1.0mg/ml nisin were selected for incorporation into nanocomposite films containing 0.5g/l halloysite. The films presented antimicrobial activity against Listeria monocytogenes, Clostridium perfringens and Bacillus cereus. Scanning electron microscopy revealed that the films had a smooth surface, but showed increased roughness with addition of liposomes and halloysite. Casein films were thinner and slightly yellowish, less rigid and very elastic as compared with gelatin films. Thermogravimetric analysis showed a decrease of the degradation temperature for casein films added with liposomes. The glass transition temperature decreased with addition of liposomes and halloysite. Gelatin and casein films containing nisin-loaded liposomes and halloysite represent an interesting alternative for development of active food packaging. Copyright © 2016 Elsevier B.V. All rights reserved.

  3. A poly(ether-ester) copolymer for the preparation of nanocarriers with improved degradation and drug delivery kinetics

    Energy Technology Data Exchange (ETDEWEB)

    Gagliardi, M., E-mail: mariacristina.gagliardi@iit.it [Center for Micro Bio-Robotics @SSSA, Istituto Italiano di Tecnologia, Viale Rinaldo Piaggio 34, 56025 Pontedera (Italy); Bertero, A. [Department of Biology, Unit of Cellular and Developmental Biology, University of Pisa, S.S.12 Abetone e Brennero 4, 56127 Pisa (Italy); Center for Neuroscience and Cognitive Systems @UNITN, Istituto Italiano di Tecnologia, Corso Bettini 31, 38068 Rovereto (Italy); Bardi, G. [Center for Bio-Molecular Nanotechnologies @UniLe, Istituto Italiano di Tecnologia, Via Barsanti, 73010 Arnesano (Italy); Bifone, A. [Center for Neuroscience and Cognitive Systems @UNITN, Istituto Italiano di Tecnologia, Corso Bettini 31, 38068 Rovereto (Italy)

    2016-02-01

    This paper reports the synthesis and the physicochemical, functional and biological characterisations of nanocarriers made of a novel di-block biodegradable poly(ether-ester) copolymer. This material presents tunable, fast biodegradation rates, but its products are less acidic than those of other biosorbable polymers like PLGA, thus presenting a better biocompatibility profile and the possibility to carry pH-sensitive payloads. A method for the production of monodisperse and spherical nanoparticles is proposed; drug delivery kinetics and blood protein adsorption were measured to evaluate the functional properties of these nanoparticles as drug carriers. The copolymer was labelled with a fluorescent dye for internalisation tests, and rhodamine B was used as a model cargo to study transport and release inside cultured cells. Biological tests demonstrated good cytocompatibility, significant cell internalisation and the possibility to vehiculate non-cell penetrating moieties into endothelial cells. Taken together, these results support the potential use of this nanoparticulate system for systemic administration of drugs. - Highlights: • We propose a novel biodegradable nanocarrier for intracellular drug delivery. • Biodegradation rates can be finely tuned by controlling copolymer composition. • Degradation products are less acidic, thus enabling delivery of pH-sensitive cargoes. • We demonstrate intracellular delivery of a non-cell-penetrating model drug. • No significant membrane damage by the polymer nanocarriers is observed.

  4. A poly(ether-ester) copolymer for the preparation of nanocarriers with improved degradation and drug delivery kinetics

    International Nuclear Information System (INIS)

    Gagliardi, M.; Bertero, A.; Bardi, G.; Bifone, A.

    2016-01-01

    This paper reports the synthesis and the physicochemical, functional and biological characterisations of nanocarriers made of a novel di-block biodegradable poly(ether-ester) copolymer. This material presents tunable, fast biodegradation rates, but its products are less acidic than those of other biosorbable polymers like PLGA, thus presenting a better biocompatibility profile and the possibility to carry pH-sensitive payloads. A method for the production of monodisperse and spherical nanoparticles is proposed; drug delivery kinetics and blood protein adsorption were measured to evaluate the functional properties of these nanoparticles as drug carriers. The copolymer was labelled with a fluorescent dye for internalisation tests, and rhodamine B was used as a model cargo to study transport and release inside cultured cells. Biological tests demonstrated good cytocompatibility, significant cell internalisation and the possibility to vehiculate non-cell penetrating moieties into endothelial cells. Taken together, these results support the potential use of this nanoparticulate system for systemic administration of drugs. - Highlights: • We propose a novel biodegradable nanocarrier for intracellular drug delivery. • Biodegradation rates can be finely tuned by controlling copolymer composition. • Degradation products are less acidic, thus enabling delivery of pH-sensitive cargoes. • We demonstrate intracellular delivery of a non-cell-penetrating model drug. • No significant membrane damage by the polymer nanocarriers is observed.

  5. A true bifurcational stenosis treated with a bioresorbable vascular scaffold and a drug-eluting metallic stent: Degradable meets durable.

    Science.gov (United States)

    Wiebe, Jens; Hamm, Christian; Nef, Holger

    2015-06-01

    The role of bioresorbable scaffolds (BRS) has mostly been investigated in simple coronary lesions. True bifurcational stenoses are one of the major challenges in interventional cardiology. We report here a successful case of a hybrid approach using a bioresorbable scaffold and a drug-eluting metallic stent to treat a true bifurcational lesion. Due to the degradable character of the BRS, only one metallic stent remains and thus the risk of restenosis can possibly be reduced. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

  6. Encapsulating contact allergens in liposomes, ethosomes, and polycaprolactone may affect their sensitizing properties

    DEFF Research Database (Denmark)

    Madsen, Jakob Torp; Vogel, Stefan; Johansen, Jeanne Duus

    2011-01-01

    dichromate compared with control solutions. However, encapsulating the lipophilic contact allergen dinitrochlorobenzene (DNCB) in polycaprolactone reduced the sensitizing capacity to 1211 ± 449 compared with liposomes (7602 ± 2658) and in acetone:olive oil (4:1) (5633 ± 666). The same trend was observed...... for encapsulating isoeugenol in polycaprolactone (1100 ± 406) compared with a formulation in acetone:olive oil (4491 ± 819) and in liposomes (3668 ± 950). Further, the size of DNCB-loaded liposomes did not affect the sensitizing properties. These results suggest that modern dermal drug-delivery systems may in some...

  7. Effects of liposomal encapsulation on the antioxidant activity of lipophilic prodrugs of idebenone.

    Science.gov (United States)

    Pignatello, Rosario; Acquaviva, Rosaria; Campisi, Agata; Raciti, Giuseppina; Musumeci, Teresa; Puglisi, Giovanni

    2011-03-01

    Increasing the lipophilicity and/or amphiphilicity of drugs is a potential strategy to improve loading and retention in lipid-based carriers, such as liposomes or lipid nanoparticles. Idebenone (IDE), an antioxidant compound structurally related to coenzyme Q, or amphiphilic prodrugs of IDE with lipoamino acids, were loaded in neutral or negatively charged SUVET unilamellar liposomes to achieve a controlled release. Technological properties of these systems in the presence of loaded drugs were evaluated in terms of vesicle size, homogeneity, and surface charge, as well as in vitro drug release. The effect of liposomal carrier on the in vitro antioxidant activity of the prodrugs was evaluated from using different biochemical assays on murine astrocyte cultures. Although a good loading efficiency was obtained, liposomes were not able to release efficiently the encapsulated drugs, at least in the in vitro serum-free conditions used for the biological tests. However, in some cases, such as in the comet assay, encapsulation of IDE prodrugs in liposomes allowed for the improvement of their protective activity, compared to the free compounds, against the oxidative damage induced on cultured astrocytes. Experimental in vitro data suggested that the high affinity shown by these lipophilic IDE derivatives for the liposomal carriers negatively affect their biological activity.

  8. PLGA nanoparticles introduction into mitoxantrone-loaded ultrasound-responsive liposomes: In vitro and in vivo investigations.

    Science.gov (United States)

    Xin, Yuxuan; Qi, Qi; Mao, Zhenmin; Zhan, Xiaoping

    2017-08-07

    A novel ultrasound-responsive liposomal system for tumor targeting was prepared in order to increase the antitumor efficacy and decrease serious side effects. In this paper, PLGA nanoparticles were used ultrasound-responsive agents instead of conventional microbubbles. The PLGA-nanoparticles were prepared by an emulsion solvent evaporation method. The liposomes were prepared by a lipid film hydration method. Particle size, zeta potential, encapsulation efficiency and drug loading capacity of the liposomes were studied by light scattering analysis and dialysis. Transmission electron microscopy (TEM) and atomic force microscope (AFM) were used to investigate the morphology of liposomes. The release in vitro was carried out in the pH 7.4 phosphate buffer solutions, as a result, liposome L3 encapsulating PLGA-nanoparticles displayed good stability under simulative physiological conditions and quickly responsive release under the ultrasound. The release in vivo was carried out on the rats, as a result, liposome L3 showed higher bioavailability than traditional intravenous injectable administration, and liposome L3 showed higher elimination ratio after stimulation by ultrasound than L3 without stimulation. Thus, the novel ultrasound-responsive liposome encapsulating PLGA-nanoparticles has a potential to be developed as a new drug delivery system for anti-tumor drug. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. Tat-functionalized liposomes for the treatment of meningitis: an in vitro study

    Science.gov (United States)

    Bartomeu Garcia, Caterina; Shi, Di; Webster, Thomas J

    2017-01-01

    Bacterial meningitis has become a global concern, because of the emergence of antibiotic-resistant bacteria. It has been demonstrated that liposomes can enter bacteria, thus providing a possible treatment for numerous infections, including meningitis. Fusogenic liposomes are pH-sensitive with a high capacity to fuse with the bacteria membrane and promote intracellular drug release. Moreover, this ability can be improved by using cell-penetrating peptides (such as Tat47–57, which is a peptide derived from the Tat protein of HIV). The purpose of this in vitro study was to demonstrate for the first time the ability of the presently prepared fusogenic liposomes, which were spherical particles with a diameter of 100 nm loaded with antibiotics and functionalized with-cell penetrating peptides (Tat47–57), to fight the main bacteria that cause meningitis. For this, vancomycin, methicillin, and ampicillin antibiotics were loaded inside fusogenic liposomes to fight Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus, and Escherichia coli. Antibacterial activity of Tat-functionalized and nonfunctionalized liposomes loaded with antibiotics was tested by determining bacteria colony-forming units and growth-curve assays coupled with live/dead assays using fluorescence microscopy. Results showed a remarkable decrease in antibiotic minimum inhibitory concentration when all of the bacteria were treated with these novel liposomes, especially for the functionalized liposomes loaded with methicillin. With antibiotic concentrations of 1.7–3 µg/mL for Tat-functionalized liposomes loaded with methicillin, the bacteria population was totally eradicated. Cytotoxicity tests with astrocytes and endothelial cells, major cellular components of the blood–brain barrier, were also performed for all of the liposomes, including free antibiotic and the Tat peptide. Results showed much promise for the further study of the presently formulated liposomes to treat meningitis

  10. Liposomal Encapsulation for Systemic Delivery of Propranolol via Transdermal Iontophoresis Improves Bone Microarchitecture in Ovariectomized Rats.

    Science.gov (United States)

    Teong, Benjamin; Kuo, Shyh Ming; Tsai, Wei-Hsin; Ho, Mei-Ling; Chen, Chung-Hwan; Huang, Han Hsiang

    2017-04-13

    The stimulatory effects of liposomal propranolol (PRP) on proliferation and differentiation of human osteoblastic cells suggested that the prepared liposomes-encapsulated PRP exerts anabolic effects on bone in vivo. Iontophoresis provides merits such as sustained release of drugs and circumvention of first pass metabolism. This study further investigated and evaluated the anti-osteoporotic effects of liposomal PRP in ovariectomized (OVX) rats via iontophoresis. Rats subjected to OVX were administered with pure or liposomal PRP via iontophoresis or subcutaneous injection twice a week for 12 weeks. Changes in the microarchitecture at the proximal tibia and the fourth lumbar spine were assessed between pure or liposomal PRP treated and non-treated groups using micro-computed tomography. Administration of liposomal PRP at low dose (0.05 mg/kg) via iontophoresis over 2-fold elevated ratio between bone volume and total tissue volume (BV/TV) in proximal tibia to 9.0% whereas treatment with liposomal PRP at low and high (0.5 mg/kg) doses via subcutaneous injection resulted in smaller increases in BV/TV. Significant improvement of BV/TV and bone mineral density (BMD) was also found in the fourth lumbar spine when low-dose liposomal PRP was iontophoretically administered. Iontophoretic low-dose liposomal PRP also elevated trabecular numbers in tibia and trabecular thickness in spine. Enhancement of bone microarchitecture volumes has highlighted that liposomal formulation with transdermal iontophoresis is promising for PRP treatment at the lower dose and with longer duration than its clinical therapeutic range and duration to exhibit optimal effects against bone loss in vivo.

  11. A new method for liposome preparation using a membrane contactor.

    Science.gov (United States)

    Jaafar-Maalej, Chiraz; Charcosset, Catherine; Fessi, Hatem

    2011-09-01

    In this article, we present a novel, scalable liposomal preparation technique suitable for the entrapment of pharmaceutical agents into liposomes. This new method is based on the ethanol-injection technique and uses a membrane contactor module, specifically designed for colloidal system preparation. In order to investigate the process, the influence of key parameters on liposome characteristics was studied. It has been established that vesicle-size distribution decreased with a decrease of the organic-phase pressure, an increase of the aqueous-phase flow rate, and a decrease of the phospholipid concentration. Additionally, special attention was paid on reproducibility and long-term stability of lipid vesicles, confirming the robustness of the membrane contactor-based technique. On the other hand, drug-loaded liposomes were prepared and filled with two hydrophobic drug models. High entrapment-efficiency values were successfully achieved for indomethacin (63%) and beclomethasone dipropionate (98%). Transmission electron microscopy images revealed nanometric quasispherical-shaped multilamellar vesicles (size ranging from 50 to 160 nm).

  12. Effects of process variables on micromeritic properties and drug release of non-degradable microparticles

    Directory of Open Access Journals (Sweden)

    Mitra Jelvehgari

    2011-06-01

    Full Text Available Introduction: The purpose of this investigation was to evaluate microencapsulated controlled release preparation of theophylline using Eudragit RS 100 as the retardant material with high entrapment efficiency. Methods: Microspheres were prepared by the emulsion-solvent evaporation method. A mixed solvent system consisting of methanol and acetone and light liquid paraffin as oily phase were chosen. Sucrose stearate was used as the surfactant to stabilize the emulsification process. The prepared microspheres were characterized by drug loading, Fourier-transform infrared spectroscopy (FTIR, differential scanning colorimetry (DSC and scanning electron microscopy (SEM. The in vitro release studies were performed at pH 1.2 and 7.4 aqueous medium. Results: Increasing the concentration of emulsifier, sucrose fatty acid ester F-70, decreased the particle size which contributed to increased drug release rate. The drug loading microparticle Eudragit RS100 (1:6 showed 60-75% of entrapment and mean particle size 205.93-352.76 µm. The results showed that, an increase in the ratio of polymer: drug (F5, 6: 1 resulted in a reduction in the release rate of the drug which may be attributed to the hydrophobic nature of the polymer. Conclusion: The release of theophylline is influenced by the drug to polymer ratio and particle size. Drug release is controlled by diffusion and the best-fit release kinetic is Higuchi model.

  13. Effects of process variables on micromeritic properties and drug release of non-degradable microparticles.

    Science.gov (United States)

    Jelvehgari, Mitra; Barar, Jaleh; Nokhodchi, Ali; Shadrou, Sanam; Valizadeh, Hadi

    2011-01-01

    The purpose of this investigation was to evaluate microencapsulated controlled release preparation of theophylline using Eudragit RS 100 as the retardant material with high entrapment efficiency. Microspheres were prepared by the emulsion-solvent evaporation method. A mixed solvent system consisting of methanol and acetone and light liquid paraffin as oily phase were chosen. Sucrose stearate was used as the surfactant to stabilize the emulsification process. The prepared microspheres were characterized by drug loading, Fourier-transform infrared spectroscopy (FTIR), differential scanning colorimetry (DSC) and scanning electron microscopy (SEM). The in vitro release studies were performed at pH 1.2 and 7.4 aqueous medium. Increasing the concentration of emulsifier, sucrose fatty acid ester F-70, decreased the particle size which contributed to increased drug release rate. The drug loading microparticle Eudragit RS100(1:6) showed 60-75% of entrapment and mean particle size 205.93-352.76 μm.The results showed that, an increase in the ratio of polymer: drug (F5, 6: 1) resulted in a reduction in the release rate of the drug which may be attributed to the hydrophobic nature of the polymer. The release of theophylline is influenced by the drug to polymer ratio and particle size. Drug release is controlled by diffusion and the best-fit release kinetic is Higuchi model.

  14. Aqueous degradation kinetics of pharmaceutical drug diclofenac by photo catalysis using nano structured titania–zirconia composite catalyst

    International Nuclear Information System (INIS)

    Das, L.; Barodia, S. K.; Sengupta, S.; Basu, J. K.

    2015-01-01

    Diclofenac is an anti-inflammatory pharmaceutical drug and its presence in a trace amount in waste water makes severe environmental pollution. The degradation of diclofenac was investigated by a photo catalytic process in presence of ultra violet irradiation at room temperature using titania and titania-zirconia nano composite catalysts in a batch reactor. The composite catalyst was prepared by sol-gel method and characterized by X-ray diffraction, transmission electron microscopy as well as BET surface area analyzer. The effect of various process parameters such as catalyst loading, initial concentration of diclofenac and p H of the experimental solution was observed on the degradation of diclofenac. The titania-zirconia nano composites exhibited reasonably higher photo catalytic activity than that of anatase form of titania without zirconia. The maximum removal of diclofenac of about 92.41% was achieved using Zr/Ti mass ratio of 11.8 wt% composite catalyst. A rate equation was proposed for the degradation of diclofenac using the composite catalyst. The values of rate constant (kc) and adsorption equilibrium constant (K1) were found to vary with the catalyst content in the reaction mixture.

  15. A mathematical relationship for hydromorphone loading into liposomes with trans-membrane ammonium sulfate gradients.

    Science.gov (United States)

    Tu, Sheng; McGinnis, Tamara; Krugner-Higby, Lisa; Heath, Timothy D

    2010-06-01

    We have studied the loading of the opioid hydromorphone into liposomes using ammonium sulfate gradients. Unlike other drugs loaded with this technique, hydromorphone is freely soluble as the sulfate salt, and, consequently, does not precipitate in the liposomes after loading. We have derived a mathematical relationship that can predict the extent of loading based on the ammonium ion content of the liposomes and the amount of drug added for loading. We have adapted and used the Berthelot indophenol assay to measure the amount of ammonium ions in the liposomes. Plots of the inverse of the fraction of hydromorphone loaded versus the amount of hydromorphone added are linear, and the slope should be the inverse of the amount of ammonium ions present in the liposomes. The inverse of the slopes obtained closely correspond to the amount of ammonium ions in the liposomes measured with the Berthelot indophenol assay. We also show that loading can be less than optimal under conditions where osmotically driven loss of ammonium ions or leakage of drug after loading may occur. (c) 2009 Wiley-Liss, Inc. and the American Pharmacists Association

  16. [Optimization of Formulation and Process of Paclitaxel PEGylated Liposomes by Box-Behnken Response Surface Methodology].

    Science.gov (United States)

    Shi, Ya-jun; Zhang, Xiao-feil; Guo, Qiu-ting

    2015-12-01

    To develop a procedure for preparing paclitaxel encapsulated PEGylated liposomes. The membrane hydration followed extraction method was used to prepare PEGylated liposomes. The process and formulation variables were optimized by "Box-Behnken Design (BBD)" of response surface methodology (RSM) with the amount of Soya phosphotidylcholine (SPC) and PEG2000-DSPE as well as the rate of SPC to drug as independent variables and entrapment efficiency as dependent variables for optimization of formulation variables while temperature, pressure and cycle times as independent variables and particle size and polydispersion index as dependent variables for process variables. The optimized liposomal formulation was characterized for particle size, Zeta potential, morphology and in vitro drug release. For entrapment efficiency, particle size, polydispersion index, Zeta potential, and in vitro drug release of PEGylated liposomes was found to be 80.3%, (97.15 ± 14.9) nm, 0.117 ± 0.019, (-30.3 ± 3.7) mV, and 37.4% in 24 h, respectively. The liposomes were found to be small, unilamellar and spherical with smooth surface as seen in transmission electron microscopy. The Box-Behnken response surface methodology facilitates the formulation and optimization of paclitaxel PEGylated liposomes.

  17. The E3 ubiquitin-ligase Bmi1/Ring1A controls the proteasomal degradation of Top2alpha cleavage complex - a potentially new drug target.

    Directory of Open Access Journals (Sweden)

    Iris Alchanati

    2009-12-01

    Full Text Available The topoisomerases Top1, Top2alpha and Top2beta are important molecular targets for antitumor drugs, which specifically poison Top1 or Top2 isomers. While it was previously demonstrated that poisoned Top1 and Top2beta are subject to proteasomal degradation, this phenomena was not demonstrated for Top2alpha.We show here that Top2alpha is subject to drug induced proteasomal degradation as well, although at a lower rate than Top2beta. Using an siRNA screen we identified Bmi1 and Ring1A as subunits of an E3 ubiquitin ligase involved in this process. We show that silencing of Bmi1 inhibits drug-induced Top2alpha degradation, increases the persistence of Top2alpha-DNA cleavage complex, and increases Top2 drug efficacy. The Bmi1/Ring1A ligase ubiquitinates Top2alpha in-vitro and cellular overexpression of Bmi1 increases drug induced Top2alpha ubiquitination. A small-molecular weight compound, identified in a screen for inhibitors of Bmi1/Ring1A ubiquitination activity, also prevents Top2alpha ubiquitination and drug-induced Top2alpha degradation. This ubiquitination inhibitor increases the efficacy of topoisomerase 2 poisons in a synergistic manner.The discovery that poisoned Top2alpha is undergoing proteasomal degradation combined with the involvement of Bmi1/Ring1A, allowed us to identify a small molecule that inhibits the degradation process. The Bmi1/Ring1A inhibitor sensitizes cells to Top2 drugs, suggesting that this type of drug combination will have a beneficial therapeutic outcome. As Bmi1 is also a known oncogene, elevated in numerous types of cancer, the identified Bmi1/Ring1A ubiquitin ligase inhibitors can also be potentially used to directly target the oncogenic properties of Bmi1.

  18. Incomplete copolymer degradation of in situ chemotherapy.

    Science.gov (United States)

    Bourdillon, Pierre; Boissenot, Tanguy; Goldwirt, Lauriane; Nicolas, Julien; Apra, Caroline; Carpentier, Alexandre

    2018-02-17

    In situ carmustine wafers containing 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) are commonly used for the treatment of recurrent glioblastoma to overcome the brain-blood barrier. In theory, this chemotherapy diffuses into the adjacent parenchyma and the excipient degrades in maximum 8 weeks but no clinical data confirms this evolution, because patients are rarely operated again. A 75-year-old patient was operated twice for recurrent glioblastoma, and a carmustine wafer was implanted during the second surgery. Eleven months later, a third surgery was performed, revealing unexpected incomplete degradation of the wafer. 1H-Nuclear Magnetic Resonance was performed to compare this wafer to pure BCNU and to an unused copolymer wafer. In the used wafer, peaks corresponding to hydrophobic units of the excipient were no longer noticeable, whereas peaks of the hydrophilic units and traces of BCNU were still present. These surprising results could be related to the formation of a hydrophobic membrane around the wafer, thus interfering with the expected diffusion and degradation processes. The clinical benefit of carmustine wafers in addition to the standard radio-chemotherapy remains limited, and in vivo behavior of this treatment is not completely elucidated yet. We found that the wafer may remain after several months. Alternative strategies to deal with the blood-brain barrier, such as drug-loaded liposomes or ultrasound-opening, must be explored to offer larger drug diffusion or allow repetitive delivery.

  19. Liposomal preparation by supercritical fluids technology | Zhong ...

    African Journals Online (AJOL)

    From 1970s, supercritical fluids technology (SCF) has been utilized in liposomal preparation because of its friendliness, nontoxicity to the environment and its possibility to achieve solvent-free liposomes and industrial-scale of liposome production under the conditions of current good manufacturing practice (cGMP).

  20. Intra and inter-molecular interactions dictate the aggregation state of irinotecan co-encapsulated with floxuridine inside liposomes

    DEFF Research Database (Denmark)

    Dicko, A.; Frazier, A.A.; Liboiron, B.D.

    2008-01-01

    PURPOSE: The inter/intramolecular interactions between drugs (floxuridine, irinotecan) and excipients (copper gluconate, triethanolamine) in the dual-drug liposomal formulation CPX-1 were elucidated in order to identify the physicochemical properties that allow coordinated release of irinotecan...... and floxuridine and maintenance of the two agents at a fixed, synergistic 1:1 molar ratio. METHODS: Release of irinotecan and floxuridine from the liposomes was assessed using an in vitro-release assay. Fluorescence, Nuclear Magnetic Resonance spectroscopy (NMR) and UV-Vis were used to characterize...... the aggregation state of the drugs within the liposomes. RESULTS: Coordinated release of the drugs from liposomes was disrupted by removing copper gluconate. Approximately 45% of the total irinotecan was detectable in the copper-containing CPX-1 formulation by NMR, which decreased to 19% without copper present...

  1. Hydrolytically degradable polymer micelles for anticancer drug delivery to solid tumors

    Czech Academy of Sciences Publication Activity Database

    Chytil, Petr; Etrych, Tomáš; Kostka, Libor; Ulbrich, Karel

    2012-01-01

    Roč. 213, č. 8 (2012), s. 858-867 ISSN 1022-1352 R&D Projects: GA AV ČR IAAX00500803; GA ČR GAP301/11/0325 Institutional research plan: CEZ:AV0Z40500505 Keywords : HPMA copolymers * drug delivery systems * doxorubicin Subject RIV: EC - Immunology Impact factor: 2.386, year: 2012

  2. Fate and antibacterial potency of anticoccidial drugs and their main abiotic degradation products

    DEFF Research Database (Denmark)

    Hansen, Martin; Krogh, Kristine A; Brandt, Asbjørn

    2009-01-01

    The antibacterial potency of eight anticoccidial drugs was tested in a soil bacteria bioassay (pour plate method), EC(50)-values between 2.4 and 19.6 microM were obtained; however, one compound, nicarbazin exhibited an EC(50)-value above the maximum tested concentration (21 microM, 9.1 mg L(-1))....

  3. Hydrolytically degradable polymer micelles for drug delivery: a SAXS/SANS kinetic study

    Czech Academy of Sciences Publication Activity Database

    Filippov, Sergey K.; Franklin, J. M.; Konarev, P. V.; Chytil, Petr; Etrych, Tomáš; Bogomolova, Anna; Dyakonova, M.; Papadakis, C. M.; Radulescu, A.; Ulbrich, Karel; Štěpánek, Petr; Svergun, D. I.

    2013-01-01

    Roč. 14, č. 11 (2013), s. 4061-4070 ISSN 1525-7797 R&D Projects: GA ČR GAP208/10/1600 Institutional support: RVO:61389013 Keywords : HPMA * micelles * drug release Subject RIV: CF - Physical ; Theoretical Chemistry Impact factor: 5.788, year: 2013

  4. Focused ultrasound influence on calcein-loaded thermosensitive stealth liposomes.

    Science.gov (United States)

    Novell, Anthony; Al Sabbagh, Chantal; Escoffre, Jean-Michel; Gaillard, Cédric; Tsapis, Nicolas; Fattal, Elias; Bouakaz, Ayache

    2015-06-01

    Focused ultrasound (FUS) is a versatile technology for non-invasive thermal therapies in oncology. Indeed, this technology has great potential for local heat-mediated drug delivery from thermosensitive liposomes (TSLs), thus improving therapeutic efficacy and reducing toxicity profiles. In the present study we evaluated the influence of FUS parameters on the release of calcein from TSLs used to model a hydrophilic drug. Quantitative calcein release from TSLs (DPPC/CHOL/DSPE-PEG2000: 90/5/5) and non-thermosensitive liposomes (NTSLs) (DPPC/CHOL/DSPE-PEG2000: 65/30/5) was measured by spectrofluorimetry after both water bath and FUS-induced in vitro heating. The heating of TSLs at 42 °C in a water bath resulted in a maximum calcein release of 45%. No additional calcein release was observed at temperatures above 42 °C. A similar percentage of calcein release was achieved when TSLs were exposed to 1 MHz sinusoidal waves at peak negative pressure of 1.5 MPa, 40% duty cycle, for 10 min (i.e. above 42 °C). No release was detected when NTSLs were heated in a water bath. For both TSLs and NTSLs, the calcein release was increased by more than 10% for acoustic pressures ranging from 1.5 MPa to 2 MPa. This additional release was attributed to the mechanical stress generated by FUS, which was sufficient to disrupt the liposomal membrane. Furthermore, analysis of cryo-TEM images showed a significant decrease in liposome size (14%) induced by the thermal effect, whereas the liposome diameter remained unaffected by the FUS-triggered non-thermal effects.

  5. Efficient delivery to human lung fibroblasts (WI-38) of pirfenidone incorporated into liposomes modified with truncated basic fibroblast growth factor and its inhibitory effect on collagen synthesis in idiopathic pulmonary fibrosis.

    Science.gov (United States)

    Togami, Kohei; Miyao, Aki; Miyakoshi, Kei; Kanehira, Yukimune; Tada, Hitoshi; Chono, Sumio

    2015-01-01

    In the present in vitro study, we assessed the delivery of pirfenidone incorporated into liposomes modified with truncated basic fibroblast growth factor (tbFGF) to lung fibroblasts and investigated the anti-fibrotic effect of the drug. The tbFGF peptide, KRTGQYKLC, was used to modify the surface of liposomes (tbFGF-liposomes). We used the thin-layer evaporation method, followed by sonication, to prepare tbFGF-liposomes containing pirfenidone. The cellular accumulation of tbFGF-liposomes was 1.7-fold greater than that of non-modified liposomes in WI-38 cells used as a model of lung fibroblasts. Confocal laser scanning microscopy showed that tbFGF-liposomes were widely localized in WI-38 cells. The inhibitory effects of pirfenidone incorporated into tbFGF-liposomes on transforming growth factor-β1 (TGF-β1)-induced collagen synthesis in WI-38 cells were evaluated by measuring the level of intracellular hydroxyproline, a major component of the protein collagen. Pirfenidone incorporated into tbFGF-liposomes at concentrations of 10, 30, and 100 µM significantly decreased the TGF-β1-induced hydroxyproline content in WI-38 cells. The anti-fibrotic effect of pirfenidone incorporated into tbFGF-liposomes was enhanced compared with that of pirfenidone solution. These results indicate that tbFGF-liposomes are a useful drug delivery system of anti-fibrotic drugs to lung fibroblasts for the treatment of idiopathic pulmonary fibrosis.

  6. Comparison of the adverse event profiles of conventional and liposomal formulations of doxorubicin using the FDA adverse event reporting system.

    Science.gov (United States)

    Fukuda, Akiho; Tahara, Kohei; Hane, Yuuki; Matsui, Toshinobu; Sasaoka, Sayaka; Hatahira, Haruna; Motooka, Yumi; Hasegawa, Shiori; Naganuma, Misa; Abe, Junko; Nakao, Satoshi; Takeuchi, Hirofumi; Nakamura, Mitsuhiro

    2017-01-01

    Doxorubicin (DOX) is an anthracycline widely used for the treatment of solid and hematological tumors. The aim of this study was to assess the adverse event profiles of conventional DOX and liposomal DOX. This is the first study to evaluate the effect of a liposomal formulation of DOX using spontaneous reporting system (SRS) databases. The SRS used was the US Food and Drug Administration Adverse Event Reporting System (FAERS). This study relied on definitions of preferred terms provided by the Medical Dictionary for Regulatory Activities (MedDRA) and the standardized MedDRA Queries (SMQ) database. We also calculated the reporting odds ratios (RORs) of suspected drugs (conventional DOX; PEGylated-liposome DOX; non-PEGylated-liposome DOX). The FAERS database contained 7,561,254 reports from January 2004 to December 2015. The number of reported AE cases for conventional DOX, PEGylated-liposome DOX, and non-PEGylated-liposome DOX was 5039, 3780, and 349, respectively. Conventional DOX and liposomal DOX have potential risks of causing myelosuppression, cardiotoxicity, alopecia, nausea, and vomiting, among other effects. The RORs (95% CI) from SMQ for haematopoietic leucopenia associated with conventional DOX, PEGylated-liposome DOX, and non-PEGylated-liposome DOX were 12.75 (11.89-13.68), 6.43 (5.81-7.13), and 14.73 (11.42-18.99), respectively. Liposomal DOX formulations were associated with lower RORs with regard to myelosuppression, cardiotoxicity, and alopecia than the conventional DOX was. The RORs (95% CI) for palmar-plantar erythrodysesthesia (PPE) associated with conventional DOX, PEGylated-liposome DOX, and non-PEGylated-liposome DOX were 6.56 (4.74-9.07), 64.77 (56.84-73.80), and 28.76 (15.77-52.45), respectively. This study is the first to evaluate the relationship between DOX liposomal formulations and their adverse event profiles. The results indicate that careful observation for PPE is recommended with the use of liposomal DOX, especially PEGylated-liposome

  7. Comparison of the adverse event profiles of conventional and liposomal formulations of doxorubicin using the FDA adverse event reporting system.

    Directory of Open Access Journals (Sweden)

    Akiho Fukuda

    Full Text Available Doxorubicin (DOX is an anthracycline widely used for the treatment of solid and hematological tumors. The aim of this study was to assess the adverse event profiles of conventional DOX and liposomal DOX. This is the first study to evaluate the effect of a liposomal formulation of DOX using spontaneous reporting system (SRS databases. The SRS used was the US Food and Drug Administration Adverse Event Reporting System (FAERS. This study relied on definitions of preferred terms provided by the Medical Dictionary for Regulatory Activities (MedDRA and the standardized MedDRA Queries (SMQ database. We also calculated the reporting odds ratios (RORs of suspected drugs (conventional DOX; PEGylated-liposome DOX; non-PEGylated-liposome DOX. The FAERS database contained 7,561,254 reports from January 2004 to December 2015. The number of reported AE cases for conventional DOX, PEGylated-liposome DOX, and non-PEGylated-liposome DOX was 5039, 3780, and 349, respectively. Conventional DOX and liposomal DOX have potential risks of causing myelosuppression, cardiotoxicity, alopecia, nausea, and vomiting, among other effects. The RORs (95% CI from SMQ for haematopoietic leucopenia associated with conventional DOX, PEGylated-liposome DOX, and non-PEGylated-liposome DOX were 12.75 (11.89-13.68, 6.43 (5.81-7.13, and 14.73 (11.42-18.99, respectively. Liposomal DOX formulations were associated with lower RORs with regard to myelosuppression, cardiotoxicity, and alopecia than the conventional DOX was. The RORs (95% CI for palmar-plantar erythrodysesthesia (PPE associated with conventional DOX, PEGylated-liposome DOX, and non-PEGylated-liposome DOX were 6.56 (4.74-9.07, 64.77 (56.84-73.80, and 28.76 (15.77-52.45, respectively. This study is the first to evaluate the relationship between DOX liposomal formulations and their adverse event profiles. The results indicate that careful observation for PPE is recommended with the use of liposomal DOX, especially PEGylated-liposome

  8. Effects of food on a gastrically degraded drug: azithromycin fast-dissolving gelatin capsules and HPMC capsules.

    Science.gov (United States)

    Curatolo, William; Liu, Ping; Johnson, Barbara A; Hausberger, Angela; Quan, Ernest; Vendola, Thomas; Vatsaraj, Neha; Foulds, George; Vincent, John; Chandra, Richa

    2011-07-01

    Commercial azithromycin gelatin capsules (Zithromax®) are known to be bioequivalent to commercial azithromycin tablets (Zithromax®) when dosed in the fasted state. These capsules exhibit a reduced bioavailability when dosed in the fed state, while tablets do not. This gelatin capsule negative food effect was previously proposed to be due to slow and/or delayed capsule disintegration in the fed stomach, resulting in extended exposure of the drug to gastric acid, leading to degradation to des-cladinose-azithromycin (DCA). Azithromycin gelatin capsules were formulated with "superdisintegrants" to provide fast-dissolving capsules, and HPMC capsule shells were substituted for gelatin capsule shells, in an effort to eliminate the food effect. Healthy volunteers were dosed with these dosage forms under fasted and fed conditions; pharmacokinetics were evaluated. DCA pharmacokinetics were also evaluated for the HPMC capsule subjects. In vitro disintegration of azithromycin HPMC capsules in media containing food was evaluated and compared with commercial tablets and commercial gelatin capsules. When the two fast-dissolving capsule formulations were dosed to fed subjects, the azithromycin AUC was 38.9% and 52.1% lower than after fasted-state dosing. When HPMC capsules were dosed to fed subjects, the azithromycin AUC was 65.5% lower than after fasted-state dosing. For HPMC capsules, the absolute fasting-state to fed-state decrease in azithromycin AUC (on a molar basis) was similar to the increase in DCA AUC. In vitro capsule disintegration studies revealed extended disintegration times for commercial azithromycin gelatin capsules and HPMC capsules in media containing the liquid foods milk and Ensure®. Interaction of azithromycin gelatin and HPMC capsules with food results in slowed disintegration in vitro and decreased bioavailability in vivo. Concurrent measurement of serum azithromycin and the acid-degradation product DCA demonstrates that the loss of azithromycin

  9. Gemcitabine-loaded liposomes: rationale, potentialities and future perspectives

    Directory of Open Access Journals (Sweden)

    Federico C

    2012-11-01

    Full Text Available Cinzia Federico, Valeria M Morittu, Domenico Britti, Elena Trapasso, Donato CoscoDepartment of Health Sciences, Building of BioSciences, University “Magna Græcia” of Catanzaro, Campus Universitario “S Venuta”, Germaneto, ItalyAbstract: This review describes the strategies used in recent years to improve the biopharmaceutical properties of gemcitabine, a nucleoside analog deoxycytidine antimetabolite characterized by activity against many kinds of tumors, by means of liposomal devices. The main limitation of using this active compound is the rapid inactivation of deoxycytidine deaminase following administration in vivo. Consequently, different strategies based on its encapsulation/complexation in innovative vesicular colloidal carriers have been investigated, with interesting results in terms of increased pharmacological activity, plasma half-life, and tumor localization, in addition to decreased side effects. This review focuses on the specific approaches used, based on the encapsulation of gemcitabine in liposomes, with particular attention to the results obtained during the last 5 years. These approaches represent a valid starting point in the attempt to obtain a novel, commercializable drug formulation as already achieved for liposomal doxorubicin (Doxil®, Caelyx®.Keywords: gemcitabine, liposomes, multidrug, poly(ethylene glycol, tumors

  10. Targeted Delivery of Protein Drugs by Nanocarriers

    Directory of Open Access Journals (Sweden)

    Antonella Battisti

    2010-03-01

    Full Text Available Recent advances in biotechnology demonstrate that peptides and proteins are the basis of a new generation of drugs. However, the transportation of protein drugs in the body is limited by their high molecular weight, which prevents the crossing of tissue barriers, and by their short lifetime due to immuno response and enzymatic degradation. Moreover, the ability to selectively deliver drugs to target organs, tissues or cells is a major challenge in the treatment of several human diseases, including cancer. Indeed, targeted delivery can be much more efficient than systemic application, while improving bioavailability and limiting undesirable side effects. This review describes how the use of targeted nanocarriers such as nanoparticles and liposomes can improve the pharmacokinetic properties of protein drugs, thus increasing their safety and maximizing the therapeutic effect.

  11. Dynamic Probing of Nanoparticle Stability In Vivo: A Liposomal Model Assessed Using In Situ Microdialysis and Optical Imaging

    OpenAIRE

    Jeng, Chien-Chung; Cheng, Shih-Hsun; Ho, Ja-an Annie; Huang, Sam Hong-Yi; Chang, Jerry C.; Tsai, Pi-Ju; Yang, Chung-Shi; Lo, Leu-Wei

    2011-01-01

    Nanoparticle-mediated drug delivery and controlled release has been a vigorous research area in contemporary nanomedicine. The in vivo stability of nanoparticle delivered on site is a prerequisite for the design of drug-controlled release by any means. In this study, the first methodology comprised of microdialysis and optical imaging to assess the liposome stability in vivo is reported. Macroscopically, we demonstrated the DPPG liposomes with negative surface charge fast accumulated in the ...

  12. Encapsulating contact allergens in liposomes, ethosomes, and polycaprolactone may affect their sensitizing properties

    DEFF Research Database (Denmark)

    Madsen, Jakob Torp; Vogel, Stefan; Johansen, Jeanne Duus

    2011-01-01

    Attempts to improve formulation of topical products are a continuing process and the development of micro- and nanovesicular systems as well as polymeric microparticles has led to marketing of topical drugs and cosmetics using these technologies. Encapsulation of some well-known contact allergens...... in ethanolic liposomes have been reported to enhance allergenicity compared with the allergens in similar vehicles without liposomes. The present report includes data on more sensitization studies using the mouse local lymph node assay with three contact allergens encapsulated in different dermal drug......-delivery systems: liposomes, ethosomes, and polycaprolactone particles. The results show that the drug-delivery systems are not sensitizers in themselves. Encapsulating the hydrophilic contact allergen potassium dichromate in all three drug-delivery systems did not affect the sensitizing capacity of potassium...

  13. Liposomes coated with hydrophobically modified hydroxyethyl cellulose: Influence of hydrophobic chain length and degree of modification.

    Science.gov (United States)

    Smistad, Gro; Nyström, Bo; Zhu, Kaizheng; Grønvold, Marthe Karoline; Røv-Johnsen, Anne; Hiorth, Marianne

    2017-08-01

    Nanoparticulate systems with an uncharged hydrophilic surface may have a great potential in mucosal drug delivery. In the present study liposomes were coated with hydrophobically modified hydroxyethyl cellulose (HM-HEC) to create a sterically stabilized liposomal system with an uncharged surface. The aim was to clarify the influence of the amount of hydrophobic modification of HEC and the length of the hydrophobic moiety, on the stability of the system and on the release properties. HM-HEC with different degrees of hydrophobic modification (1 and 2mol%) and hydrophobic groups with different chain lengths (C8, C12, C16) were included in the study, as well as fluid phase and gel phase liposomes. Both types of liposomes were successfully coated with HM-HEC containing 1mol% of hydrophobic groups, while 2mol% did not work for the intended pharmaceutical applications. The polymer coated gel phase liposomes were stable (size, zeta potential, leakage) for 24 weeks at 4°C, with no differences between the C8 and C16 HM-HEC coating. For the fluid phase liposomes a size increase was observed after 24 weeks at 4°C for all formulations; the C8 HM-HEC coated liposomes increased the most. No differences in the leakage during storage at 4°C or in the release at 35°C were observed between the fluid phase formulations. To conclude; HM-HEC with a shorter hydrophobic chain length resulted in a less stable product for the fluid phase liposomes, while no influence of the chain length was observed for the gel phase liposomes (1mol% HM). Copyright © 2017 Elsevier B.V. All rights reserved.

  14. Visualization of liposomes by magnetic resonance imaging: an opportunity to improve antitumoral liposome therapies

    International Nuclear Information System (INIS)

    Martinez Bedoya, Darel

    2012-01-01

    Controlled release of drugs at the tumor site and the development of non-invasive monitoring techniques are two of the main challenges currently facing antitumoral therapies. The paper analyzes some of the potential uses of liposomes as vehicles for the transport of drugs to the tumors, particularly directionalized variants to tumor antigens through antibody coupling (immunoliposomes). These vesicles may also be used in combination with magnetic resonance, one of the most widely used imaging techniques, and one exhibiting great visualization potential at molecular level. Joint use of these two techniques makes it possible to control the amount of drug administered, as well as predict the efficacy of the treatment and monitor its progress

  15. Lactosylated liposomes for targeted delivery of doxorubicin to hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Zhou X

    2012-10-01

    Full Text Available Xiaoju Zhou,1,2,* Mengzi Zhang,2,* Bryant Yung,2 Hong Li,2 Chenguang Zhou,2 L James Lee,3,4 Robert J Lee2,41State Key Laboratory of Virology, Ministry of Education Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Wuhan University School of Pharmaceutical Sciences, Wuhan, People’s Republic of China; 2Division of Pharmaceutics, 3Department of Chemical and Biomolecular Engineering, 4NSF Nanoscale Science and Engineering Center for Affordable Nanoengineering of Polymeric Biomedical Devices, The Ohio State University, Columbus, OH, USA*These authors contributed equally to this workBackground: N-lactosyl-dioleoylphosphatidylethanolamine (Lac-DOPE was synthesized and evaluated as a liver-specific targeting ligand via asialoglycoprotein receptors for liposomal delivery of doxorubicin.Methods: Lactosylated liposomes encapsulating calcein (Lac-L-calcein or doxorubicin (Lac-L-DOX composed of egg phosphatidylcholine, cholesterol, monomethoxy polyethylene glycol 2000-distearoyl phosphatidylethanolamine, and Lac-DOPE at 50:35:5:10 (mol/mol were prepared by polycarbonate membrane extrusion and evaluated in human hepatocellular carcinoma HepG2 cells. Cellular uptake of Lac-L-calcein was monitored by confocal microscopy and by flow cytometry. The cytotoxicity of Lac-L-DOX was evaluated by MTT assay. The pharmacokinetic properties of Lac-L-DOX were studied in normal mice, and its biodistribution and antitumor activity were studied in nude mice with HepG2 xenografts.Results: The size of Lac-L-DOX was less than 100 nm and the liposomes demonstrated excellent colloidal stability. In vitro uptake of Lac-L-calcein by HepG2 cells was four times greater than that of non-targeted L-calcein. In the presence of 20 mM lactose, the uptake of Lac-L-calcein was inhibited, suggesting that asialoglycoprotein receptors mediated the observed cellular uptake. Lac-L-DOX exhibited enhanced in vivo cytotoxicity compared with the nontargeted liposomal doxorubicin (L

  16. Lipossomas: a bala mágica acertou? Liposomes: has the magic bullet hit the target?

    Directory of Open Access Journals (Sweden)

    Nuno C. Santos

    2002-12-01

    Full Text Available Efficient drug delivery systems are as important as drug themselves. A powerful drug unable to reach the target cell is useless in practice. Ehrlich's Magic Bullet was the first carrier system to be proposed. The evolution in this domain has been quite slow as the natural mechanisms of mammals against foreign products are hard to overcome. However, lipid-based systems (liposomes and related vesicles have attained reasonable success. The basic preparations and structural features of liposomes and related vesicles as well as their applications are addressed from the chemist's and biochemist's point of view.

  17. Hydrolytically degradable polymer micelles for drug delivery: a SAXS/SANS kinetic study.

    Science.gov (United States)

    Filippov, Sergey K; Franklin, John M; Konarev, Petr V; Chytil, Petr; Etrych, Tomas; Bogomolova, Anna; Dyakonova, Margarita; Papadakis, Christine M; Radulescu, Aurel; Ulbrich, Karel; Stepanek, Petr; Svergun, Dmitri I

    2013-11-11

    We report kinetic studies of therapeutically highly potent polymer-drug conjugates consisting of amphiphilic N-(2-hydroxypropyl) methacrylamide (HPMA)-based copolymers bearing the anticancer drug doxorubicin (Dox). Highly hydrophobic cholesterol moieties as well as the drug were attached to the polymer backbone by a pH-sensitive hydrazone bond. Moreover, the structure of the spacer between the polymer carrier and the cholesterol moiety differed in order to influence the release rate of the hydrophobic moiety, and thus the disintegration of the high-molecular-weight micellar nanoparticle structure. We performed time-dependent SAXS/SANS measurements after changing pH from a typical blood value (pH 7.2) to that of tumor cells (pH 5.0) to characterize the drug release and changes in particle size and shape. Nanoparticles composed of the conjugates containing Dox were generally larger than the drug-free ones. For most conjugates, nanoparticle growth or decay was observed in the time range of several hours. It was established that the growth/decay rate and the steady-state size of nanoparticles depend on the spacer structure. From analytical fitting, we conclude that the most probable structure of the nanoparticles was a core-shell or a core with attached Gaussian chains. We concluded that the spacer structure determined the fate of a cholesterol derivative after the pH jump. Fitting results for 5α-cholestan-3-onecholestan-3-one and cholesteryl-4-oxopentanoate (Lev-chol) implied that cholesterol moieties continuously escape from the core of the nanoparticle core and concentrate in the hydrophilic shell. In contrast, cholest-4-en-3-one spacer prevent cholesterol escaping. Dox moiety release was only observed after a change in pH. Such findings justify the model proposed in our previous paper. Lastly, the cholesteryl 4-(2-oxopropyl)benzoate (Opb-Chol) was a different case where after the release of hydrophobic Opb-Chol moieties, the core becomes more compact. The

  18. Filter-extruded liposomes revisited

    DEFF Research Database (Denmark)

    Hinna, Askell; Steiniger, Frank; Hupfeld, Stefan

    2016-01-01

    (pore-size, number of filter passages, and flow-rate), flow field-flow fractionation in conjunction with multi-angle laser light scattering (AF4-MALLS, Wyatt Technology Corp., Santa Barbara, CA) was employed. Liposome size-distributions determined by AF4-MALLS were compared with those of dynamic light...... is suggested to prepare large (300 nm) liposomes with rather narrow size distribution, based on the filter extrusion at defined flow-rates in combination with freeze-/ thaw-cycling and bench-top centrifugation....

  19. pH-sensitive liposomes containing polymerized phosphatidylethanolamine and fatty acid.

    Science.gov (United States)

    Choi, M J; Han, H S; Kim, H

    1992-11-01

    With the ultimate aim of targeting cancer drugs to malignant tissues, liposomes containing polymeric phosphatidylethanolamine and a fatty acid were prepared. For this purpose diacetylenic phosphatidylethanolamine (DAPE), a phosphatidylethanolamine containing diacetylene, was synthesized. Liposomes containing DAPE, fatty acid, and either phosphatidylethanolamine (PE) or phosphatidylethanolamine-beta-oleoyl-gamma-palmitoyl (POPE) were then prepared. Polymerization of DAPE was effected by UV illumination. The polymeric liposomes so obtained were stable at physiological pH but became leaky below pH 6.5. Of various compositions studied, the greatest pH-sensitivity was found with liposomes composed of 35 mol% DAPE, 35 mol% POPE, and 30 mol% saturated fatty acid. The presence of blood plasma albumin decreased vesicle stability while apolipoprotein A-I (apo A-I) had the opposite effect and plasma as a whole had a slightly stabilizing effect.

  20. "Nail" and "comb" effects of cholesterol modified NIPAm oligomers on cancer targeting liposomes

    KAUST Repository

    Li, Wengang

    2014-01-01

    Thermosensitive liposomes are a promising approach to controlled release and reduced drug cytotoxicity. Low molecular weight N-isopropylacrylamide (NIPAm) oligomers (NOs) with different architectures (main chain NOs (MCNOs) and side chain NOs (SCNOs)) were synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization and radical polymerization and then separately used to prepare thermosensitive liposomes. A more controlled and enhanced release was observed for both NO liposomes compared to pristine ones. Two release mechanisms depending on the oligomer architecture, namely "nail" for MCNOs and "comb" for SCNOs, are proposed. In addition to thermosensitivity, the cancer targeting property of NO liposomes was achieved by further biotinylation of the delivery system. © The Royal Society of Chemistry.

  1. Design and characterization of anionic PEGylated liposomal formulation loaded with paclitax for ovarian cancer

    Directory of Open Access Journals (Sweden)

    K Makwana

    2012-01-01

    Full Text Available Despite its strong antitumor activity, paclitaxel (Taxol® has limited clinical applications due to its low aqueous solubility and hypersensitivity caused by cremophor EL and ethanol which is the vehicle used in the current commercial product. In an attempt to develop a pharmaceutically acceptable formulation that could replace Taxol® , we have prepared PEGylated liposomes containing paclitaxel to improve its solubility and physicochemical stability. Its percent drug entrapment (PDE, mean particle size, zeta potential and in vitro release profile were determined. The optimized PEGylated liposomes provided high percent entrapment efficiency (64.29% and mean particle size of 228.6 nm. The electroflocculation method showed 5 mol% of DSPE-mPEG2000 was required to obtain maximum stability for PEGylated liposome. In vitro release data showed its long circulating characteristic. Paclitaxel loaded PEGylated liposomes can be considered a promising long circulating paclitaxel delivery with absence of side effects related to Taxol® .

  2. BODIPY-based fluorescent liposomes with sesquiterpene lactone trilobolide

    Czech Academy of Sciences Publication Activity Database

    Škorpilová, Ludmila; Rimpelová, S.; Jurášek, M.; Buděšínský, Miloš; Lokajová, Jana; Effenberg, R.; Slepička, P.; Ruml, T.; Kmoníčková, Eva; Drašar, P. B.; Wimmer, Zdeněk

    2017-01-01

    Roč. 13, JUL 4 (2017), s. 1316-1324 ISSN 1860-5397 R&D Projects: GA MŠk LD15012; GA MŠk(CZ) LO1304 Institutional support: RVO:61389030 ; RVO:61388963 ; RVO:68378041 Keywords : BODIPY conjugates * Cancer targeting * Drug delivery * Liposomes * Natural compounds * Sesquiterpene lactone trilobolide Subject RIV: CC - Organic Chemistry; FR - Pharmacology ; Medidal Chemistry (UEM-P) OBOR OECD: Organic chemistry; Pharmacology and pharmacy (UEM-P) Impact factor: 2.337, year: 2016

  3. Sterically stabilized pH-sensitive liposomes. Intracellular delivery of aqueous contents and prolonged circulation in vivo.

    Science.gov (United States)

    Slepushkin, V A; Simões, S; Dazin, P; Newman, M S; Guo, L S; Pedroso de Lima, M C; Düzgüneş, N

    1997-01-24

    Liposomes that destabilize at mildly acidic pH are efficient tools for delivering water-soluble drugs into the cell cytoplasm. However, their use in vivo is limited because of their rapid uptake from circulation by the reticuloendothelial system. Lipid-anchored polyethylene glycol (PEG-PE) prolongs the circulation time of liposomes by steric stabilization. We have found that addition of PEG-PE to the membrane of pH-sensitive liposomes composed of cholesteryl hemisuccinate (CHEMS) and dioleoylphosphatidylethanolamine (DOPE) confers steric stability to these vesicles. This modification significantly decreases the pH-dependent release of a charged water-soluble fluorophore, calcein, from liposomes suspended in buffer or cell culture medium. However, the ability of such liposomes to release calcein intracellularly, measured by a novel flow cytometry technique involving dual fluorescence labeling, remains unaltered. As expected, the release of calcein from liposomes endocytosed by cells is inhibited upon pretreatment of the cells with NH4Cl, an inhibitor of endosome acidification. The unique properties of these liposomes were also demonstrated in vivo. The distribution kinetics of 111In-containing CHEMS/DOPE/PEG-PE liposomes injected intravenously into rats has pharmacokinetic parameters similar to control, non-pH-sensitive, sterically stabilized CHEMS/distearoylphosphatidylcholine/PEG-PE liposomes. In contrast, regular pH-sensitive liposomes lacking the PEG-PE component are cleared rapidly. Sterically stabilized pH-sensitive liposomes may therefore be useful for the intracellular delivery in vivo of highly negatively charged molecules such as genes, antisense oligonucleotides, and ribozymes for the treatment of various diseases.

  4. Cytoprotective and enhanced anti-inflammatory activities of liposomal piroxicam formulation in lipopolysaccharide-stimulated RAW 264.7 macrophages.

    Science.gov (United States)

    Chiong, Hoe Siong; Yong, Yoke Keong; Ahmad, Zuraini; Sulaiman, Mohd Roslan; Zakaria, Zainul Amiruddin; Yuen, Kah Hay; Hakim, Muhammad Nazrul

    2013-01-01

    Liposomal drug delivery systems, a promising lipid-based nanoparticle technology, have been known to play significant roles in improving the safety and efficacy of an encapsulated drug. Liposomes, prepared using an optimized proliposome method, were used in the present work to encapsulate piroxicam, a widely prescribed nonsteroidal anti-inflammatory drug. The cytotoxic effects as well as the in vitro efficacy in regulation of inflammatory responses by free-form piroxicam and liposome-encapsulated piroxicam were evaluated using a lipopolysaccharide-sensitive macrophage cell line, RAW 264.7. Cells treated with liposome-encapsulated piroxicam demonstrated higher cell viabilities than those treated with free-form piroxicam. In addition, the liposomal piroxicam formulation resulted in statistically stronger inhibition of pro-inflammatory mediators (ie, nitric oxide, tumor necrosis factor-α, interleukin-1β, and prostaglandin E2) than piroxicam at an equivalent dose. The liposome-encapsulated piroxicam also caused statistically significant production of interleukin-10, an anti-inflammatory cytokine. This study affirms the potential of a liposomal piroxicam formulation in reducing cytotoxicity and enhancing anti-inflammatory responses in vitro.

  5. Liposomal Systems as Nanocarriers for the Antiviral Agent Ivermectin

    Directory of Open Access Journals (Sweden)

    Romina Croci

    2016-01-01

    Full Text Available RNA virus infections can lead to the onset of severe diseases such as fever with haemorrhage, multiorgan failure, and mortality. The emergence and reemergence of RNA viruses continue to pose a significant public health threat worldwide with particular attention to the increasing incidence of flaviviruses, among others Dengue, West Nile Virus, and Yellow Fever viruses. Development of new and potent antivirals is thus urgently needed. Ivermectin, an already known antihelminthic drug, has shown potent effects in vitro on Flavivirus helicase, with EC50 values in the subnanomolar range for Yellow Fever and submicromolar EC50 for Dengue Fever, Japanese encephalitis, and tick-borne encephalitis viruses. However ivermectin is hampered in its application by pharmacokinetic problems (little solubility and high cytotoxicity. To overcome such problems we engineered different compositions of liposomes as ivermectin carriers characterizing and testing them on several cell lines for cytotoxicity. The engineered liposomes were less cytotoxic than ivermectin alone and they showed a significant increase of the antiviral activity in all the Dengue stains tested (1, 2, and S221. In the current study ivermectin is confirmed to be an effective potential antiviral and liposomes, as drug carriers, are shown to modulate the drug activity. All together the results represent a promising starting point for future improvement of ivermectin as antiviral and its delivery.

  6. Optimizing Liposomal Cisplatin Efficacy through Membrane Composition Manipulations

    Science.gov (United States)

    Zisman, Natalia; Dos Santos, Nancy; Johnstone, Sharon; Tsang, Alan; Bermudes, David; Mayer, Lawrence; Tardi, Paul

    2011-01-01

    The first liposomal formulation of cisplatin to be evaluated clinically was SPI-077. Although the formulation demonstrated enhanced cisplatin tumor accumulation in preclinical models it did not enhance clinical efficacy, possibly due to limited cisplatin release from the formulation localized within the tumor. We have examined a series of liposomal formulations to address the in vivo relationship between cisplatin release rate and formulation efficacy in the P388 murine leukemia model. The base formulation of phosphatidylcholine: phosphatidylglycerol: cholesterol was altered in the C18 and C16 phospholipid content to influence membrane fluidity and thereby impacting drug circulation lifetime and drug retention. Phase transition temperatures (Tm) ranged from 42–55°C. The high Tm formulations demonstrated enhanced drug retention properties accompanied by low antitumor activity while the lowest Tm formulations released the drug too rapidly in the plasma, limiting drug delivery to the tumor which also resulted in low antitumor activity. A formulation composed of DSPC : DPPC : DSPG : Chol; (35 : 35 : 20 : 10) with an intermediate drug release rate and a cisplatin plasma half-life of 8.3 hours showed the greatest antitumor activity. This manuscript highlights the critical role that drug release rates play in the design of an optimized drug delivery vehicle. PMID:22312548

  7. Endothelial targeting of liposomes encapsulating SOD/catalase mimetic EUK-134 alleviates acute pulmonary inflammation.

    Science.gov (United States)

    Howard, Melissa D; Greineder, Colin F; Hood, Elizabeth D; Muzykantov, Vladimir R

    2014-03-10

    Production of excessive levels of reactive oxygen species (ROS) in the vascular endothelium is a common pathogenic pathway in many dangerous conditions, including acute lung injury, ischemia-reperfusion, and inflammation. Ineffective delivery of antioxidants to the endothelium limits their utility for management of these conditions. In this study, we devised a novel translational antioxidant intervention targeted to the vascular endothelium using PEG-liposomes loaded with EUK-134 (EUK), a potent superoxide dismutase/catalase mimetic. EUK loaded into antibody-coated liposomes (size 197.8±4.5 nm diameter, PDI 0.179±0.066) exerted partial activity in the intact carrier, while full activity was recovered upon liposome disruption. For targeting we used antibodies (Abs) to platelet-endothelial cell adhesion molecule (PECAM-1). Both streptavidin-biotin and SATA/SMCC conjugation chemistries provided binding of 125-150 Ab molecules per liposome. Ab/EUK/liposomes, but not IgG/EUK/liposomes: i) bound to endothelial cells and inhibited cytokine-induced inflammatory activation in vitro; and, ii) accumulated in lungs after intravascular injection, providing >60% protection against pulmonary edema in endotoxin-challenged mice (vs <6% protection afforded by IgG/liposome/EUK counterpart). Since the design elements of this drug delivery system are already in clinical use (PEG-liposomes, antibodies, SATA/SMCC conjugation), it is an attractive candidate for translational interventions using antioxidant molecules such as EUK and other clinically acceptable drugs. Copyright © 2014 Elsevier B.V. All rights reserved.

  8. Liposome and niosome preparation using a membrane contactor for scale-up.

    Science.gov (United States)

    Pham, Thi Thuy; Jaafar-Maalej, Chiraz; Charcosset, Catherine; Fessi, Hatem

    2012-06-01

    The scaling-up ability of liposome and niosome production, from laboratory scale using a syringe-pump device to a pilot scale using the membrane contactor module, was investigated. For this aim, an ethanol injection-based method was applied for liposome and niosome preparation. The syringe-pump device was used for laboratory scale batches production (30 ml for liposomes, 20 ml for niosomes) then a pilot scale (750 ml for liposomes, 1000 ml for niosomes) were obtained using the SPG membrane contactor. Resulted nanovesicles were characterized in terms of mean vesicles size, polydispersity index (PdI) and zeta potential. The drug encapsulation efficiency (E.E.%) was evaluated using two drug-models: caffeine and spironolactone, a hydrophilic and a lipophilic molecule, respectively. As results, nanovectors mean size using the syringe-pump device was comprised between 82 nm and 95 nm for liposomes and between 83 nm and 127 nm for niosomes. The optimal E.E. of caffeine within niosomes, was found around 9.7% whereas the spironolactone E.E. reached 95.6% which may be attributed to its lipophilic properties. For liposomes these values were about 9.7% and 86.4%, respectively. It can be clearly seen that the spironolactone E.E. was slightly higher within niosomes than liposomes. Optimized formulations, which offered smaller size and higher E.E., were selected for pilot scale production using the SPG membrane. It has been found that vesicles characteristics (size and E.E.%) were reproducible using the membrane contactor module. Thus, the current study demonstrated the usefulness of the membrane contactor as a device for scaling-up both liposome and niosome preparations with small mean sizes. Copyright © 2012 Elsevier B.V. All rights reserved.

  9. The Effects of Lyophilization on the Physico-Chemical Stability of Sirolimus Liposomes

    Directory of Open Access Journals (Sweden)

    Parvin Zakeri-Milani

    2013-02-01

    Full Text Available Purpose: The major limitation in the widespread use of liposome drug delivery system is its instability. Lyophilization is a promising approach to ensure the long-term stability of liposomes. The aim of this study was to prepare sirolimus-loaded liposomes, study their stability and investigate the effect of lyophilization either in the presence or in the absence of lyoprotectant on liposome properties. Methods: Two types of multi-lamellar liposomes, conventional and fusogenic, containing sirolimus were prepared by modified thin film hydration method with different ratio of dipalmitoylphosphatidylcholine (DPPC, cholesterol and dioleoylphosphoethanolamine (DOPE, and were lyophilized with or without dextrose as lyoprotectant. Chemical stability investigation was performed at 4°C and 25°C until 6 months using a validated HPLC method. Physical stability was studied with determination of particle size (PS and encapsulation efficiency (EE % of formulations through 6 months. Results: Chemical stability test at 4°C and 25°C until 6 months showed that drug content of liposomes decreased 8.4% and 20.2% respectively. Initial mean EE % and PS were 72.8 % and 582 nm respectively. After 6 months mean EE % for suspended form, lyophilized without lyoprotectant and lyophilized with lyoprotectant were 54.8 %, 62.3% and 67.1 % at 4°C and 48.2%, 60.4 % and 66.8 % at 25°C respectively. Corresponding data for mean PS were 8229 nm, 2397 nm and 688nm at 4°C and 9362 nm, 1944 nm and 737 nm at 25°C respectively. Conclusion: It is concluded that lyophilization with and without dextrose could increase shelf life of liposome and dextrose has lyoprotectant effect that stabilized liposomes in the lyophilization process.

  10. Techniques for Loading Technetium-99m and Rhenium-186/188 Radionuclides into Preformed Liposomes for Diagnostic Imaging and Radionuclide Therapy.

    Science.gov (United States)

    Goins, Beth; Bao, Ande; Phillips, William T

    2017-01-01

    Liposomes can serve as carriers of radionuclides for diagnostic imaging and therapeutic applications. Herein, procedures are outlined for radiolabeling liposomes with the gamma-emitting radionuclide, technetium-99m ( 99m Tc), for noninvasive detection of disease and for monitoring the pharmacokinetics and biodistribution of liposomal drugs, and/or with therapeutic beta-emitting radionuclides, rhenium-186/188 ( 186/188 Re), for radionuclide therapy. These efficient and practical liposome radiolabeling methods use a post-labeling mechanism to load 99m Tc or 186/188 Re into preformed liposomes prepared in advance of the labeling procedure. For all liposome radiolabeling methods described, a lipophilic chelator is used to transport 99m Tc or 186/188 Re across the lipid bilayer of the preformed liposomes. Once within the liposome interior, the pre-encapsulated glutathione or ammonium sulfate (pH) gradient provides for stable entrapment of the 99m Tc and 186/188 Re within the liposomes. In the first method, 99m Tc is transported across the lipid bilayer by the lipophilic chelator, hexamethylpropyleneamine oxime (HMPAO) and 99m Tc-HMPAO becomes trapped by interaction with the pre-encapsulated glutathione within the liposomes. In the second method, 99m Tc or 186/188 Re is transported across the lipid bilayer by the lipophilic chelator, N,N-bis(2-mercaptoethyl)-N',N'-diethylethylenediamine (BMEDA), and 99m Tc-BMEDA or 186/188 Re-BMEDA becomes trapped by interaction with pre-encapsulated glutathione within the liposomes. In the third method, an ammonium sulfate (pH) gradient loading technique is employed using liposomes with an extraliposomal pH of 7.4 and an interior pH of 5.1. BMEDA, which is lipophilic at pH 7.4, serves as a lipophilic chelator for 99m Tc or 186/188 Re to transport the radionuclides across the lipid bilayer. Once within the more acidic liposome interior, 99m Tc/ 186/188 Re-BMEDA complex becomes protonated and more hydrophilic, which results in stable

  11. Dynamic Probing of Nanoparticle Stability In Vivo: A Liposomal Model Assessed Using In Situ Microdialysis and Optical Imaging

    Directory of Open Access Journals (Sweden)

    Chien-Chung Jeng

    2011-01-01

    Full Text Available Nanoparticle-mediated drug delivery and controlled release has been a vigorous research area in contemporary nanomedicine. The in vivo stability of nanoparticle delivered on site is a prerequisite for the design of drug-controlled release by any means. In this study, the first methodology comprised of microdialysis and optical imaging to assess the liposome stability in vivo is reported. Macroscopically, we demonstrated the DPPG liposomes with negative surface charge fast accumulated in the rat liver upon their i.v. administration using optical imaging. Microscopically, the concurrent analysis of fluorescent molecules leaching from the liposomes, in situ sampled using microdialysis probe, provides the dynamic information of stability of DPPG liposomes locus in quo. The current combination of in situ microdialysis and optical imaging possesses a great potential for use as a platform technology to evaluate the nanoparticle stability and the bioavailability of drug payload released on targeted site in vivo.

  12. Propylene glycol liposomes as a topical delivery system for miconazole nitrate: comparison with conventional liposomes.

    Science.gov (United States)

    Elmoslemany, Riham M; Abdallah, Ossama Y; El-Khordagui, Labiba K; Khalafallah, Nawal M

    2012-06-01

    Propylene glycol (PG)-phospholipid vesicles have been advocated as flexible lipid vesicles for enhanced skin delivery of drugs. To further characterize the performance of these vesicles and to address some relevant pharmaceutical issues, miconazole nitrate(MN)-loaded PG nanoliposomes were prepared and characterized for vesicle size, entrapment efficiency, in vitro release, and vesicle stability. An issue of pharmaceutical importance is the time-dependent, dilution-driven diffusion of propylene glycol out of the vesicles. This was addressed by assessing propylene glycol using gas chromatography in the separated vesicles and monitoring its buildup in the medium after repeated dispersion of separated vesicles in fresh medium. Further, the antifungal activity of liposomal formulations under study was assessed using Candida albicans, and their in vitro skin permeation and retention were studied using human skin. At all instances, blank and drug-loaded conventional liposomes were included for comparison. The results provided evidence of controlled MN delivery, constant percent PG uptake in the vesicles (≈45.5%) in the PG concentration range 2.5 to 10%, improved vesicle stability, and enhanced skin deposition of MN with minimum skin permeation. These are key issues for different formulation and performance aspects of propylene glycol-phospholipid vesicles.

  13. trimethylammoniumpropane-based Liposomes

    African Journals Online (AJOL)

    continuous lymphoid tissue so as to protect the antigen against degradation on mucosal surfaces, and enhance its uptake in mucosa- associated lymphoid tissue. The vaccines used for ND control must be able to protect the susceptible poultry against velogenic strains of the virus. Antibody titres of 23 are protective, but.

  14. Enhanced transfection of tumor cells in vivo using “Smart” pH-sensitive TAT-modified pegylated liposomes

    Science.gov (United States)

    Kale, Amit A.; Torchilin, Vladimir P.

    2012-01-01

    Liposomes have been prepared loaded with DNA (plasmid encoding for the green fluorescent protein, GFP) and additionally modified with TATp and PEG, with PEG being attached to the liposome surface via both pH-sensitive hydrazone and non-pH-sensitive bonds. The pGFP-loaded liposomal preparations have been administered intratumorarly in tumor-bearing mice and the efficacy of tumor cell transfection was followed after 72 h. The administration of pGFP–TATp–liposomes with non-pH-sensitive PEG coating has resulted in only minimal transfection of tumor cells because of steric hindrances for the liposome-to-cell interaction created by the PEG coat, which shielded the surface-attached TATp. At the same time, the administration of pGFP–TATp–liposomes with the low pH-detachable PEG resulted in at least three times more efficient transfection since the removal of PEG under the action of the decreased intratumoral pH leads to the exposure of the liposome-attached TATp residues, enhanced penetration of the liposomes inside tumor cells and more effective intracellular delivery of the pGFP. This result can be considered as an important step in the development of tumor-specific stimuli-sensitive drug and gene delivery systems. PMID:17671900

  15. Preparation of a Sustained-Release Nebulized Aerosol of R-terbutaline Hydrochloride Liposome and Evaluation of Its Anti-asthmatic Effects via Pulmonary Delivery in Guinea Pigs.

    Science.gov (United States)

    Li, Qingrui; Zhan, Shuyao; Liu, Qing; Su, Hao; Dai, Xi; Wang, Hai; Beng, Huimin; Tan, Wen

    2018-01-01

    An aerosolized liposome formulation for the pulmonary delivery of an anti-asthmatic medication was developed. Asthma treatment usually requires frequent administration of medication for a sustained bronchodilator response. Liposomes are known for their sustained drug release capability and thus would be a suitable delivery system for prolonging the therapeutic effect of anti-asthmatic medication. Liposomes prepared by thin film hydration were loaded with a model drug, R-terbutaline hydrochloride(R-TBH), using an ammonium sulfate-induced transmembrane electrochemical gradient. This technique provided an encapsulation efficiency of up to 71.35% and yielded R-TBH liposomes with a particle size of approximately 145 ± 20 nm. According to stability studies, these R-TBH liposomes should be stored at 4°C before usage. Compared to R-TBH solution, which showed 90.84% release within 8 h, liposomal R-TBH had a cumulative release of 73.53% at 37°C over 192 h. A next generation impactor (NGI) was used to analyze the particle size distribution in the lungs of R-TBH liposome aerosol in vitro at 5°C. The therapeutic efficacy of the nebulized aerosol of the R-TBH liposomes was assessed via pulmonary delivery in guinea pigs. The results showed that, compared to the R-TBH solution group, the R-TBH liposome group had a prolonged anti-asthma effect.

  16. Secretory phospholipase A2 responsive liposomes exhibit a potent anti-neoplastic effect in vitro, but induce unforeseen severe toxicity in vivo

    DEFF Research Database (Denmark)

    Østrem, Ragnhild Garborg; Parhamifar, Ladan; Pourhassan, Houman

    2017-01-01

    enzyme specific drug release. Treatment of two different cancer cell lines with liposomal oxaliplatin revealed efficient growth inhibition compared to that of clinically used stealth liposomes. The in vivo therapeutic effect was evaluated in nude NMRI mice using the sPLA2 secreting mammary carcinoma cell...

  17. Charge effect of a liposomal delivery system encapsulating simvastatin to treat experimental ischemic stroke in rats

    Directory of Open Access Journals (Sweden)

    Campos-Martorell M

    2016-06-01

    were able to reach the brain and accumulate specifically in the infarcted area. Moreover, neutral liposomes exhibited higher bioavailability in plasma 4 hours after being administered. The detection of simvastatin by ultra-high-protein liquid chromatography confirmed its ability to cross the blood–brain barrier, when administered either as a free drug or encapsulated into liposomes. Conclusion: This study confirms that liposome charge is critical to promote its accumulation in the brain infarct after MCAOt. Furthermore, simvastatin can be delivered after being encapsulated. Thus, simvastatin encapsulation might be a promising strategy to ensure that the drug reaches the brain, while increasing its bioavailability and reducing possible side effects. Keywords: simvastatin, liposomes, delivery, brain, stroke, rat

  18. Dysregulation of protein degradation pathways may mediate the liver injury and phospholipidosis associated with a cationic amphiphilic antibiotic drug

    Energy Technology Data Exchange (ETDEWEB)

    Mosedale, Merrie [Hamner-University of North Carolina Institute for Drug Safety Sciences, The Hamner Institutes for Health Sciences, Research Triangle Park, NC 27709 (United States); Wu, Hong [Drug Safety Research and Development, Pfizer Global Research and Development, Groton, CT06340 (United States); Kurtz, C. Lisa [Hamner-University of North Carolina Institute for Drug Safety Sciences, The Hamner Institutes for Health Sciences, Research Triangle Park, NC 27709 (United States); Schmidt, Stephen P. [Drug Safety Research and Development, Pfizer Global Research and Development, Groton, CT06340 (United States); Adkins, Karissa, E-mail: Karissa.Adkins@pfizer.com [Drug Safety Research and Development, Pfizer Global Research and Development, Groton, CT06340 (United States); Harrill, Alison H. [Hamner-University of North Carolina Institute for Drug Safety Sciences, The Hamner Institutes for Health Sciences, Research Triangle Park, NC 27709 (United States); University of Arkansas for Medical Sciences, Little Rock, AR72205 (United States)

    2014-10-01

    A large number of antibiotics are known to cause drug-induced liver injury in the clinic; however, interpreting clinical risk is not straightforward owing to a lack of predictivity of the toxicity by standard preclinical species and a poor understanding of the mechanisms of toxicity. An example is PF-04287881, a novel ketolide antibiotic that caused elevations in liver function tests in Phase I clinical studies. In this study, a mouse diversity panel (MDP), comprised of 34 genetically diverse, inbred mouse strains, was utilized to model the toxicity observed with PF-04287881 treatment and investigate potential mechanisms that may mediate the liver response. Significant elevations in serum alanine aminotransferase (ALT) levels in PF-04287881-treated animals relative to vehicle-treated controls were observed in the majority (88%) of strains tested following a seven day exposure. The average fold elevation in ALT varied by genetic background and correlated with microscopic findings of hepatocellular hypertrophy, hepatocellular single cell necrosis, and Kupffer cell vacuolation (confirmed as phospholipidosis) in the liver. Global liver mRNA expression was evaluated in a subset of four strains to identify transcript and pathway differences that distinguish susceptible mice from resistant mice in the context of PF-04287881 treatment. The protein ubiquitination pathway was highly enriched among genes associated with PF-04287881-induced hepatocellular necrosis. Expression changes associated with PF-04287881-induced phospholipidosis included genes involved in drug transport, phospholipid metabolism, and lysosomal function. The findings suggest that perturbations in genes involved in protein degradation leading to accumulation of oxidized proteins may mediate the liver injury induced by this drug. - Highlights: • Identified susceptible and resistant mouse strains to liver injury induced by a CAD • Liver injury characterized by single cell necrosis, and phospholipidosis

  19. Dysregulation of protein degradation pathways may mediate the liver injury and phospholipidosis associated with a cationic amphiphilic antibiotic drug

    International Nuclear Information System (INIS)

    Mosedale, Merrie; Wu, Hong; Kurtz, C. Lisa; Schmidt, Stephen P.; Adkins, Karissa; Harrill, Alison H.

    2014-01-01

    A large number of antibiotics are known to cause drug-induced liver injury in the clinic; however, interpreting clinical risk is not straightforward owing to a lack of predictivity of the toxicity by standard preclinical species and a poor understanding of the mechanisms of toxicity. An example is PF-04287881, a novel ketolide antibiotic that caused elevations in liver function tests in Phase I clinical studies. In this study, a mouse diversity panel (MDP), comprised of 34 genetically diverse, inbred mouse strains, was utilized to model the toxicity observed with PF-04287881 treatment and investigate potential mechanisms that may mediate the liver response. Significant elevations in serum alanine aminotransferase (ALT) levels in PF-04287881-treated animals relative to vehicle-treated controls were observed in the majority (88%) of strains tested following a seven day exposure. The average fold elevation in ALT varied by genetic background and correlated with microscopic findings of hepatocellular hypertrophy, hepatocellular single cell necrosis, and Kupffer cell vacuolation (confirmed as phospholipidosis) in the liver. Global liver mRNA expression was evaluated in a subset of four strains to identify transcript and pathway differences that distinguish susceptible mice from resistant mice in the context of PF-04287881 treatment. The protein ubiquitination pathway was highly enriched among genes associated with PF-04287881-induced hepatocellular necrosis. Expression changes associated with PF-04287881-induced phospholipidosis included genes involved in drug transport, phospholipid metabolism, and lysosomal function. The findings suggest that perturbations in genes involved in protein degradation leading to accumulation of oxidized proteins may mediate the liver injury induced by this drug. - Highlights: • Identified susceptible and resistant mouse strains to liver injury induced by a CAD • Liver injury characterized by single cell necrosis, and phospholipidosis

  20. Analysis of liposomes using asymmetrical flow field-flow fractionation

    DEFF Research Database (Denmark)

    Kuntsche, Judith; Decker, Christiane; Fahr, Alfred

    2012-01-01

    of larger vesicles was underestimated. Imbalance in the osmolality between the inner and outer aqueous phase resulted in liposome swelling after dilution in hypoosmotic carrier liquids. In contrast, liposome shrinking under hyperosmotic conditions was barely visible. The liposomes themselves eluted...

  1. Solid Lipid Particles for Oral Delivery of Peptide and Protein Drugs II - The Digestion of Trilaurin Protects Desmopressin from Proteolytic Degradation

    DEFF Research Database (Denmark)

    Christophersen, Philip Carsten; Zhang, Long; Müllertz, Anette

    2014-01-01

    , which is the same rank order as the lipid degradation rate. A reverse rank order was found for the protection of desmopressin from enzymatic degradation due to spatial separation of desmopressin from the protease. TG12 accelerated the release of desmopressin from all lipid particles when added as either...... and protease was determined. Trilaurin (TG12), trimyristin (TG14), tripalmitin (TG16), and tristearin (TG18) were used as lipid excipients to produce solid lipid microparticles. RESULTS: In the presence of lipase, the rate of drug release from different lipid particles was in the order of TG14 > TG16 > TG18...... drug-free microparticles to the lipolysis medium or incorporated in TG16 particles. Additionally, TG12 particles protected desmopressin from degradation when present in the lipolysis medium with the other lipid microparticles. CONCLUSIONS: TG12 is a very interesting lipid for oral lipid formulations...

  2. Encapsulation of ropivacaine in a combined (donor-acceptor, ionic-gradient liposomal system promotes extended anesthesia time.

    Directory of Open Access Journals (Sweden)

    Camila Morais Gonçalves da Silva

    Full Text Available Ropivacaine is a local anesthetic with similar potency but lower systemic toxicity than bupivacaine, the most commonly used spinal anesthetic. The present study concerns the development of a combined drug delivery system for ropivacaine, comprised of two types of liposomes: donor multivesicular vesicles containing 250 mM (NH42SO4 plus the anesthetic, and acceptor large unilamellar vesicles with internal pH of 5.5. Both kinds of liposomes were composed of hydrogenated soy-phosphatidylcholine:cholesterol (2:1 mol% and were prepared at pH 7.4. Dynamic light scattering, transmission electron microscopy and electron paramagnetic resonance techniques were used to characterize the average particle size, polydispersity, zeta potential, morphology and fluidity of the liposomes. In vitro dialysis experiments showed that the combined liposomal system provided significantly longer (72 h release of ropivacaine, compared to conventional liposomes (~45 h, or plain ropivacaine (~4 h (p <0.05. The pre-formulations tested were significantly less toxic to 3T3 cells, with toxicity increasing in the order: combined system < ropivacaine in donor or acceptor liposomes < ropivacaine in conventional liposomes < plain ropivacaine. The combined formulation, containing 2% ropivacaine, increased the anesthesia duration up to 9 h after subcutaneous infiltration in mice. In conclusion, a promising drug delivery system for ropivacaine was described, which can be loaded with large amounts of the anesthetic (2%, with reduced in vitro cytotoxicity and extended anesthesia time.

  3. General and programmable synthesis of hybrid liposome/metal nanoparticles

    OpenAIRE

    Lee, Jin-Ho; Shin, Yonghee; Lee, Wooju; Whang, Keumrai; Kim, Dongchoul; Lee, Luke P.; Choi, Jeong-Woo; Kang, Taewook

    2016-01-01

    Hybrid liposome/metal nanoparticles are promising candidate materials for biomedical applications. However, the poor selectivity and low yield of the desired hybrid during synthesis pose a challenge. We designed a programmable liposome by selective encoding of a reducing agent, which allows self-crystallization of metal nanoparticles within the liposome to produce stable liposome/metal nanoparticles alone. We synthesized seven types of liposome/monometallic and more complex liposome/bimetalli...

  4. Liposome-Based Delivery Systems in Plant Polysaccharides

    Directory of Open Access Journals (Sweden)

    Meiwan Chen

    2012-01-01

    Full Text Available Plant polysaccharides consist of many monosaccharide by α- or β-glycosidic bond which can be extracted by the water, alcohol, lipophile liquid from a variety of plants including Cordyceps sinensis, astragalus, and mushrooms. Recently, many evidences illustrate that natural plant polysaccharides possess various biological activities including strengthening immunity, lowering blood sugar, regulating lipid metabolism, antioxidation, antiaging, and antitumour. Plant polysaccharides have been widely used in the medical field due to their special features and low toxicity. As an important drug delivery system, liposomes can not only encapsulate small-molecule compound but also big-molecule drug; therefore, they present great promise for the application of plant polysaccharides with unique physical and chemical properties and make remarkable successes. This paper summarized the current progress in plant polysaccharides liposomes, gave an overview on their experiment design method, preparation, and formulation, characterization and quality control, as well as in vivo and in vitro studies. Moreover, the potential application of plant polysaccharides liposomes was prospected as well.

  5. Physical and biological characterization of sericin-loaded copolymer liposomes stabilized by polyvinyl alcohol.

    Science.gov (United States)

    Suktham, Kunat; Koobkokkruad, Thongchai; Saesoo, Somsak; Saengkrit, Nattika; Surassmo, Suvimol

    2016-12-01

    Sericin protein (SP) is widely used as a nutrient biomaterial for biomedical and cosmeceutical applications although it shows low stability to heat and light. To overcome these problems and add value to wastewater from the silk industry, sericin protein was recovered as sericin-loaded copolymer-liposomes (SP-PVA-LP), prepared through thin film hydration. The size and morphology of the liposomes were investigated using dynamic light scattering (DLS), and electron microscopy (SEM and TEM). The particle size, liposome surface morphology and encapsulation efficiency of SP were dependent on PVA concentration. The hydrodynamic size of the nanoparticles was between 200 and 400nm, with the degree of negative charge contingent on sericin loading. SEM and TEM images confirmed the mono-dispersity, and spherical nature of the particles, with FTIR measurements confirming the presence of surface bound PVA. Exposure of liposomes to 500ppm sericin highlighted a dependence of encapsulation efficiency on PVA content; 2% surface PVA proved the optimal level for sericin loading. Cytotoxicity and viability assays revealed that SP-loaded surface modified liposomes promote cellular attachment and proliferation of human skin fibroblasts without adverse toxic effects. Surface modified copolymer liposomes show high performance in maintaining structural stability, and promoting enhancements in the solubility and bio-viability of sericin. Taken together, these biocompatible constructs allow for effective controlled release, augmenting sericin activity and resulting in effective drug delivery systems. Copyright © 2016 Elsevier B.V. All rights reserved.

  6. Fast high-throughput screening of temoporfin-loaded liposomal formulations prepared by ethanol injection method.

    Science.gov (United States)

    Yang, Kewei; Delaney, Joseph T; Schubert, Ulrich S; Fahr, Alfred

    2012-03-01

    A new strategy for fast, convenient high-throughput screening of liposomal formulations was developed, utilizing the automation of the so-called ethanol-injection method. This strategy was illustrated by the preparation and screening of the liposomal formulation library of a potent second-generation photosensitizer, temoporfin. Numerous liposomal formulations were efficiently prepared using a pipetting robot, followed by automated size characterization, using a dynamic light scattering plate reader. Incorporation efficiency of temoporfin and zeta potential were also detected in selected cases. To optimize the formulation, different parameters were investigated, including lipid types, lipid concentration in injected ethanol, ratio of ethanol to aqueous solution, ratio of drug to lipid, and the addition of functional phospholipid. Step-by-step small liposomes were prepared with high incorporation efficiency. At last, an optimized formulation was obtained for each lipid in the following condition: 36.4 mg·mL(-1) lipid, 13.1 mg·mL(-1) mPEG(2000)-DSPE, and 1:4 ethanol:buffer ratio. These liposomes were unilamellar spheres, with a diameter of approximately 50 nm, and were very stable for over 20 weeks. The results illustrate this approach to be promising for fast high-throughput screening of liposomal formulations.

  7. Continuous-Flow Production of Injectable Liposomes via a Microfluidic Approach

    Directory of Open Access Journals (Sweden)

    Alessandra Zizzari

    2017-12-01

    Full Text Available Injectable liposomes are characterized by a suitable size and unique lipid mixtures, which require time-consuming and nonstraightforward production processes. The complexity of the manufacturing methods may affect liposome solubility, the phase transition temperatures of the membranes, the average particle size, and the associated particle size distribution, with a possible impact on the drug encapsulation and release. By leveraging the precise steady-state control over the mixing of miscible liquids and a highly efficient heat transfer, microfluidic technology has proved to be an effective and direct methodology to produce liposomes. This approach results particularly efficient in reducing the number of the sizing steps, when compared to standard industrial methods. Here, Microfluidic Hydrodynamic Focusing chips were produced and used to form liposomes upon tuning experimental parameters such as lipids concentration and Flow-Rate-Ratios (FRRs. Although modelling evidenced the dependence of the laminar flow on the geometric constraints and the FRR conditions, for the specific formulation investigated in this study, the lipids concentration was identified as the primary factor influencing the size of the liposomes and their polydispersity index. This was attributed to a predominance of the bending elasticity modulus over the vesiculation index in the lipid mixture used. Eventually, liposomes of injectable size were produced using microfluidic one-pot synthesis in continuous flow.

  8. Absorption and tissue distribution of doxorubicin entrapped in liposomes following intravenous or intraperitoneal administration.

    Science.gov (United States)

    Rosa, P; Clementi, F

    1983-01-01

    Absorption and tissue distribution of free doxorubicin (Dxn) and Dxn entrapped into liposomes have been examined after intravenous (i.v.) or intraperitoneal (i.p.) injection into C57/B1/6 mice. Liposomal encapsulation of Dxn altered its plasma kinetics and tissue distribution. After i.v. administration Dxn in liposomes has a half-life longer than that of free Dxn and it is taken up mostly by tissues rich in reticuloendothelial cells, such as liver and spleen. In the heart and kidney liposomal Dxn reaches a lower concentration than free Dxn. After i.p. injection the tissue distribution of liposomal Dxn is drastically changed. We did not observe the first peak of high concentration in the tissues, the Dxn content in liver and spleen is decreased and its concentration in heart is even more reduced. The results of this study suggest that the route of administration of liposome-entrapped drugs may change both the kinetics of absorption and their tissue distribution and this could result in a different pharmacological effect.

  9. The adjuvant mechanism of cationic dimethyldioctadecylammonium liposomes

    DEFF Research Database (Denmark)

    Korsholm, Karen Smith; Agger, Else Marie; Foged, Camilla

    2007-01-01

    Cationic liposomes are being used increasingly as efficient adjuvants for subunit vaccines but their precise mechanism of action is still unknown. Here, we investigated the adjuvant mechanism of cationic liposomes based on the synthetic amphiphile dimethyldioctadecylammonium (DDA). The liposomes...... concentrations. This efficient adsorption onto the liposomes led to an enhanced uptake of OVA by BM-DCs as assessed by flow cytometry and confocal fluorescence laser-scanning microscopy. This was an active process, which was arrested at 4 degrees and by an inhibitor of actin-dependent endocytosis, cytochalasin D....... In vivo studies confirmed the observed effect because adsorption of OVA onto DDA liposomes enhanced the uptake of the antigen by peritoneal exudate cells after intraperitoneal injection. The liposomes targeted antigen preferentially to antigen-presenting cells because we only observed a minimal uptake...

  10. Improving total knee arthroplasty perioperative pain management using a periarticular injection with bupivacaine liposomal suspension

    Directory of Open Access Journals (Sweden)

    Mark A. Snyder, MD

    2016-03-01

    Full Text Available Patients undergoing total knee arthroplasty (TKA report low satisfaction with postoperative pain control. The purpose of this study is to examine if there is a difference in post-operative pain for TKA patients without femoral nerve block receiving an intra-operative pericapsular injection of bupivacaine liposome suspension (EXPAREL; Pacira Pharmaceuticals, Inc., San Diego, California versus a concentrated multi drug cocktail. Seventy TKA patients were randomly assigned to either the bupivacaine liposome or the multi-drug cocktail. Post-operative pain scores, morphine sulfate equivalence consumption values, adverse events, and overall pain control satisfaction scores were collected. Patients reported significantly higher pain level for the cocktail group on post-op day 1 (p < .05 and post-op day 2 (p < .01 versus the bupivacaine liposome group. This same trend was found for morphine sulfate equivalence consumption in the PACU (p < .01 and post-op day 2 (p < .01. Higher satisfaction in pain control (p < .001 and overall experience (p < .01 was also found in the bupivacaine liposome group. Finally, significantly more adverse events were found in the multi-drug group versus the bupivacaine liposome group (p < .05. The study findings demonstrated a non-inferior difference, albeit not a clinically significant difference, in patient-perceived pain scores, morphine sulfate equivalence consumption, adverse events, and overall satisfaction.

  11. Liposome sensing and monitoring by organic electrochemical transistors integrated in microfluidics.

    Science.gov (United States)

    Tarabella, Giuseppe; Balducci, Anna Giulia; Coppedè, Nicola; Marasso, Simone; D'Angelo, Pasquale; Barbieri, Stefano; Cocuzza, Matteo; Colombo, Paolo; Sonvico, Fabio; Mosca, Roberto; Iannotta, Salvatore

    2013-09-01

    Organic electrochemical transistors (OECTs), which are becoming more and more promising devices for applications in bioelectronics and nanomedicine, are proposed here as ideally suitable for sensing and real time monitoring of liposome-based structures. This is quite relevant since, currently, the techniques used to investigate liposomal structures, their stability in different environments as well as drug loading and delivery mechanisms, operate basically off-line and/or with pre-prepared sampling. OECTs, based on the PEDOT:PSS conductive polymer, have been employed as sensors of liposome-based nanoparticles in electrolyte solutions to assess sensitivity and monitoring capabilities based on ion-to-electron amplified transduction. We demonstrate that OECTs are very efficient, reliable and sensitive devices for detecting liposome-based nanoparticles on a wide dynamic range down to 10(-5)mg/ml (with a lowest detection limit, assessed in real-time monitoring, of 10(-7)mg/ml), thus matching the needs of typical drug loading/drug delivery conditions. They are hence particularly well suited for real-time monitoring of liposomes in solution. Furthermore, OECTs are shown to sense and discriminate successive injection of different liposomes, so that they could be good candidates in quality-control assays or in the pharmaceutical industry. Drug loading and delivery by liposome-based structures is a fast growing and very promising field that will strongly benefit from real-time, highly sensitive and low cost monitoring of their dynamics in different pharma and biomedical environments, with a particular reference to the pharmaceutical and production processes, where a major issue is monitoring and measuring the formation and concentration of liposomes and the relative drug load. The demonstrated ability to sense and monitor complex bio-structures, such as liposomes, paves the way for very promising developments in biosensing and nanomedicine. This article is part of a Special

  12. The use of liposomal amphotericin B in the management of Xylohypha bantiana mycosis in a dog

    Directory of Open Access Journals (Sweden)

    A.L. Leisewitz

    2002-07-01

    Full Text Available Xylohypha bantiana is a rare neurotropic fungal infection reported in humans, dogs and cats. In dogs it has only been identified on post mortem examination and thus no successful treatments have previously been reported. Amphotericin B is a potent antifungal drug with a low therapeutic index because of its nephrotoxicity. Liposomal encapsulation of the drug has resulted in much safer use in humans. This article reports a case of Xylohypha bantiana infection in a dog that was diagnosed antemortally and managed with liposomal amphotericin B, which resulted in the prolongation of quality of life for an infection that invariably results in rapid death.

  13. Liposomal delivery of radionuclides for cancer diagnostics and radiotherapy

    DEFF Research Database (Denmark)

    Petersen, Anncatrine Luisa

    requirements governing quality assurance and considerations during development of a liposomal PET radiopharmaceutical for clinical use. In addition, the opportunity to use larger animals as clinical cancer patients for improving 64Culiposomes as PET imaging agents is briefly described followed by a short......Molecular imaging is increasingly being used as an integrated discipline in designing radiotherapeutic agents and diagnostic imaging agents, and in developing drugs in general. In recent years, the use of the radionuclide and positron emitter copper-64 (64Cu) has become increasingly important......, as the use of positron emission tomography (PET) scanners for molecular and diagnostic imaging has become more attractive. Furthermore, the importance of molecular and diagnostic imaging in nanotechnology has also been recognized, and significant research has been conducted on radiolabeled liposomes...

  14. Development of curcumin liposome formulations using polyol dilution method

    Directory of Open Access Journals (Sweden)

    Lalana Kongkaneramit

    2016-12-01

    Full Text Available This study was aimed to formulate curcumin liposomes (CLs by using polyol dilution method which is advantageous for no residue of organic solvent. CLs were the mixture of hydrogenated phosphatidylcholine (PC and cholesterol (CH at the molar ratio of 9:1. Propylene glycol (PG, glycerin, and polyethylene glycol 400 (PEG-400 were used as polyol solvent. Extrusion was applied after the suspension formed. The amount of polyol and curcumin and preparing temperature were investigated. The obtained suspensions were observed for appearance, size, size distribution, zeta potential, morphology, and percentage of entrapment. The results showed that type and amount of polyol had an impact on both liposomal size and the amount of entrapped curcumin, while preparing temperature was also an important factor. However, the solubility of lipids and drug in a given polyol should be considered because of loading efficiency in the formulation.

  15. Encapsulation, controlled release, and antitumor efficacy of cisplatin delivered in liposomes composed of sterol-modified phospholipids.

    Science.gov (United States)

    Kieler-Ferguson, Heidi M; Chan, Darren; Sockolosky, Jonathan; Finney, Lydia; Maxey, Evan; Vogt, Stefan; Szoka, Francis C

    2017-05-30

    We employed a recently introduced class of sterol-modified lipids (SML) to produce m-PEG-DSPE containing liposome compositions with a range of cis-platinum content release rates. SML have a cholesterol succinate attached to the phosphatidylglycerol head group and a fatty acid at the 2 position. These compositions were compared to the well-studied liposome phospholipid compositions: mPEG-DSPE/Hydrogenated Soy PC/cholesterol or mPEG-DSPE/POPC/cholesterol to determine the effect of the cis-platinum release extent on C26 tumor proliferation in the BALB/c colon carcinoma mouse model. The release rates of cis-platinum from liposomes composed of SML are a function of the acyl chain length. SML-liposomes with shorter acyl chain lengths C-8 provided more rapid cisplatin release, lower in vitro IC50, and were easier to formulate compared to liposomes using traditional phospholipid compositions. Similar to other liposome cis-platinum formulations, the half-life of m-PEG-DSPE SML liposome cisplatin is substantially longer than the free drug. This resulted in a higher tumor cisplatin concentration at 48h post-dosing compared to the free drug and higher Pt-DNA adducts in the tumor. Moreover, the maximum tolerated dose of the liposome formulations where up to four fold greater than the free drug. Using X-ray fluorescence spectroscopy on tumor sections, we compared the location of platinum, to the location of a fluorescence lipid incorporated in the liposomes. The liposome platinum co-localized with the fluorescent lipid and both were non-uniformly distributed in the tumor. Non-encapsulated Cis-platinum, albeit at a low concentration, was more uniformly distributed thorough the tumor. Three liposome formulations, including the well-studied hydrogenated HSPC composition, had better antitumor activity in the murine colon 26 carcinoma model as compared to the free drug at the same dose but the SML liposome platinum formulations did not perform better than the HSPC formulation

  16. Folate receptor-targeted liposomes enhanced the antitumor potency of imatinib through the combination of active targeting and molecular targeting

    Science.gov (United States)

    Ye, Peng; Zhang, Wendian; Yang, Tan; Lu, Yao; Lu, Miao; Gai, Yongkang; Ma, Xiang; Xiang, Guangya

    2014-01-01

    Purpose Imatinib inhibits platelet-derived growth factor receptor (PDGFR), and evidence shows that PDGFR participates in the development and progression of cervical cancer. Although imatinib has exhibited preclinical activity against cervical cancer, only minimal clinical therapeutic efficacy was observed. This poor therapeutic efficacy may be due to insufficient drug delivery to the tumor cells and plasma protein binding. Therefore, the purpose of this study was to explore a novel folate receptor (FR)-targeted delivery system via imatinib-loaded liposomes to enhance drug delivery to tumor cells and to reduce plasma protein binding. Methods Imatinib was remote-loaded into FR-targeted liposomes which were prepared by thin film hydration followed by polycarbonate membrane extrusion. Encapsulation efficiency, mean size diameter, and drug retention were characterized and cellular uptake, cell cytotoxicity, and cell apoptosis on cervical cancer HeLa cells were evaluated. Comparative pharmacokinetic studies were also carried out with FR-targeted imatinib liposomes, simple imatinib liposomes, and free imatinib. Results High encapsulation efficiency (>90%), appropriate mean particle size (143.5 nm), and zeta potential (−15.97 mV) were obtained for FR-targeted imatinib liposomes. The drug release profile showed minimal imatinib leakage (25%) was observed in PBS at pH =5.5. This indicates that these liposomes possess a certain degree of pH sensitivity. Cytotoxicity assays demonstrated that the FR-targeted imatinib liposomes promoted a six-fold IC50 reduction on the non-targeted imatinib liposomes from 910 to 150 μM. In addition, FR-targeted imatinib liposomes enhanced HeLa cell apoptosis in vitro compared to the non-targeted imatinib liposomes. Pharmacokinetic parameters indicated that both targeted and non-targeted liposomes exhibited long circulation properties in Kunming mice. Conclusion These findings indicate that the nano-sized FR-targeted PDGFR antagonist imatinib

  17. Impact of volume expansion on the efficacy and pharmacokinetics of liposome bupivacaine

    Directory of Open Access Journals (Sweden)

    Hadzic A

    2015-12-01

    Full Text Available Admir Hadzic,1,2 John A Abikhaled,3 William J Harmon4 1Department of Anesthesiology, The New York School of Regional Anesthesia (NYSORA, New York, NY, USA; 2Department of Anesthesiology, Ziekenhouse Oost Limburgh, Genk, Belgium; 3Austin Surgeons, Austin, TX, 4Urology San Antonio, San Antonio, TX, USA Abstract: Liposome bupivacaine is a prolonged-release liposomal formulation of bupivacaine indicated for single-dose infiltration into the surgical site to produce postsurgical analgesia of longer duration than traditional local anesthetics. This review summarizes the available data on how volume expansion may impact the analgesic efficacy of liposome bupivacaine. The Phase II and III clinical studies that involved surgical site administration of liposome bupivacaine at various concentrations in different surgical settings revealed no apparent concentration–efficacy relationship. A single-center, prospective study comparing the efficacy of transversus abdominis plane infiltration with liposome bupivacaine administered in a lower (266 mg/40 mL vs a higher (266 mg/20 mL dose concentration in subjects undergoing robotic-assisted laparoscopic prostatectomy also reported similar postsurgical pain intensity scores and opioid usage in both treatment groups. The pharmacokinetic profile of liposome bupivacaine following subcutaneous injections in rats was unaltered by differences in drug concentration, dose, or injection volume within the ranges tested. Volume expansion of liposome bupivacaine to a total volume of 300 mL or less does not appear to impact its clinical efficacy or pharmacokinetic profile, thus allowing flexibility to administer the formulation across a wide range of diluent volumes. Keywords: pain, analgesia, liposome bupivacaine, dose, concentration, dilution 

  18. Improvement in physicochemical parameters of DPPC liposomes and increase in skin permeation of aciclovir and minoxidil by the addition of cationic polymers.

    Science.gov (United States)

    Hasanovic, Amra; Hollick, Caroline; Fischinger, Kerstin; Valenta, Claudia

    2010-06-01

    1,2-Dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) liposomes were prepared by high-pressure homogeniser and coated with two cationic polymers, chitosan (CS) and for the first time Eudragit EPO (EU), respectively. Compared to the control liposomes, the polymeric liposomes showed greater physicochemical stability in terms of mean particle size and zeta potential at room temperature. In the present study, aciclovir and minoxidil have been used as hydrophilic and hydrophobic candidates. In the presence of the drugs, the polymeric liposomes still showed constant particle size and zeta potential. Influences of polymers and model drugs on thermotropic phase transition of DPPC liposomes were studied by micro-differential scanning calorimetry (microDSC). The influences on configuration of DPPC liposomes were investigated by Fourier transform infrared spectroscopy (FTIR). According to DSC results, cationic polymers had a stabilising effect, whereas aciclovir and minoxidil changed the physical properties of the DPPC bilayers by influencing the main phase transition temperature and erasing the pre-transition. The investigation of CO stretching bands of DPPC at 1736 cm(-1) in FTIR spectra showed that aciclovir has strong hydrogen bonding with CO groups of DPPC, whereas carbonyl groups were free in minoxidil presence. Moreover, the coating of liposomes with CS or EU led to higher skin diffusion for both drugs. This could be explained as an effect of positively charged liposomes to interact stronger with skin negatively charged surface and their possible interactions with structures below the stratum corneum. Copyright 2010 Elsevier B.V. All rights reserved.

  19. Preparation and ocular pharmacokinetics of ganciclovir liposomes

    OpenAIRE

    Shen, Yan; Tu, Jiasheng

    2007-01-01

    Ophthalmic liposomes of ganciclovir (GCV) were prepared by the reverse phase evaporation method, and their ocular pharmacokinetics in albino rabbits were compared with those obtained after dosing with GCV solution. The in vitro transcorneal permeability of GCV liposomes was found to be 3.9-fold higher than that of the solution. After in vivo instillation in albino rabbits, no difference was found in the precorneal elimination rate of GCV from liposome vs solution dosing. The aqueous humor con...

  20. Evaluation of Extrusion Technique for Nanosizing Liposomes

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    Sandy Gim Ming Ong

    2016-12-01

    Full Text Available The aim of the present study was to study the efficiency of different techniques used for nanosizing liposomes. Further, the aim was also to evaluate the effect of process parameters of extrusion techniques used for nanosizing liposomes on the size and size distribution of the resultant liposomes. To compare the efficiency of different nanosizing techniques, the following techniques were used to nanosize the liposomes: extrusion, ultrasonication, freeze-thaw sonication (FTS, sonication and homogenization. The extrusion technique was found to be the most efficient, followed by FTS, ultrasonication, sonication and homogenization. The extruder used in the present study was fabricated using readily available and relatively inexpensive apparatus. Process parameters were varied in extrusion technique to study their effect on the size and size distribution of extruded liposomes. The results obtained indicated that increase in the flow rate of the extrusion process decreased the size of extruded liposomes however the size homogeneity was negatively impacted. Furthermore, the liposome size and distribution was found to decline with decreasing membrane pore size. It was found that by extruding through a filter with a pore size of 0.2 µm and above, the liposomes produced were smaller than the pore size, whereas, when they were extruded through a filter with a pore size of less than 0.2 µm the resultant liposomes were slightly bigger than the nominal pore size. Besides that, increment of extrusion temperature above transition temperature of the pro-liposome had no effect on the size and size distribution of the extruded liposomes. In conclusion, the extrusion technique was reproducible and effective among all the methods evaluated. Furthermore, processing parameters used in extrusion technique would affect the size and size distribution of liposomes. Therefore, the process parameters need to be optimized to obtain a desirable size range and homogeneity

  1. A quality by design (QbD) case study on liposomes containing hydrophilic API: I. Formulation, processing design and risk assessment.

    Science.gov (United States)

    Xu, Xiaoming; Khan, Mansoor A; Burgess, Diane J

    2011-10-31

    The purpose of this study was to extend QbD principles to liposomal drug products containing a hydrophilic active pharmaceutical ingredient (API) to demonstrate both the feasibility and the advantages of applying QbD concepts to liposome based complex parenteral controlled release systems. The anti-viral drug Tenofovir was selected as a model compound. Desired properties for two of the key liposome drug product qualities, namely the particle size and drug encapsulation efficiency, were defined and evaluated. It was observed that the liposome preparation process significantly affects liposome particle size, and this resulted in considerable variation in the drug encapsulation efficiency. Lipid chain length did not have a significant effect on drug encapsulation efficiency. However, lipid concentration did affect the drug encapsulation efficiency with higher lipid concentrations resulting in higher drug encapsulation. The use of risk assessment in this study assisted the identification of eight high risk factors that may impact liposome drug encapsulation efficiency and particle size. Copyright © 2011 Elsevier B.V. All rights reserved.

  2. Enzyme-induced shedding of a poly(amino acid)-coating triggers contents release from dioleoyl phosphatidylethanolamine liposomes.

    Science.gov (United States)

    Romberg, Birgit; Flesch, Frits M; Hennink, Wim E; Storm, Gert

    2008-05-01

    The enzymatically degradable poly(amino acid)-lipid conjugate poly(hydroxyethyl l-glutamine)-N-succinyl-dioctadecylamine (PHEG-DODASuc) has been shown to effectively prolong liposome circulation times. In this paper, we investigated whether PHEG-DODASuc can stabilize liposomes composed of the fusogenic, non-bilayer-forming lipid dioleoyl phosphatidylethanolamine (DOPE). Moreover, we evaluated the release of an entrapped compound after enzyme-induced shedding of the PHEG-coating, interbilayer contact and membrane destabilizing phase changes. Contents release was monitored using the fluorescent model compound calcein. Liposome destabilization and lipid mixing was studied by dynamic light scattering (DLS), fluorescence resonance energy transfer (FRET) and cryogenic-temperature transmission electron microscopy (cryo-TEM). It was shown that PHEG-DODASuc is able to stabilize DOPE-based liposomes and that contents release can be triggered by shedding of the PHEG-coating.

  3. Photophysical studies of zinc phthalocyanine and chloroaluminum phthalocyanine incorporated into liposomes in the presence of additives

    Directory of Open Access Journals (Sweden)

    S.M.T. Nunes

    2004-02-01

    Full Text Available The photophysical properties of zinc phthalocyanine (ZnPC and chloroaluminum phthalocyanine (AlPHCl incorporated into liposomes of dimyristoyl phosphatidylcholine in the presence and absence of additives such as cholesterol or cardiolipin were studied by time-resolved fluorescence, laser flash photolysis and steady-state techniques. The absorbance of the drugs changed linearly with drug concentration, at least up to 5.0 µM in homogeneous and heterogeneous media, indicating that aggregation did not occur in these media within this concentration range. The incorporation of the drugs into liposomes increases the dimerization constant by one order of magnitude (for ZnPC, 3.6 x 10(4 to 1.0 x 10(5 M-1 and for AlPHCl, 3.7 x 10(4 to 1.5 x 10(5 M-1, but this feature dose does not rule out the use of this carrier, since the incorporation of these hydrophobic drugs into liposomes permits their systemic administration. Probe location in biological membranes and predominant positions of the phthalocyanines in liposomes were inferred on the basis of their fluorescence and triplet state properties. Both phthalocyanines are preferentially distributed in the internal regions of the liposome bilayer. The additives affect the distribution of these drugs within the liposomes, a fact that controls their delivery when both are used in a biological medium, retarding their release. The addition of the additives to the liposomes increases the internalization of phthalocyanines. The interaction of the drugs with a plasma protein, bovine serum albumin, was examined quantitatively by the fluorescence technique. The results show that when the drugs were incorporated into small unilamellar liposomes, the association with albumin was enhanced when compared with organic media, a fact that should increase the selectivity of tumor targeting by these phthalocyanines (for ZnPC, 0.71 x 10(6 to 1.30 x 10(7 M-1 and for AlPHCl, 4.86 x 10(7 to 3.10 x 10(8 M-1.

  4. Laccases stabilization with phosphatidylcholine liposomes

    OpenAIRE

    Martí, M.; Zille, Andrea; Paulo, Artur Cavaco; Parra, J. L.; Coderch, L.

    2012-01-01

    In recent years, there has been an upsurge of interest in enzyme treatment of textile fibres. Enzymes are globular proteins whose catalytic function is due to their three dimensional structure. For this reason, stability strategies make use of compounds that avoid dismantling or distorting protein 3D structures. This study is concerned with the use of microencapsulation techniques to optimize enzyme stabilization. Laccases were embedded in phophatidylcholine liposomes and their encaps...

  5. Comparative therapeutic efficacy of rhenium-188 radiolabeled-liposome and 5-fluorouracil in LS-174T human colon carcinoma solid tumor xenografts.

    Science.gov (United States)

    Hsu, Chin-Wei; Chang, Ya-Jen; Chang, Chih-Hsien; Chen, Liang-Cheng; Lan, Keng-Li; Ting, Gann; Lee, Te-Wei

    2012-10-01

    Nanoliposomes are important carriers capable of packaging drugs for various delivery applications. Rhenium-188-radiolabeled liposome ((188)Re-liposome) has potential for radiotherapy and diagnostic imaging. To evaluate the targeting of (188)Re-liposome, biodistribution, microSPECT/CT, whole-body autoradiography (WBAR), and pharmacokinetics were performed in LS-174T human tumor-bearing mice. The comparative therapeutic efficacy of (188)Re-liposome and 5-fluorouracil (5-FU) was assessed according to inhibition of tumor growth and the survival ratio. The highest uptake of (188)Re-liposome in LS-174T tumor was found at 24 hours by biodistribution and microSPECT/CT imaging, showing a positive correlation for tumor targeting of (188)Re-liposome using the Pearson's correlation analysis (r=0.997). Pharmacokinetics of (188)Re-liposome showed the properties of high circulation time and high bioavailability (mean residence time [MRT]=18.8 hours, area under the curve [AUC]=1371%ID/g·h). For therapeutic efficacy, the tumor-bearing mice treated with (188)Re-liposome (80% maximum tolerated dose [MTD], 23.7 MBq) showed better tumor growth inhibition and longer survival time than those treated with 5-FU (80% MTD, 144 mg/kg). The median survival time for mice treated with (188)Re-liposome (58.5 days; p0.05) and normal saline-treated mice (43.63 days). Dosimetry study revealed that the (188)Re-liposome did not lead to high absorbed doses in normal tissue, but did in small tumors. These results of imaging and biodistribution indicated the highly specific accumulation of tumor after intravenous (i.v.) injection of (188)Re-liposome. The therapeutic efficacy of radiotherapeutics of (188)Re-liposome have been confirmed in a LS-174T solid tumor animal model, which points to the potential benefit and promise of passive nanoliposome delivered radiotherapeutics for cancer treatment.

  6. Characterization and cytotoxicity studies of DPPC:M(2+) novel delivery system for cisplatin thermosensitivity liposome with improving loading efficiency.

    Science.gov (United States)

    Liu, Hong; Zhang, Yongle; Han, Yazhu; Zhao, Sha; Wang, Lu; Zhang, Zhaoxin; Wang, Jing; Cheng, Jianxin

    2015-07-01

    A novel, metal ion-assisted drug-loading model, in which the metal ion was used to modify the microstructure of DPPC bilayers, has been developed to improve the drug-loading efficiency of cisplatin thermosensitivity liposomes. The reactions of dipalmitoyl phosphatidylcholine (DPPC) with diverse metal ions (Zn(2+), Cu(2+), Mn(2+) and Mg(2+)) yield four typical liposomes, which have been characterized by FT-IR, Raman and fluorescence techniques; the mechanism for higher drug encapsulation efficiency has also been investigated. In these prepared liposomes, the conformation of DPPC is changed due to the electrostatic interaction between the metal ions and phospholipid acyl group, leading to a closer arrangement of the lipid hydrocarbon chains and higher Tm of DPPC. As a result, the encapsulation efficiency of metal ion-assisted loading liposome is significantly higher than that of metal ion-free state. While for the release time, all four metal ion-assisted liposomes could be released within 10min at 42±0.5°C, which approach to the phase transition temperature, indicating that the introduction of metal ions into the DPPC bilayer membranes has no influence on the thermosensitivity of the liposome. Furthermore, the higher cytotoxicity of metal ion-bounded liposomes than that of free cisplatin solution suggests that high encapsulation efficiency can cause cytotoxicity increase. Hence, this work highlighted that metal ion-assisted loading model increased the encapsulation efficiency and cell cytotoxicity of cisplatin in thermosensitive liposomes with no obvious effects on sustained and temperature-dependent drug release. Copyright © 2015 Elsevier B.V. All rights reserved.

  7. Fusion between fluid liposomes and intact bacteria: study of driving parameters and in vitro bactericidal efficacy

    Directory of Open Access Journals (Sweden)

    Wang Z

    2016-08-01

    Full Text Available Zhao Wang,1,2* Yufan Ma,1,3,4* Hayssam Khalil,1 Rutao Wang,1–3 Tingli Lu,1 Wen Zhao,1 Yang Zhang,3 Jamin Chen,1,2 Tao Chen,1–3  1Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi, 2Shaanxi Liposome Research Center, Xi'an, Shaanxi, 3Xi'an Libang Pharmaceuticals Co, Ltd, Xi'an, 4School of Medicine, Xi'an Jiaotong University, Xi'an, People's Republic of China *These authors contributed equally to this work. Background: Pseudomonas aeruginosa represents a good model of antibiotic resistance. These organisms have an outer membrane with a low level of permeability to drugs that is often combined with multidrug efflux pumps, enzymatic inactivation of the drug, or alteration of its molecular target. The acute and growing problem of antibiotic resistance of bacteria to conventional antibiotics made it imperative to develop new liposome formulations for antibiotics, and investigate the fusion between liposome and bacterium. Methods: In this study, the factors involved in fluid liposome interaction with bacteria have been investigated. We also demonstrated a mechanism of fusion between liposomes (1,2-dipalmitoyl-sn-glycero-3-phosphocholine [DPPC]/dimyristoylphosphatidylglycerol [DMPG] 9:1, mol/mol in a fluid state, and intact bacterial cells, by lipid mixing assay. Results: The observed fusion process is shown to be mainly dependent on several key factors. Perturbation of liposome fluidity by addition of cholesterol dramatically decreased the degree of fusion with P. aeruginosa from 44% to 5%. It was observed that fusion between fluid liposomes and bacteria and also the bactericidal activities were strongly dependent upon the properties of the bacteria themselves. The level of fusion detected when fluid liposomes were mixed with Escherichia coli (66% or P. aeruginosa (44% seems to be correlated to their outer membrane phosphatidylethanolamine (PE phospholipids

  8. Radio Frequency-Activated Nanoliposomes for Controlled Combination Drug Delivery.

    Science.gov (United States)

    Malekar, Swapnil A; Sarode, Ashish L; Bach, Alvin C; Bose, Arijit; Bothun, Geoffrey; Worthen, David R

    2015-12-01

    This work was conducted in order to design, characterize, and evaluate stable liposomes containing the hydrophobic drug raloxifene HCl (RAL) and hydrophilic doxycycline HCl (DOX), two potentially synergistic agents for treating osteoporosis and other bone lesions, in conjunction with a radio frequency-induced, hydrophobic magnetic nanoparticle-dependent triggering mechanism for drug release. Both drugs were successfully incorporated into liposomes by lipid film hydration, although combination drug loading compromised liposome stability. Liposome stability was improved by reducing the drug load and by including Pluronics® (PL) in the formulations. DOX did not appear to interact with the phospholipid membranes comprising the liposomes, and its release was maximized in the presence of radio frequency (RF) heating. In contrast, differential scanning calorimetry (DSC) and phosphorus-31 nuclear magnetic resonance ((31)P-NMR) analysis revealed that RAL developed strong interactions with the phospholipid membranes, most notably with lipid phosphate head groups, resulting in significant changes in membrane thermodynamics. Likewise, RAL release from liposomes was minimal, even in the presence of RF heating. These studies may offer useful insights into the design and optimization of multidrug containing liposomes. The effects of RAL on liposome characteristics and drug release performance underscore the importance of appropriate physical-chemical analysis in order to identify and characterize drug-lipid interactions that may profoundly affect liposome properties and performance early in the formulation development process.

  9. DISSOLUTION CHARACTERISTIC OF CHLORAMPHENICOL PALMITATE-LIPOSOMAL PREPARATION

    Directory of Open Access Journals (Sweden)

    Morteza Rafiee-Tehrani

    1990-07-01

    Full Text Available Solid dispersions of chloramphenicol palmitate and dipalmitoyl-phosphatidylcholine (lecithin have been produced both as copreci-pitate and physical mixtures. The dissolution behavior of both forms were compared with pure chloramphenicol palrnitate st different weight ratios of chloramphenicol palrnitate-lecithin (liposomal system; as well as various pH. The dissolution characteristic of physical mixtures for different weight ratios of chloramphenicol palmitate-lecithin was similar to the pure drug. Whereas, the coprecipitates produced a 2.8 fold greater initial dissolution rate (1DR and a 2.4 fold greater drug release concentration after 60 min at a chloramphenicol palmitatc-lecithin weight ratio of 19:1. However, lecithin content enhancement to 9:1, 4:1 and 1.5:1 compositions, resulted in a further increase of 6%, 21%. and 24%. respectively in the initial dissolution rate. In¬creasing the lecithin content shows only a slight increase (8.5°c on drug release after 60 min when, the chloramphenicol palrnitate lecithin weight ratio was 1.5:1. However, other weight ratios did not show any effect on the improvement of drug release after 60 min. I he effect of pH of the medium on dissolution was slight, but varied with composition of the system."nIn conclusion, liposome encapsulation of chloramphenicol palmitale has a significant effect on dissolution improvement of this drug.

  10. Thr 163 phosphorylation causes Mcl-1 stabilization when degradation is independent of the adjacent GSK3-targeted phosphodegron, promoting drug resistance in cancer.

    Directory of Open Access Journals (Sweden)

    Shanna K Nifoussi

    Full Text Available The antiapoptotic Bcl-2 family member Mcl-1 is a PEST protein (containing sequences enriched in proline, glutamic acid, serine, and threonine and is subject to rapid degradation via multiple pathways. Impaired degradation leading to the maintenance of Mcl-1 expression is an important determinant of drug resistance in cancer. Phosphorylation at Thr 163 in the PEST region, stimulated by 12-O-tetradecanoylphorbol acetic acid (TPA-induced activation of extracellular signal-regulated kinase (ERK, is associated with Mcl-1 stabilization in BL41-3 Burkitt lymphoma cells. This contrasts with the observation that Thr 163 phosphorylation in normal fibroblasts primes glycogen synthase kinase (GSK3-induced phosphorylation at Ser 159, producing a phosphodegron that targets Mcl-1 for degradation. In the present follow-up studies in BL41-3 cells, Mcl-1 degradation was found to be independent of the GSK3-mediated pathway, providing a parallel to emerging findings showing that Mcl-1 degradation through this pathway is lost in many different types of cancer. Findings in Mcl-1-transfected CHO cells corroborated those in BL41-3 cells in that the GSK3-targeted phosphodegron did not play a major role in Mcl-1 degradation, and a phosphomimetic T163E mutation resulted in marked Mcl-1 stabilization. TPA-treated BL41-3 cells, in addition to exhibiting Thr 163 phosphorylation and Mcl-1 stabilization, exhibited an ∼10-fold increase in resistance to multiple chemotherapeutic agents, including Ara-C, etoposide, vinblastine, or cisplatin. In these cancer cells in which Mcl-1 degradation is not dependent on the GSK3/phosphodegron-targeted pathway, ERK activation and Thr 163 phosphorylation are associated with pronounced Mcl-1 stabilization and drug resistance - effects that can be suppressed by inhibition of ERK activation.

  11. Sirolimus encapsulated liposomes for cancer therapy: physicochemical and mechanical characterization of sirolimus distribution within liposome bilayers.

    Science.gov (United States)

    Onyesom, Ichioma; Lamprou, Dimitrios A; Sygellou, Lamprini; Owusu-Ware, Samuel K; Antonijevic, Milan; Chowdhry, Babur Z; Douroumis, Dennis

    2013-11-04

    Sirolimus has recently been introduced as a therapeutic agent for breast and prostate cancer. In the current study, conventional and Stealth liposomes were used as carriers for the encapsulation of sirolimus. The physicochemical characteristics of the sirolimus liposome nanoparticles were investigated including the particle size, zeta potential, stability and membrane integrity. In addition atomic force microscopy was used to study the morphology, surface roughness and mechanical properties such as elastic modulus deformation and deformation. Sirolimus encapsulation in Stealth liposomes showed a high degree of deformation and lower packing density especially for dipalmitoyl-phosphatidylcholine (DPPC) Stealth liposomes compared to unloaded. Similar results were obtained by differential scanning calorimetry (DSC) studies; sirolimus loaded liposomes were found to result in a distorted state of the bilayer. X-ray photon electron (XPS) analysis revealed a uniform distribution of sirolimus in multilamellar DPPC Stealth liposomes compared to a nonuniform, greater outer layer lamellar distribution in distearoylphosphatidylcholine (DSPC) Stealth liposomes.

  12. Engineering of (10-hydroxycamptothecin intercalated layered double hydroxide)@liposome nanocomposites with excellent water dispersity

    Science.gov (United States)

    Zhang, Yongfang; Wu, Xiaowen; Mi, Yuwei; Li, Haiping; Hou, Wanguo

    2017-09-01

    A hierarchical nanocomposite of 10-hydroxycamptothecin (HCPT), a nonionic and lipophilic anticancer drug, intercalated layered double hydroxide (LDH) encapsulated in liposomes was constructed. HCPT molecules were first incorporated into sodium cholate (Ch) micelles, and the resultant negatively charged HCPT-loaded Ch micelles were then co-assembled with positively charged LDH single-layer nanosheets, forming a HCPT/Ch intercalated LDH (HCPT-Ch-LDH) host-gest nanohybrid. The nanohybrid particles were further coated with liposomes (LSs), gaining a core-shell nanocomposite, denoted as (HCPT-Ch-LDH)@LS. The so-obtained samples were characterized using TEM, SAXS, FT-IR, DLS, and elemental analyses. Special emphasis was placed on the effect of liposome-coating for the HCPT-Ch-LDH on its water dispersity and drug-release. The results showed that the nanocomposite has excellent water dispersity and enhanced drug sustained-release performance in comparison with the HCPT-Ch-LDH, demonstrating that the liposome-coating for drug-LDH nanohybrids is an effective strategy to enhance their water dispersity and sustained-release performances. This work provides an effective strategy for engineering of LDH-based delivery systems for nonionic and lipophilic drugs.

  13. Synthesis of diethylenetriaminepentaacetic acid conjugated inulin and utility for cellular uptake of liposomes

    International Nuclear Information System (INIS)

    Essien, H.; Lai, J.Y.; Hwang, K.J.

    1988-01-01

    The synthesis, binding of radioactive cations, liposomal encapsulation, and biodistribution of the oxidized-inulin reaction product with ethylenediamine and diethylenetriaminepentaacetic acid (4) are described. The four-step synthesis of the inulin derivative proceeded in a good overall yield of 72%. The complex of the inulin derivative with either 67 Ga3+ or 111 In3+ was stable in vivo and did not readily distribute into tissues, being excreted primarily in urine after intravenous administration to mice. The liposome-entrapped inulin derivative can be loaded with radioactive heavy metal cations by mobile ionophores in high radiochemical yields of 80-91%. Following the intravenous administration of the liposomal encapsulation of the indium-111-labeled inulin derivative, the entrapped compound had a biodistribution characteristic of liposomes and allowed an estimation of the extent of the intracellular uptake of liposomes. The ability of the inulin derivative to chelate many different types of metals will allow the use of this probe for studying subtle differences in tissue distribution resulting from different drug targeting or delivery protocols in the same animal by multiple labeling techniques. Moreover, the chelate-conjugated inulin permits studies of the applications of drug delivery systems in primates or human subjects by noninvasive techniques such as gamma-scintigraphic or nuclear magnetic resonance imaging methods

  14. Polymer-associated liposomes for the oral delivery of grape pomace extract.

    Science.gov (United States)

    Manconi, Maria; Marongiu, Francesca; Castangia, Ines; Manca, Maria Letizia; Caddeo, Carla; Tuberoso, Carlo Ignazio Giovanni; D'hallewin, Guy; Bacchetta, Gianluigi; Fadda, Anna Maria

    2016-10-01

    The pomaces from red grapes were used as a source of phenolic antioxidants, which are known to have health-promoting effects. Environmentally-friendly extraction strategies were investigated to improve the rate and recovery of an extract with high phenolic content and antioxidant activity, which were evaluated by the Folin-Ciocalteu, DPPH, ABTS(+), CUPRAC and FRAP assays. The extract was incorporated in liposomes, which were stabilized by the addition of a natural polysaccharide, sodium alginate or arabic gum, widely used in pharmaceutical and food industries as thickeners and stabilizers. Results showed that the polymer-associated liposomes were approximately 300nm in size, spherical in shape, and with high entrapment efficiency. The polymers prevented vesicle degradation in the gastric environment, and played a key role in improving liposomes' performances, especially arabic gum. The polymer-associated liposomes were biocompatible and protected Caco-2 cells against oxidative stress. The achieved results suggest a potential application of the polymer-associated liposomes loaded with the grape pomace extract in the nutraceutical field. Copyright © 2016 Elsevier B.V. All rights reserved.

  15. Cationic liposomes as non-viral vector for RNA delivery in cancer immunotherapy.

    Science.gov (United States)

    Vitor, Micaela T; Bergami-Santos, Patrícia C; Barbuto, José A M; de la Torre, Lucimara G

    2013-08-01

    This review presents the current status in the use of liposomes as non-viral vector for nucleic acid delivery in cancer immunotherapy. Currently, cancer treatment uses surgery, radiotherapy and/or chemotherapy. The search for new strategies to improve the efficiency of conventional treatments is a challenge, and biological therapy has emerged as a promising technique. Immunotherapy is a branch of biological therapy that uses the body's immune system to detect and destroy cancer cells. One immunotherapy approach is the activation of T lymphocytes from cancer patients by dendritic cells (DCs) loaded with tumor antigens. Among different antigens, mRNA coding the tumor antigens is advantageous due to its capability to be amplified from small amounts of tumor tissue, its safety because it is easily degraded without integrating into the host genome, and it does not need to cross the nuclear barrier to exert its biological activity. Nanotechnology is an approach to deliver tumor antigens into DCs. Specially; we review the use of nanoliposomes in the field of cancer therapy because cationic liposomes can be used as non-viral vectors for mRNA delivery. Aside from the promise of liposomes, the development of scalable processes and facilities to the use this individualized therapy is still a challenge. Thus, we also present the recent techniques used for liposome production. In this context, the integration between technological knowledge in the production of cationic liposomes and immunotherapy using mRNA may contribute to the development of new strategies for cancer therapy.

  16. A first step toward liposome-mediated intracellular bacteriophage therapy.

    Science.gov (United States)

    Nieth, Anita; Verseux, Cyprien; Barnert, Sabine; Süss, Regine; Römer, Winfried

    2015-01-01

    The emergence of antibiotic-resistant bacteria presents a severe challenge to medicine and public health. While bacteriophage therapy is a promising alternative to traditional antibiotics, the general inability of bacteriophages to penetrate eukaryotic cells limits their use against resistant bacteria, causing intracellular diseases like tuberculosis. Bacterial vectors show some promise in carrying therapeutic bacteriophages into cells, but also bring a number of risks like an overload of bacterial antigens or the acquisition of virulence genes from the pathogen. As a first step in the development of a non-bacterial vector for bacteriophage delivery into pathogen-infected cells, we attempted to encapsulate bacteriophages into liposomes. Here we report effective encapsulation of the model bacteriophage λeyfp and the mycobacteriophage TM4 into giant liposomes. Furthermore, we show that liposome-associated bacteriophages are taken up into eukaryotic cells more efficiently than free bacteriophages. These are important milestones in the development of an intracellular bacteriophage therapy that might be useful in the fight against multi-drug-resistant intracellular pathogens like Mycobacterium tuberculosis.

  17. Anomalous freezing behavior of nanoscale liposomes

    DEFF Research Database (Denmark)

    Spangler, E. J.; Kumar, P. B. S.; Laradji, M.

    2012-01-01

    The effect of the finite size of one-component liposomes on their phase behavior is investigated via simulations of an implicit-solvent model of self-assembled lipid bilayers. We found that the high curvature of nanoscale liposomes has a significant effect on their freezing behavior. While...

  18. Relaxivity of liposomal paramagnetic MRI contrast agents

    NARCIS (Netherlands)

    Strijkers, G. J.; Mulder, W. J. M.; van Heeswijk, R. B.; Frederik, P. M.; Bomans, P.; Magusin, P. C. M. M.; Nicolay, K.

    2005-01-01

    Paramagnetic liposomes, spherical particles formed by a lipid bilayer, are able to accommodate a high payload of Gd-containing lipid and therefore can serve as a highly potent magnetic resonance imaging contrast agent. In this paper the relaxation properties of paramagnetic liposomes were studied as

  19. Methods for using redox liposome biosensors

    Science.gov (United States)

    Cheng, Quan; Stevens, Raymond C.

    2002-01-01

    The present invention provides methods and compositions for detecting the presence of biologically-important analytes by using redox liposome biosensors. In particular, the present invention provides liposome/sol-gel electrodes suitable for the detection of a wide variety of organic molecules, including but not limited to bacterial toxins.

  20. Correlation between radioactivity and chemotherapeutics of the 111In-VNB-liposome in pharmacokinetics and biodistribution in rats

    Directory of Open Access Journals (Sweden)

    Tsai TH

    2012-02-01

    Full Text Available Wen-Chuan Lee1,*, Chih-Hsien Chang2,3,*, Chih-Min Huang1, Yu-Tse Wu1, Liang-Cheng Chen2, Chung-Li Ho2, Tsui-Jung Chang2, Te-Wei Lee2, Tung-Hu Tsai1,41Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei, 2Division of Isotope Application, Institute of Nuclear Energy Research, Taoyuan, 3Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, 4Department of Education and Research, Taipei City Hospital, Taipei, Taiwan*These authors contributed equally to this workBackground: The combination of a radioisotope with a chemotherapeutic agent in a liposomal carrier (ie, Indium-111-labeled polyethylene glycol pegylated liposomal vinorelbine, [111In-VNB-liposome] has been reported to show better therapeutic efficiency in tumor growth suppression. Nevertheless, the challenge remains as to whether this therapeutic effect is attributable to the combination of a radioisotope with chemotherapeutics. The goal of this study was to investigate the pharmacokinetics, biodistribution, and correlation of Indium-111 radioactivity and vinorelbine concentration in the 111In-VNB-liposome.Methods: The VNB-liposome and 111In-VNB-liposome were administered to rats. Blood, liver, and spleen tissue were collected to determine the distribution profile of the 111In-VNB-liposome. A liquid chromatography tandem mass spectrometry system and gamma counter were used to analyze the concentration of vinorelbine and radioactivity of Indium-111.Results: High uptake of the 111In-VNB-liposome in the liver and spleen demonstrated the properties of a nanosized drug delivery system. Linear regression showed a good correlation (r = 0.97 between Indium-111 radioactivity and vinorelbine concentration in the plasma of rats administered the 111In-VNB-liposome.Conclusion: A significant positive correlation between the pharmacokinetics and biodistribution of 111Indium radioactivity and vinorelbine in blood, spleen

  1. Cytoprotective and enhanced anti-inflammatory activities of liposomal piroxicam formulation in lipopolysaccharide-stimulated RAW 264.7 macrophages

    Directory of Open Access Journals (Sweden)

    Chiong HS

    2013-03-01

    Full Text Available Hoe Siong Chiong,1 Yoke Keong Yong,1 Zuraini Ahmad,1 Mohd Roslan Sulaiman,1 Zainul Amiruddin Zakaria,1 Kah Hay Yuen,2 Muhammad Nazrul Hakim1,31Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Malaysia; 2School of Pharmaceutical Sciences, Universiti Sains Malaysia, Gelugor, Malaysia; 3Sports Academy, Universiti Putra Malaysia, Serdang, MalaysiaBackground: Liposomal drug delivery systems, a promising lipid-based nanoparticle technology, have been known to play significant roles in improving the safety and efficacy of an encapsulated drug.Methods: Liposomes, prepared using an optimized proliposome method, were used in the present work to encapsulate piroxicam, a widely prescribed nonsteroidal anti-inflammatory drug. The cytotoxic effects as well as the in vitro efficacy in regulation of inflammatory responses by free-form piroxicam and liposome-encapsulated piroxicam were evaluated using a lipopolysaccharide-sensitive macrophage cell line, RAW 264.7.Results: Cells treated with liposome-encapsulated piroxicam demonstrated higher cell viabilities than those treated with free-form piroxicam. In addition, the liposomal piroxicam formulation resulted in statistically stronger inhibition of pro-inflammatory mediators (ie, nitric oxide, tumor necrosis factor-α, interleukin-1β, and prostaglandin E2 than piroxicam at an equivalent dose. The liposome-encapsulated piroxicam also caused statistically significant production of interleukin-10, an anti-inflammatory cytokine.Conclusion: This study affirms the potential of a liposomal piroxicam formulation in reducing cytotoxicity and enhancing anti-inflammatory responses in vitro.Keywords: liposomes, nitric oxide, cytokines, prostaglandin E2, interleukin-1β, piroxicam

  2. Two Synthetic Methods for Preparation of Chiral Stationary Phases Using Crystalline Degradation Products of Vancomycin: Column Performance for Enantioseparation of Acidic and Basic Drugs.

    Science.gov (United States)

    Abdollahpour, Assem; Heydari, Rouhollah; Shamsipur, Mojtaba

    2017-07-01

    Two chiral stationary phases (CSPs) based on crystalline degradation products (CDPs) of vancomycin by using different synthetic methods were prepared and compared. Crystalline degradation products of vancomycin were produced by hydrolytic loss of ammonia from vancomycin molecules. Performances of two chiral columns prepared with these degradation products were investigated using several acidic and basic drugs as model analytes. Retention and resolution of these analytes on the prepared columns, as two main parameters, in enantioseparation were studied. The results demonstrated that the stationary phase preparation procedure has a significant effect on the column performance. The resolving powers of prepared columns for enantiomers resolution were changed with the variation in vancomycin-CDP coverage on the silica support. Elemental analysis was used to monitor the surface coverage of silica support by vancomycin-CDP. The results showed that both columns can be successfully applied to chiral separation studies.

  3. Liposome-encapsulated EF24-HP{beta}CD inclusion complex: a preformulation study and biodistribution in a rat model

    Energy Technology Data Exchange (ETDEWEB)

    Agashe, H.; Lagisetty, P.; Sahoo, K.; Bourne, D. [University of Oklahoma Health Sciences Center, Department of Pharmaceutical Sciences (United States); Grady, B. [School of Chemical, Biological and Materials Engineering (United States); Awasthi, V., E-mail: vawasthi@ouhsc.edu [University of Oklahoma Health Sciences Center, Department of Pharmaceutical Sciences (United States)

    2011-06-15

    3,5-Bis(2-fluorobenzylidene)-4-piperidone (EF24) is an anti-proliferative diphenyldifluoroketone analog of curcumin with more potent activity. The authors describe a liposome preparation of EF24 using a 'drug-in-CD-in liposome' approach. An aqueous solution of EF24 and hydroxypropyl-{beta}-cyclodextrin (HP{beta}CD) inclusion complex (IC) was used to prepare EF24 liposomes. The liposome size was reduced by a combination of multiple freeze-thaw cycles. Co-encapsulation of glutathione inside the liposomes conferred them with the capability of labeling with imageable radionuclide Tc-99m. Phase solubility analysis of EF24-HP{beta}CD mixture provided k{sub 1:1} value of 9.9 M{sup -1}. The enhanced aqueous solubility of EF24 (from 1.64 to 13.8 mg/mL) due to the presence of HP{beta}CD helped in the liposome preparation. About 19% of the EF24 IC was encapsulated inside the liposomes (320.5 {+-} 2.6 nm) by dehydration-rehydration technique. With extrusion technique, the size of 177 {+-} 6.5 nm was obtained without any effect on encapsulation efficiency. The EF24-liposomes were evaluated for anti-proliferative activity in lung adenocarcinoma H441 and prostate cancer PC-3 cells. The EF24-liposomes demonstrated anti-proliferative activity superior to that of plain EF24 at 10 {mu}M dose. When injected in rats, the Tc-99m-labeled EF24-liposomes cleared from blood with an {alpha}-t{sub 1/2} of 21.4 min and {beta}-t{sub 1/2} of 397 min. Tissue radioactivity counting upon necropsy showed that the majority of clearance was due to the uptake in liver and spleen. The results suggest that using 'drug-in-CD-in liposome' approach is a feasible strategy to formulate an effective parenteral preparation of EF24. In vitro studies show that the liposomal EF24 remains anti-proliferative, while presenting an opportunity to image its biodistribution.

  4. Liposome-encapsulated EF24-HPβCD inclusion complex: a preformulation study and biodistribution in a rat model

    Science.gov (United States)

    Agashe, H.; Lagisetty, P.; Sahoo, K.; Bourne, D.; Grady, B.; Awasthi, V.

    2011-06-01

    3,5-Bis(2-fluorobenzylidene)-4-piperidone (EF24) is an anti-proliferative diphenyldifluoroketone analog of curcumin with more potent activity. The authors describe a liposome preparation of EF24 using a "drug-in-CD-in liposome" approach. An aqueous solution of EF24 and hydroxypropyl-β-cyclodextrin (HPβCD) inclusion complex (IC) was used to prepare EF24 liposomes. The liposome size was reduced by a combination of multiple freeze-thaw cycles. Co-encapsulation of glutathione inside the liposomes conferred them with the capability of labeling with imageable radionuclide Tc-99m. Phase solubility analysis of EF24-HPβCD mixture provided k 1:1 value of 9.9 M-1. The enhanced aqueous solubility of EF24 (from 1.64 to 13.8 mg/mL) due to the presence of HPβCD helped in the liposome preparation. About 19% of the EF24 IC was encapsulated inside the liposomes (320.5 ± 2.6 nm) by dehydration-rehydration technique. With extrusion technique, the size of 177 ± 6.5 nm was obtained without any effect on encapsulation efficiency. The EF24-liposomes were evaluated for anti-proliferative activity in lung adenocarcinoma H441 and prostate cancer PC-3 cells. The EF24-liposomes demonstrated anti-proliferative activity superior to that of plain EF24 at 10 μM dose. When injected in rats, the Tc-99m-labeled EF24-liposomes cleared from blood with an α- t 1/2 of 21.4 min and β- t 1/2 of 397 min. Tissue radioactivity counting upon necropsy showed that the majority of clearance was due to the uptake in liver and spleen. The results suggest that using "drug-in-CD-in liposome" approach is a feasible strategy to formulate an effective parenteral preparation of EF24. In vitro studies show that the liposomal EF24 remains anti-proliferative, while presenting an opportunity to image its biodistribution.

  5. Application of Pharmacokinetic and Pharmacodynamic Analysis to the Development of Liposomal Formulations for Oncology

    Directory of Open Access Journals (Sweden)

    Sihem Ait-Oudhia

    2014-03-01

    Full Text Available Liposomal formulations of anticancer agents have been developed to prolong drug circulating lifetime, enhance anti-tumor efficacy by increasing tumor drug deposition, and reduce drug toxicity by avoiding critical normal tissues. Despite the clinical approval of numerous liposome-based chemotherapeutics, challenges remain in the development and clinical deployment of micro- and nano-particulate formulations, as well as combining these novel agents with conventional drugs and standard-of-care therapies. Factors requiring optimization include control of drug biodistribution, release rates of the encapsulated drug, and uptake by target cells. Quantitative mathematical modeling of formulation performance can provide an important tool for understanding drug transport, uptake, and disposition processes, as well as their role in therapeutic outcomes. This review identifies several relevant pharmacokinetic/pharmacodynamic models that incorporate key physical, biochemical, and physiological processes involved in delivery of oncology drugs by liposomal formulations. They capture observed data, lend insight into factors determining overall antitumor response, and in some cases, predict conditions for optimizing chemotherapy combinations that include nanoparticulate drug carriers.

  6. Solid lipid particles for oral delivery of peptide and protein drugs III - the effect of fed state conditions on the in vitro release and degradation of desmopressin

    DEFF Research Database (Denmark)

    Christophersen, Philip C; Vaghela, Dimple; Müllertz, Anette

    2014-01-01

    of oleic acid glycerides accelerated the release of desmopressin significantly from all solid lipid particles both in the presence and absence of lipase. The presence of oleic acid glycerides also reduced the degradation rate of desmopressin, probably due to the interactions between the lipids......The effect of food intake on the release and degradation of peptide drugs from solid lipid particles is unknown and was therefore investigated in vitro using different fed state media in a lipolysis model. Desmopressin was used as a model peptide and incorporated into solid lipid particles...... and the protease or desmopressin. Addition of a medium chain triglyceride, trilaurin, in combination with drug-loaded lipid particles diminished the food effect on the TG18 particles, and trilaurin is therefore proposed to be a suitable excipient for reduction of the food effect. Overall, the present study shows...

  7. Multiparameter Quantification of Liposomal Nanomedicines at the Single-Particle Level by High-Sensitivity Flow Cytometry.

    Science.gov (United States)

    Chen, Chaoxiang; Zhu, Shaobin; Wang, Shuo; Zhang, Wenqiang; Cheng, Yu; Yan, Xiaomei

    2017-04-26

    Drug-encapsulated liposomes have been considered the most clinically acceptable drug-delivery systems. However, current methods fall short in the quantitative characterization of individual nanoliposomes because of their small sizes and large heterogeneity. Here, we report a high-throughput method for the absolute quantification of particle size, drug content, fraction of drug encapsulation, and particle concentration of liposomal nanomedicines at the single-particle level. A laboratory-built high-sensitivity flow cytometer was used to simultaneously detect the side-scatter and fluorescence signals generated by individual nanomedicine particles at a speed up to 10 000 nanoparticles/min. To cope with the size dependence of the refractive index of liposomal nanomedicines, different sizes of doxorubicin-loaded liposomes were fabricated and characterized to serve as the calibration standards for the measurement of both particle size and drug content. This method provides a highly practical platform for the characterization of liposomal nanomedicines, and broad applications can be envisioned.

  8. Vincristine liposomal--INEX: lipid-encapsulated vincristine, onco TCS, transmembrane carrier system--vincristine, vincacine, vincristine sulfate liposomes for injection, VSLI.

    Science.gov (United States)

    2004-01-01

    INEX Pharmaceuticals is developing a liposomal formulation of vincristine [Onco TCS, vincacine, VSLI, Vincristine sulfate liposomes for injection] for the treatment of relapsed aggressive non-Hodgkin's lymphoma (NHL) and other cancers. It is being developed using INEX's proprietary drug-delivery technology platform called the transmembrane carrier systems (TCS), which enables the targeted intracellular delivery of various therapeutic agents. Liposomal vincristine is expected to have certain advantages over the existing standard preparation of vincristine because the use of TCS technology enables the vincristine to circulate in the blood for longer, accumulate in the tumour, and be released over an extended period of time at the tumour site. The application of TCS technology to any agent, including vincristine, has the potential to increase the efficacy and decrease the side effects of the agent. INEX decided in 1998 to focus on gaining approval for liposomal vincristine in the treatment of relapsed aggressive NHL because no standard therapy was approved for this indication. In 1999, liposomal vincristine was granted accelerated development status by the US FDA, which enables the FDA to approve it based on the surrogate endpoint of a single clinical trial. In addition, the FDA granted liposomal vincristine fast track status in August 2000. In April 2001, INEX and Elan Corporation formed a joint venture for the development and commercialisation of liposomal vincristine, with both companies contributing assets to the venture including worldwide rights to the product and intellectual property rights. The joint venture was called IE Oncology. However, in June 2002, Elan announced that it was going to focus its business strategy on three specific areas, which would not include cancer therapies. INEX announced it had regained 100% ownership of liposomal vincristine in April 2003, by reacquiring the 19.9% equity interest held by Elan and in addition retaining a fully paid

  9. Characterization of forced degradation products of torasemide through MS tools and explanation of unusual losses observed during mass fragmentation of drug and degradation products through density functional theory.

    Science.gov (United States)

    Kurmi, Moolchand; Patel, Neha; Jhajra, Shalu; Bharatam, Prasad V; Singh, Saranjit

    2017-10-25

    Mass spectrometry tools (HRMS/LC-HRMS, MS n , and/or on-line H/D exchange) were employed to establish mass fragmentation pattern of torasemide and to characterize its degradation products. During collision-induced dissociation, multiple rearrangement processes and unusual losses of sulfur (S), sulfanyl (HS), sulfur dioxide (SO 2 ), sulphinic acid radical (HSO 2 ), sulfur monoxide (SO), carbon monoxide (CO), formyl radical (CHO) and C 5 H 3 NOS were observed. The same were successfully explained by study of energy profiles, established by application of density functional theory (DFT). Copyright © 2017 Elsevier B.V. All rights reserved.

  10. Incorporation of triclosan and acridine orange into liposomes for evaluating the susceptibility of Candida albicans.

    Science.gov (United States)

    Romio, Karla B; Dos Santos, Kevin F; da Silva, Romário J; Pedro, Maria F C; Kalck, Alessandro S; da Silva Sousa, Marcos; Possamai, Leandro M; Souto, Paula C S; Silva, Josmary R; de Souza, Nara C

    2017-08-01

    Candida albicans is responsible for many of the infections affecting immunocompromised individuals. Although most C. albicans are susceptible to antifungal drugs, uncontrolled use of these drugs has promoted the development of resistance to current antifungals. The clinical implication of resistant strains has led to the search for safer and more effective drugs as well as alternative approaches, such as controlled drug release using liposomes and photodynamic inactivation (PDI), to eliminate pathogens by combining light and photosensitizers. In this study, we used layer-by-layer (LBL) assembly to immobilize triclosan and acridine orange encapsulated in liposomes and investigated the possibility of controlled release using light. Experiments were carried out to examine the susceptibility of C. albicans to PDI. The effects of laser irradiation were investigated by fluorescence microscopy, atomic force microscopy, and release kinetics. Liposomes were successfully prepared and immobilized using the self-assembly LBL technique. Triclosan was released more quickly when the LBL film was irradiated. The release rate was approximately 40% higher in irradiated films (fluence of 15J/cm 2 ) than in non-irradiated films. The results of the susceptibility experiments and surface morphological analysis indicated that C. albicans cell death is caused by photodynamic inactivation. Liposomes containing triclosan and acridine orange may be useful for inactivating C. albicans using light. Our results lay the foundation for the development of new clinical strategies to control resistant strains. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. Multi-parametric assessment of the anti-angiogenic effects of liposomal glucocorticoids

    NARCIS (Netherlands)

    Kluza, Ewelina; Heisen, Marieke; Schmid, Sophie; van der Schaft, Daisy W. J.; Schiffelers, Raymond M.; Storm, Gert; ter Haar Romeny, Bart M.; Strijkers, Gustav J.; Nicolay, Klaas

    2011-01-01

    Inflammation plays a prominent role in tumor growth. Anti-inflammatory drugs have therefore been proposed as anti-cancer therapeutics. In this study, we determined the anti-angiogenic activity of a single dose of liposomal prednisolone phosphate (PLP-L), by monitoring tumor vascular function and

  12. Biocompatibility of Liposome Nanocarriers in the Rat Inner Ear After Intratympanic Administration

    NARCIS (Netherlands)

    Zou, Jing; Feng, Hao; Sood, Rohit; Kinnunen, Paavo K. J.; Pyykko, Ilmari

    2017-01-01

    Liposome nanocarriers (LPNs) are potentially the future of inner ear therapy due to their high drug loading capacity and efficient uptake in the inner ear after a minimally invasive intratympanic administration. However, information on the biocompatibility of LPNs in the inner ear is lacking. The

  13. Topophore C: a liposomal nanoparticle formulation of topotecan for treatment of ovarian cancer.

    Science.gov (United States)

    Patankar, Nilesh A; Waterhouse, Dawn; Strutt, Dita; Anantha, Malathi; Bally, Marcel B

    2013-02-01

    We have recently developed a liposomal nanoparticle (LNP) formulation of irinotecan based on loading method that involves formation of a complex between copper and the water soluble camptothecin. The loading methodology developed for irinotecan was evaluated to develop a LNP topotecan formulation (referred to herein as Topophore C) and test its activity in pre-clinical model of ovarian carcinoma. Topotecan was encapsulated into preformed liposomes containing 300 mM copper sulfate and the divalent metal ionophore A23187. Formulation optimization studies included assessments of loading efficiency, influence of temperature on drug loading and in vitro stability of the resulting formulation. In vivo assessments included drug and liposome pharmacokinetics, drug levels within plasma and the peritoneal cavity following intravenous (i.v.) administration in mice and efficacy studies on ES2 ovarian cancer model. Topotecan loading into liposomes was optimized with encapsulation efficiency of >98 % at a final drug-to-lipid (D/L) mole ratio of 0.1. Higher D/L ratios could be achieved, but the resulting formulations were less stable as judged by in vitro drug release studies. Following Topophore C administration in mice the topotecan plasma half-life and AUC were increased compared to free topotecan by 10-and 22-fold, respectively. Topophore C was 2-to 3-fold more toxic than free topotecan, however showed significantly better anti-tumor activity than free topotecan administered at doses with no observable toxic effects. Topophore C is a therapeutically interesting drug candidate and we are particularly interested in developing its use in combination with liposomal doxorubicin for treatment of platinum refractory ovarian cancer.

  14. Application of multifunctional targeting epirubicin liposomes in the treatment of non-small-cell lung cancer

    Directory of Open Access Journals (Sweden)

    Song X

    2017-10-01

    Full Text Available Xiao-li Song,1 Rui-jun Ju,2 Yao Xiao,1 Xin Wang,1 Shuang Liu,1 Min Fu,1 Jing-jing Liu,1 Li-yan Gu,1 Xue-tao Li,1 Lan Cheng1 1School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian, 2Department of Pharmaceutical Engineering, Beijing Institute of Petrochemical Technology, Beijing, China Abstract: Chemotherapy for aggressive non-small-cell lung cancer (NSCLC usually results in a poor prognosis due to tumor metastasis, vasculogenic mimicry (VM channels, limited killing of tumor cells, and severe systemic toxicity. Herein, we developed a kind of multifunctional targeting epirubicin liposomes to enhance antitumor efficacy for NSCLC. In the liposomes, octreotide was modified on liposomal surface for obtaining a receptor-mediated targeting effect, and honokiol was incorporated into the lipid bilayer for inhibiting tumor metastasis and eliminating VM channels. In vitro cellular assays showed that multifunctional targeting epirubicin liposomes not only exhibited the strongest cytotoxic effect on Lewis lung tumor cells but also showed the most efficient inhibition on VM channels. Action mechanism studies showed that multifunctional targeting epirubicin liposomes could downregulate PI3K, MMP-2, MMP-9, VE-Cadherin, and FAK and activate apoptotic enzyme caspase 3. In vivo results exhibited that multifunctional targeting epirubicin liposomes could accumulate selectively in tumor site and display an obvious antitumor efficacy. In addition, no significant toxicity of blood system and major organs was observed at a test dose. Therefore, multifunctional targeting epirubicin liposomes may provide a safe and efficient therapy strategy for NSCLC. Keywords: octreotide, honokiol, chemotherapy, vasculogenic mimicry, tumor metastasis, targeting drug delivery

  15. Development and pharmacokinetic of antimony encapsulated in liposomes of phosphatidylserine using radioisotopes in experimental leishmaniasis; Desenvolvimento e farmacocinetica de antimonio encapsulado em lipossomas de fosfatidilserina utilizando radioisotopos em leishmaniose experimental

    Energy Technology Data Exchange (ETDEWEB)

    Borborema, Samanta Etel Treiger

    2010-07-01

    Leishmaniasis are a complex of parasitic diseases caused by intra macrophage protozoa of the genus Leishmania, and is fatal if left untreated. Pentavalent antimonials, though toxic and their mechanism of action being unclear, remain the first-line drugs for treatment. Effective therapy could be achieved by delivering antileishmanial drugs to these sites of infection. Liposomes are phospholipid vesicles that promote improvement in the efficacy and action of drugs in target cell. Liposomes are taken up by the cells of mononuclear phagocytic system (MPS). The purpose of this study was to develop a preparation of meglumine antimonate encapsulated in liposomes of phosphatidylserine and to study its pharmacokinetic in healthy mice to establish its metabolism and distribution. Quantitative analysis of antimony from liposomes demonstrated that Neutron Activation Analysis was the most sensitive technique with almost 100 % of accuracy. All liposome formulations presented a mean diameter size of 150 nm. The determination of IC{sub 50} in infected macrophage showed that liposome formulations were between 10 - 63 fold more effective than the free drug, indicating higher selectivity index. By fluorescence microscopy, an increased uptake of fluorescent-liposomes was seen in infected macrophages during short times of incubation compared with non-infected macrophages. Biodistribution studies showed that meglumine antimonate irradiated encapsulated in liposomes of phosphatidylserine promoted a targeting of antimony for MPS tissues and maintained high doses in organs for a prolonged period. In conclusion, these data suggest that meglumine antimonate encapsulated in liposomes showed higher effectiveness than the non-liposomal drug against Leishmania infection. The development of liposome formulations should be a new alternative for the chemotherapy of infection diseases, especially Leishmaniasis, as they are used to sustain and target pharmaceuticals to the local of infection. (author)

  16. Mechanistic model and analysis of doxorubicin release from liposomal formulations.

    Science.gov (United States)

    Fugit, Kyle D; Xiang, Tian-Xiang; Choi, Du H; Kangarlou, Sogol; Csuhai, Eva; Bummer, Paul M; Anderson, Bradley D

    2015-11-10

    Reliable and predictive models of drug release kinetics in vitro and in vivo are still lacking for liposomal formulations. Developing robust, predictive release models requires systematic, quantitative characterization of these complex drug delivery systems with respect to the physicochemical properties governing the driving force for release. These models must also incorporate changes in release due to the dissolution media and methods employed to monitor release. This paper demonstrates the successful development and application of a mathematical mechanistic model capable of predicting doxorubicin (DXR) release kinetics from liposomal formulations resembling the FDA-approved nanoformulation DOXIL® using dynamic dialysis. The model accounts for DXR equilibria (e.g. self-association, precipitation, ionization), the change in intravesicular pH due to ammonia release, and dialysis membrane transport of DXR. The model was tested using a Box-Behnken experimental design in which release conditions including extravesicular pH, ammonia concentration in the release medium, and the dilution of the formulation (i.e. suspension concentration) were varied. Mechanistic model predictions agreed with observed DXR release up to 19h. The predictions were similar to a computer fit of the release data using an empirical model often employed for analyzing data generated from this type of experimental design. Unlike the empirical model, the mechanistic model was also able to provide reasonable predictions of release outside the tested design space. These results illustrate the usefulness of mechanistic modeling to predict drug release from liposomal formulations in vitro and its potential for future development of in vitro - in vivo correlations for complex nanoformulations. Copyright © 2015 Elsevier B.V. All rights reserved.

  17. Pharmacokinetics of the iron chelator desferrioxamine as affected by liposome encapsulation: potential in treatment of chronic hemosiderosis

    Energy Technology Data Exchange (ETDEWEB)

    Guilmette, R.A.; Cerny, E.A.; Rahman, Y.E.

    1978-01-23

    Desferrioxamine (DF), the chelator of choice for removal of excess stored iron, is limited by its rapid excretion, metabolic breakdown, and low cell uptake. We have encapsulated DF in unilamellar and multilamellar liposomes, and have compared the short-term pharmacokinetics of nonencapsulated and encapsulated /sup 59/Fe-labeled DF after intravenous administration. Disappearance of /sup 59/Fe-DF from the plasma was very rapid in mice receiving multilamellar liposome-encapsulated and nonencapsulated drug, but much slower in mice receiving unilamellar liposomes. Between 1 and 24 hours after injection, nonencapsulated /sup 59/Fe-DF never exceeded 1 to 5% of the injected dose (ID) in liver or <0.7% in spleen; whereas after either multilamellar or unilamellar liposomes, the uptake in liver was 30 to 35% ID, and in spleen was 1 to 5% ID. Excretion of /sup 59/Fe-DF was much slower with liposome encapsulation. These results indicate that liposomes can effectively deliver DF to critical organs of iron storage. Thus this drug delivery system is potentially useful for treatment of iron overload.

  18. Designer lipids for drug delivery: from heads to tails

    Science.gov (United States)

    Kohli, Aditya G.; Kierstead, Paul H.; Venditto, Vincent J.; Walsh, Colin L.; Szoka, Francis C.

    2014-01-01

    For four decades, liposomes composed of both naturally occurring and synthetic lipids have been investigated as delivery vehicles for low molecular weight and macromolecular drugs. These studies paved the way for the clinical and commercial success of a number of liposomal drugs, each of which required a tailored formulation; one liposome size does not fit all drugs! Instead, the physicochemical properties of the liposome must be matched to the pharmacology of the drug. An extensive biophysical literature demonstrates that varying lipid composition can influence the size, membrane stability, in vivo interactions, and drug release properties of a liposome. In this review we focus on recently described synthetic lipid headgroups, linkers and hydrophobic domains that can provide control over the intermolecular forces, phase preference, and macroscopic behavior of liposomes. These synthetic lipids further our understanding of lipid biophysics, promote targeted drug delivery, and improve liposome stability. We further highlight the immune reactivity of novel synthetic headgroups as a key design consideration. For instance it was originally thought that synthetic PEGylated lipids were immunologically inert; however, it’s been observed that under certain conditions PEGylated lipids induce humoral immunity. Such immune activation may be a limitation to the use of other engineered lipid headgroups for drug delivery. In addition to the potential immunogenicity of engineered lipids, future investigations on liposome drugs in vivo should pay particular attention to the location and dynamics of payload release. PMID:24816069

  19. Inhibition of HIV Virus by Neutralizing Vhh Attached to Dual Functional Liposomes Encapsulating Dapivirine

    Science.gov (United States)

    Wang, Scarlet Xiaoyan; Michiels, Johan; Ariën, Kevin K.; New, Roger; Vanham, Guido; Roitt, Ivan

    2016-07-01

    Although highly active antiretroviral therapy (HAART) has greatly improved the life expectancy of HIV/AIDS patients, the treatment is not curative. It is a global challenge which fosters an urgent need to develop an effective drug or neutralizing antibody delivery approach for the prevention and treatment of this disease. Due to the low density of envelope spikes with restricted mobility present on the surface of HIV virus, which limit the antibody potency and allow virus mutation and escape from the immune system, it is important for a neutralizing antibody to form bivalent or multivalent bonds with the virus. Liposome constructs could fulfil this need due to the flexible mobility of the membrane with its attached antibodies and the capacity for drug encapsulation. In this study, we evaluated the neutralization activity of a range of liposome formulations in different sizes coated with anti-gp120 llama antibody fragments (Vhhs) conjugated via either non-covalent metal chelation or a covalent linkage. The non-covalent construct demonstrated identical binding affinity to HIV-1 envelope glycoprotein gp120 and neutralizing ability for HIV virus as free Vhh. Although covalently linked Vhh showed significant binding affinity to gp120, it unexpectedly had a lower neutralization potency. This may be due to the comparability in size of the viral and liposome particles restricting the number which can be bound to the liposome surface so involving only a fraction of the antibodies, whereas non-covalently attached antibodies dissociate from the surface after acting with gp120 and free the remainder to bind further viruses. Covalently conjugated Vhh might also trigger the cellular uptake of a liposome-virion complex. To explore the possible ability of the antibody-coated liposomes to have a further function, we encapsulated the hydrophobic antiviral drug dapivirine into both of the non-covalently and covalently conjugated liposome formulations, both of which revealed high

  20. Large-scale preparation of clove essential oil and eugenol-loaded liposomes using a membrane contactor and a pilot plant.

    Science.gov (United States)

    Sebaaly, Carine; Greige-Gerges, Hélène; Agusti, Géraldine; Fessi, Hatem; Charcosset, Catherine

    2016-01-01

    Based on our previous study where optimal conditions were defined to encapsulate clove essential oil (CEO) into liposomes at laboratory scale, we scaled-up the preparation of CEO and eugenol (Eug)-loaded liposomes using a membrane contactor (600 mL) and a pilot plant (3 L) based on the principle of ethanol injection method, both equipped with a Shirasu Porous Glass membrane for injection of the organic phase into the aqueous phase. Homogenous, stable, nanometric-sized and multilamellar liposomes with high phospholipid, Eug loading rates and encapsulation efficiency of CEO components were obtained. Saturation of phospholipids and drug concentration in the organic phase may control the liposome stability. Liposomes loaded with other hydrophobic volatile compounds could be prepared at large scale using the ethanol injection method and a membrane for injection.

  1. The influence of oscillating electromagnetic fields on membrane structure and function: Synthetic liposome and natural membrane bilayer systems with direct application to the controlled delivery of chemical agents

    Energy Technology Data Exchange (ETDEWEB)

    Liburdy, R.P.; de Manincor, D.; Fingado, B.

    1989-09-01

    Investigations have been conducted to determine if an imposed electromagnetic field can influence membrane transport, and ion and drug permeability in both synthetic and natural cell membrane systems. Microwave fields enhance accumulation of sodium in the lymphocyte and induce protein shedding at Tc. Microwaves also trigger membrane permeability of liposome systems under specific field exposure conditions. Sensitivity varies in a defined way in bilayers displaying a membrane structural phase transition temperature, Tc; maximal release was observed at or near Tc. Significantly, liposome systems without a membrane phase transition were also found to experience permeability increases but, in contrast, this response was temperature independent. The above results indicate that field-enhanced drug release occurs in liposome vesicles that possess a Tc as well as non-Tc liposomes. Additional studies extend non-Tc liposome responses to the in vivo case in which microwaves trigger Gentamicin release from a liposome depot'' placed subcutaneously in the rat hind leg. In addition, evidence is provided that cell surface sequestered liposomes can be triggered by microwave fields to release drugs directly into target cells. 24 refs., 6 figs.

  2. Clove essential oil-in-cyclodextrin-in-liposomes in the aqueous and lyophilized states: From laboratory to large scale using a membrane contactor.

    Science.gov (United States)

    Sebaaly, Carine; Charcosset, Catherine; Stainmesse, Serge; Fessi, Hatem; Greige-Gerges, Hélène

    2016-03-15

    This work is dedicated to prepare liposomal dry powder formulations of inclusion complexes of clove essential oil (CEO) and its main component eugenol (Eug). Ethanol injection method and membrane contactor were applied to prepare liposomes at laboratory and large scale, respectively. Various liposomal formulations were tested: (1) free hydroxypropyl-β-cyclodextrin loaded liposomes; (2) drug in hydroxypropyl-β-cyclodextrin in liposomes (DCL); (3) DCL2 obtained by double loading technique, where the drug is added in the organic phase and the inclusion complex in the aqueous phase. Liposomes were characterized for their particle size, polydispersity index, Zeta potential, morphology, encapsulation efficiency of CEO components and Eug loading rate. Reproducible results were obtained with both injection devices. Compared to Eug-loaded liposomes, DCL and DCL2 improved the loading rate of Eug and possessed smaller vesicles size. The DPPH(•) scavenging activity of Eug and CEO was maintained upon incorporation of Eug and CEO into DCL and DCL2. Contrary to DCL2, DCL formulations were stable after 1 month of storage at 4°C and upon reconstitution of the dried lyophilized cakes. Hence, DCL in aqueous and lyophilized forms, are considered as a promising carrier system to preserve volatile and hydrophobic drugs enlarging their application in cosmetic, pharmaceutical and food industries. Copyright © 2015 Elsevier Ltd. All rights reserved.

  3. The influence of oscillating electromagnetic fields on membrane structure and function: Synthetic liposome and natural membrane bilayer systems with direct application to the controlled delivery of chemical agents

    International Nuclear Information System (INIS)

    Liburdy, R.P.; de Manincor, D.; Fingado, B.

    1989-09-01

    Investigations have been conducted to determine if an imposed electromagnetic field can influence membrane transport, and ion and drug permeability in both synthetic and natural cell membrane systems. Microwave fields enhance accumulation of sodium in the lymphocyte and induce protein shedding at Tc. Microwaves also trigger membrane permeability of liposome systems under specific field exposure conditions. Sensitivity varies in a defined way in bilayers displaying a membrane structural phase transition temperature, Tc; maximal release was observed at or near Tc. Significantly, liposome systems without a membrane phase transition were also found to experience permeability increases but, in contrast, this response was temperature independent. The above results indicate that field-enhanced drug release occurs in liposome vesicles that possess a Tc as well as non-Tc liposomes. Additional studies extend non-Tc liposome responses to the in vivo case in which microwaves trigger Gentamicin release from a liposome ''depot'' placed subcutaneously in the rat hind leg. In addition, evidence is provided that cell surface sequestered liposomes can be triggered by microwave fields to release drugs directly into target cells. 24 refs., 6 figs

  4. Preparation and ocular pharmacokinetics of ganciclovir liposomes.

    Science.gov (United States)

    Shen, Yan; Tu, Jiasheng

    2007-12-07

    Ophthalmic liposomes of ganciclovir (GCV) were prepared by the reverse phase evaporation method, and their ocular pharmacokinetics in albino rabbits were compared with those obtained after dosing with GCV solution. The in vitro transcorneal permeability of GCV liposomes was found to be 3.9-fold higher than that of the solution. After in vivo instillation in albino rabbits, no difference was found in the precorneal elimination rate of GCV from liposome vs solution dosing. The aqueous humor concentration-time profiles of both liposomes and solution were well described by 2-compartmental pharmacokinetics with first-order absorption. The area under the curve of the aqueous humor concentration-time profiles of GCV liposomes was found to be 1.7-fold higher than that of GCV solution. Ocular tissue distribution of GCV from liposomes was 2 to 10 times higher in the sclera, cornea, iris, lens, and vitreous humor when compared with those observed after solution dosing. These results suggested that liposomes may hold some promise in ocular GCV delivery.

  5. Influence of the Encapsulation Efficiency and Size of Liposome on the Oral Bioavailability of Griseofulvin-Loaded Liposomes

    OpenAIRE

    Sandy Gim Ming Ong; Long Chiau Ming; Kah Seng Lee; Kah Hay Yuen

    2016-01-01

    The objective of the present study was to investigate the influence of the encapsulation efficiency and size of liposome on the oral bioavailability of griseofulvin-loaded liposomes. Griseofulvin-loaded liposomes with desired characteristics were prepared from pro-liposome using various techniques. To study the effect of encapsulation efficiency, three preparations of griseofulvin, namely, griseofulvin aqueous suspension and two griseofulvin-loaded liposomes with different amounts of griseofu...

  6. Influence of massage and occlusion on the ex vivo skin penetration of rigid liposomes and invasomes

    DEFF Research Database (Denmark)

    Trauer, S.; Richter, H.; Kuntsche, Judith

    2014-01-01

    the in vivo movement of hairs in the hair follicles. In the present study, massage was applied to skin mounted to Franz diffusion cells. By means of confocal laser scanning microscopy, the influence of massage and occlusion on the follicular penetration depths of rigid and flexible liposomes loaded......Liposomes are frequently described as drug delivery systems for dermal and transdermal applications. Recently, it has been shown that particulate substances penetrate effectively into hair follicles and that the follicular penetration depth can be increased by massaging the skin, which simulates...... confirm that massage is an important tool for increasing follicular penetration in ex vivo studies using Franz diffusion cells. Occlusion may reduce the efficacy of follicular penetration depending on the specific liposomal preparation. Rigidity in particular appears to be a relevant parameter. (c) 2013...

  7. Doxorubicin-loaded photosensitive magnetic liposomes for multi-modal cancer therapy.

    Science.gov (United States)

    Shah, Saqlain A; Aslam Khan, M U; Arshad, M; Awan, S U; Hashmi, M U; Ahmad, N

    2016-12-01

    Multifunctional magnetic nanosystems have attracted an enormous attention of researchers for their potential applications in cancer diagnostics and therapy. The localized nanotherapies triggered by the external stimuli, like magnetic fields and visible light, are significant in clinical applications. We report a liposomal system that aims to treat cancer by magnetic hyperthermia, photodynamic therapy and chemotherapy simultaneously. The liposomes enclose clinically used photosensitizer m-THPC (Foscan) and anti-cancer drug doxorubicin, in its hydrophobic lipid bilayers, and contains magnetite nanoparticles in hydrophilic core. Three different sizes of magnetic nanoparticles (10, 22 and 30nm) and liposomes (40, 70 and 110nm) were used in this study. Magnetite single domain nanoparticles forming the magnetic core were superparamagnetic but liposomes expressed slight coercivity and hysteresis due to the clustering of nanoparticles in the core. This enhanced the heating efficiency (specific power loss) of the liposomes under an AC field (375kHz, 170Oe). Cell viability and toxicity were studied on HeLa cells using MTT assay and proteomic analysis. Confocal and fluorescence microscopy were used to study the photosensitizer's profile and cells response to combined therapy. It revealed that combined therapy almost completely eliminated the cancer cells as opposed to the separate treatments. Magnetic hyperthermia and photodynamic therapies were almost equally effective whereas chemotherapy showed the least effect. Copyright © 2016. Published by Elsevier B.V.

  8. Process Variables and Design of Experiments in Liposome and Nanoliposome Research.

    Science.gov (United States)

    Zoghi, Alaleh; Khosravi-Darani, Kianoush; Omri, Abdelwahab

    2018-01-01

    Liposomes vesicles consisting of one or more phospholipid bilayers are microcarriers used in numerous scientific disciplines. During the last decade, nanostructured liposomes, or nanoliposomes, have been utilized in biomedical investigations due to their unique characteristics including nanoscale size, sustained release, biocompatibility, and biodegradability. The extensive literature covering the field of liposomology is an indication of increasing interests and applications in many areas, especially as carriers of active substances in nanomedicine, agriculture, food technology, and cosmetics. Nanoliposomes application as drug carriers resulted in more effective treatment of such diseases as cancers, atherosclerosis, infectious diseases and ocular disorders. In this communication, we will introduce commonly used methods for the preparation of liposome, pointing the therapeutic report of liposomes, and explaining the common process variables in liposome encapsulations. We will also review different screening methods and full and fractional factorial designs that impact independent variables in certain applications and the end-user response. We will review such key factors as encapsulation efficiency, loading capacity, particles' biologic, structural and physicochemical properties, and lipid composition in an effort to provide a comprehensive guide for liposomologists in different fields of interest. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  9. Nanocapsule of cationic liposomes obtained using "in situ" acrylic acid polymerization: stability, surface charge and biocompatibility.

    Science.gov (United States)

    Scarioti, Giovana Danieli; Lubambo, Adriana; Feitosa, Judith P A; Sierakowski, Maria Rita; Bresolin, Tania M B; de Freitas, Rilton Alves

    2011-10-15

    In this work, didecyldimethylammonium bromide (DDAB) and 1,2-dioleoyl-sn-glycero-3-phosphatidylethanolamine (DOPE) (2.5:1) were used to prepare liposomes coated with polyacrylic acid (PAA) using "in situ" polymerization with 2.5, 5 and 25 mM of acrylic acid (AA). The PAA concentrations were chosen to achieve partially to fully covered capsules, and the polymerization reaction was observed with real-time monitoring using dynamic light scattering (NanoDLS). The DDAB:DOPE liposomes showed stability in the tested temperature range (25-70°C), whereas the results confirmed the success of the polymerization according to superficial charge (zeta potential of +66.7±1.2 mV) results and AFM images. For the liposomes that were fully coated with PAA (zeta potential of +0.3±3.9 mV), cytotoxicity was independent of the concentration of albumin. Cationic liposomes and nanocapsules of the stable liposomes coated with PAA were obtained by controlling the surface charge, which was the most important factor related to cytotoxicity. Thus, a potential, safe drug nanocarrier was successfully developed in this work. Copyright © 2011 Elsevier B.V. All rights reserved.

  10. Assembling nanoparticle coatings to improve the drug delivery performance of lipid based colloids.

    Science.gov (United States)

    Simovic, Spomenka; Barnes, Timothy J; Tan, Angel; Prestidge, Clive A

    2012-02-21

    Lipid based colloids (e.g. emulsions and liposomes) are widely used as drug delivery systems, but often suffer from physical instabilities and non-ideal drug encapsulation and delivery performance. We review the application of engineered nanoparticle layers at the interface of lipid colloids to improve their performance as drug delivery systems. In addition we focus on the creation of novel hybrid nanomaterials from nanoparticle-lipid colloid assemblies and their drug delivery applications. Specifically, nanoparticle layers can be engineered to enhance the physical stability of submicron lipid emulsions and liposomes, satbilise encapsulated active ingredients against chemical degradation, control molecular transport and improve the dermal and oral delivery characteristics, i.e. increase absorption, bioavailability and facilitate targeted delivery. It is feasible that hybrid nanomaterials composed of nanoparticles and colloidal lipids are effective encapsulation and delivery systems for both poorly soluble drugs and biological drugs and may form the basis for the next generation of medicines. Additional pre-clinical research including specific animal model studies are required to advance the peptide/protein delivery systems, whereas the silica lipid hybrid systems have now entered human clinical trials for poorly soluble drugs. This journal is © The Royal Society of Chemistry 2012

  11. Remote loading of doxorubicin into liposomes by transmembrane pH gradient to reduce toxicity toward H9c2 cells

    Directory of Open Access Journals (Sweden)

    Mohamed Alyane

    2016-03-01

    Full Text Available The use of doxorubicin (DOX is limited by its dose-dependent cardiotoxicity. Entrapped DOX in liposome has been shown to reduce cardiotoxicity. Results showed that about 92% of the total drug was encapsulated in liposome. The release experiments showed a weak DOX leakage in both culture medium and in PBS, more than 98% and 90% of the encapsulated DOX respectively was still retained in liposomes after 24 h of incubation. When the release experiments were carried out in phosphate buffer pH5.3, the leakage of DOX from liposomes reached 37% after 24 h of incubation. Evaluation of cellular uptake of the liposomal DOX indicated the possible endocytosis of liposomes because the majority of visible fluorescence of DOX was mainly in the cytoplasm, whereas the nuclear compartment showed a weak intensity. When using unloaded fluorescent-liposomes, the fluorescence was absent in nuclei suggests that liposomes cannot cross the nuclear membrane. MTT assay and measurement of LDH release suggest that necrosis is the form of cellular death predominates in H9c2 cells exposed to high doses of DOX, while for weak doses apoptosis could be the predominate form. Entrapped DOX reduced significantly DOX toxicity after 3 and 6 h of incubation, but after 20 h entrapped DOX is more toxic than free one.

  12. Preparation of redispersible liposomal dry powder using an ultrasonic spray freeze-drying technique for transdermal delivery of human epithelial growth factor.

    Science.gov (United States)

    Yin, Fei; Guo, Shiyan; Gan, Yong; Zhang, Xinxin

    2014-01-01

    In this work, an ultrasonic spray freeze-drying (USFD) technique was used to prepare a stable liposomal dry powder for transdermal delivery of recombinant human epithelial growth factor (rhEGF). Morphology, particle size, entrapment efficiency, in vitro release, and skin permeability were systematically compared between rhEGF liposomal dry powder prepared using USFD and that prepared using a conventional lyophilization process. Porous and spherical particles with high specific area were produced under USFD conditions. USFD effectively avoided formation of ice crystals, disruption of the bilayer structure, and drug leakage during the liposome drying process, and maintained the stability of the rhEGF liposomal formulation during storage. The reconstituted rhEGF liposomes prepared from USFD powder did not show significant changes in morphology, particle size, entrapment efficiency, or in vitro release characteristics compared with those of rhEGF liposomes before drying. Moreover, the rhEGF liposomal powder prepared with USFD exhibited excellent enhanced penetration in ex vivo mouse skin compared with that for powder prepared via conventional lyophilization. The results suggest that ultrasonic USFD is a promising technique for the production of stable protein-loaded liposomal dry powder for application to the skin.

  13. Heating treatments affect the thermal behaviour of doxorubicin loaded in PEGylated liposomes.

    Science.gov (United States)

    Perinelli, Diego R; Cespi, Marco; Bonacucina, Giulia; Rendina, Filippo; Palmieri, Giovanni Filippo

    2017-12-20

    Doxil ® is a stealth marketed PEGylated liposomal formulation, containing the anticancer drug doxorubicin. After loading via a pH gradient, fibrillar supramolecular structures of doxorubicin sulfate originates inside the core of the liposomes. Recently, the crystallinity of doxorubicin sulfate has been confirmed by high-resolution calorimetry. However, no detailed information are available on the nature of doxorubicin sulfate nanocrystals and on the effect of different thermal treatments. Thus, the aim of this work was to characterize the thermal behaviour of Doxil ® in comparison to the unloaded liposomes using microcalorimetry, dynamic light scattering and high-resolution ultrasound spectroscopy (HR-US). Different thermal programmes were applied with the aim to highlight the effect of the treatments on the formulation. The used techniques confirmed the ordered state of doxorubicin nanocrystals inside PEGylated liposomes. Particularly, microcalorimetry and HR-US highlighted the changes in the thermal behaviour of the drug under different heating programmes. Doxorubicin nanocrystals were found to be stable after heating up to 80°C, but an irreversible thermal behaviour was observed after a prolonged heating at elevated temperature (2h at 80°C). The non-reversibility could be related to the formation of a different ordered structure and enhanced by the slight leakage of the drug occurring after a prolonged heating. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. Magnetic liposomes for colorectal cancer cells therapy by high-frequency magnetic field treatment

    Science.gov (United States)

    Hardiansyah, Andri; Huang, Li-Ying; Yang, Ming-Chien; Liu, Ting-Yu; Tsai, Sung-Chen; Yang, Chih-Yung; Kuo, Chih-Yu; Chan, Tzu-Yi; Zou, Hui-Ming; Lian, Wei-Nan; Lin, Chi-Hung

    2014-09-01

    In this study, we developed the cancer treatment through the combination of chemotherapy and thermotherapy using doxorubicin-loaded magnetic liposomes. The citric acid-coated magnetic nanoparticles (CAMNP, ca. 10 nm) and doxorubicin were encapsulated into the liposome (HSPC/DSPE/cholesterol = 12.5:1:8.25) by rotary evaporation and ultrasonication process. The resultant magnetic liposomes ( ca. 90 to 130 nm) were subject to characterization including transmission electron microscopy (TEM), dynamic light scattering (DLS), X-ray diffraction (XRD), zeta potential, Fourier transform infrared (FTIR) spectrophotometer, and fluorescence microscope. In vitro cytotoxicity of the drug carrier platform was investigated through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay using L-929 cells, as the mammalian cell model. In vitro cytotoxicity and hyperthermia (inductive heating) studies were evaluated against colorectal cancer (CT-26 cells) with high-frequency magnetic field (HFMF) exposure. MTT assay revealed that these drug carriers exhibited no cytotoxicity against L-929 cells, suggesting excellent biocompatibility. When the magnetic liposomes with 1 μM doxorubicin was used to treat CT-26 cells in combination with HFMF exposure, approximately 56% cells were killed and found to be more effective than either hyperthermia or chemotherapy treatment individually. Therefore, these results show that the synergistic effects between chemotherapy (drug-controlled release) and hyperthermia increase the capability to kill cancer cells.

  15. Hyaluronan-conjugated liposomes encapsulating gemcitabine for breast cancer stem cells

    Directory of Open Access Journals (Sweden)

    Han NK

    2016-04-01

    Full Text Available Na-Kyung Han,1,* Dae Hwan Shin,1,* Jung Seok Kim,1 Kwon Yeon Weon,2 Chang-Young Jang,1 Jin-Seok Kim1 1Research Center for Cell Fate Control (RCCFC and College of Pharmacy, Sookmyung Women’s University, Seoul, 2College of Pharmacy, Catholic University of Daegu, Gyeongbuk, Korea *These authors contributed equally to this work Abstract: Investigation of potential therapeutics for targeting breast cancer stem cells (BCSCs is important because these cells are regarded as culprit of breast cancer relapse. Accomplishing this kind of strategy requires a specific drug-delivery system using the distinct features of liposomes. Studies on targeted liposomal delivery systems have indicated the conjugation of hyaluronan (HA, a primary ligand for CD44 surface markers, as an appropriate method for targeting BCSCs. For this study, enriched BCSCs were obtained by culturing MCF-7 breast cancer cells in nonadherent conditions. The enriched BCSCs were challenged with HA-conjugated liposomes encapsulating gemcitabine (2, 2-difluoro-2-deoxycytidine, GEM. In vitro study showed that the HA-conjugated liposomes significantly enhanced the cytotoxicity, anti-migration, and anti-colony formation abilities of GEM through targeting of CD44 expressed on BCSCs. In pharmacokinetic study, area under the drug concentration vs time curve (AUC of the immunoliposomal GEM was 3.5 times higher than that of free GEM, indicating that the HA-conjugated liposomes enhanced the stability of GEM in the bloodstream and therefore prolonged its half-life time. The antitumor effect of the immunoliposomal GEM was 3.3 times higher than that of free GEM in a xenograft mouse model, probably reflecting the unique targeting of the CD44 receptor by HA and the increased cytotoxicity and stability through the liposomal formulation. Furthermore, marginal change in body weight demonstrated that the use of liposomes considerably reduced the systemic toxicity of GEM on normal healthy cells. Taken together