WorldWideScience

Sample records for barrier drug targeting

  1. Smuggling Drugs into the Brain: An Overview of Ligands Targeting Transcytosis for Drug Delivery across the Blood-Brain Barrier

    NARCIS (Netherlands)

    Zuhorn, Inge; Georgieva, Julia V.; Hoekstra, Dick

    2015-01-01

    The blood-brain barrier acts as a physical barrier that prevents free entry of blood-derived substances, including those intended for therapeutic applications. The development of molecular Trojan horses is a promising drug targeting technology that allows for non-invasive delivery of therapeutics in

  2. Impacts of Blood-Brain Barrier in Drug Delivery and Targeting of Brain Tumors

    Directory of Open Access Journals (Sweden)

    Yadollah Omidi

    2012-02-01

    Full Text Available Introduction: Entry of blood circulating agents into the brain is highly selectively controlled by specific transport machineries at the blood brain barrier (BBB, whose excellent barrier restrictiveness make brain drug delivery and targeting very challenging. Methods: Essential information on BBB cellular microenvironment were reviewed and discussed towards impacts of BBB on brain drug delivery and targeting. Results: Brain capillary endothelial cells (BCECs form unique biological structure and architecture in association with astrocytes and pericytes, in which microenvironment the BCECs express restrictive tight junctional complexes that block the paracellular inward/outward traverse of biomolecules/compounds. These cells selectively/specifically control the transportation process through carrier and/or receptor mediated transport machineries that can also be exploited for the delivery of pharmaceuticals into the brain. Intelligent molecular therapies should be designed using such transport machineries for the efficient delivery of designated drugs into the brain. For better clinical outcomes, these smart pharmaceuticals should be engineered as seamless nanosystems to provide simultaneous imaging and therapy (multimodal theranostics. Conclusion: The exceptional functional presence of BBB selectively controls inward and outward transportation mechanisms, thus advanced smart multifunctional nanomedicines are needed for the effective brain drug delivery and targeting. Fully understanding the biofunctions of BBB appears to be a central step for engineering of intelligent seamless therapeutics consisting of homing device for targeting, imaging moiety for detecting, and stimuli responsive device for on-demand liberation of therapeutic agent.

  3. 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 cros

  4. Ultrasound-mediated blood-brain barrier disruption for targeted drug delivery in the central nervous system

    Science.gov (United States)

    McDannold, Nathan; Zhang, Yongzhi; Power, Chanikarn; Arvanitis, Costas D.; Vykhodtseva, Natalia; Livingstone, Margaret

    2015-05-01

    The physiology of the vasculature in the central nervous system (CNS), which includes the blood-brain barrier (BBB) and other factors, complicates the delivery of most drugs to the brain. Different methods have been used to bypass the BBB, but they have limitations such as being invasive, non-targeted or requiring the formulation of new drugs. Focused ultrasound (FUS), when combined with circulating microbubbles, is a noninvasive method to locally and transiently disrupt the BBB at discrete targets. The method presents new opportunities for the use of drugs and for the study of the brain.

  5. Tumor vascular endothelium : Barrier or target in tumor directed drug delivery and immunotherapy

    NARCIS (Netherlands)

    Molema, Ingrid; de Leij, Lou; Meijer, D.K F

    1997-01-01

    The therapy of solid tumors with conventional chemotherapeutics, drug delivery preparations and immunomodulatory agents directed against the tumor cells is corrupted by a major barrier presented by the tumor vasculature. Permeability of the tumor blood vessels for transport of small molecules and ma

  6. Transient disruption of vascular barriers using focused ultrasound and microbubbles for targeted drug delivery in the brain

    Science.gov (United States)

    Aryal, Muna

    The physiology of the vasculature in the central nervous system (CNS) which includes the blood-brain-barrier (BBB) and other factors, prevents the transport of most anticancer agents to the brain and restricts delivery to infiltrating brain tumors. The heterogeneous vascular permeability in tumor vessels (blood-tumor barrier; BTB), along with several other factors, creates additional hurdles for drug treatment of brain tumors. Different methods have been used to bypass the BBB/BTB, but they have their own limitations such as being invasive, non-targeted or requiring the formulation of new drugs. Magnetic Resonance Imaging guided Focused Ultrasound (MRIgFUS), when combined with circulating microbubbles, is an emerging noninvasive method to temporarily permeabilize the BBB and BTB. The purpose of this thesis was to use this alternative approach to deliver chemotherapeutic agents through the BBB/BTB for brain tumor treatment in a rodent model to overcome the hinderances encountered in prior approaches tested for drug delivery in the CNS. The results presented in thesis demonstrate that MRIgFUS can be used to achieve consistent and reproducible BBB/BTB disruption in rats. It enabled us to achieve clinically-relevant concentrations of doxorubicin (~ 4.8+/-0.5 microg/g) delivered to the brain with the sonication parameters (0.69 MHz; 0.55 MPa; 10 ms bursts; 1 Hz PRF; 60 s duration), microbubble concentration (Definity, 10 microl/kg), and liposomoal doxorubicin (Lipo-DOX) dose (5.67 mg/kg) used. The resulting doxorubicin concentration was reduced by 32% when the agent was injected 10 minute after the last sonication. Three weekly sessions of FUS and Lipo-DOX appeared to be safe in the rat brain, despite some minor tissue damage. Importantly, the severe neurotoxicity seen in earlier works using other approaches does not appear to occur with delivery via FUS-BBB disruption. The resuls from three weekly treatments of FUS and Lipo-DOX in a rat glioma model are highly

  7. A novel blood-brain barrier co-culture system for drug targeting of Alzheimer's disease: establishment by using acitretin as a model drug.

    Directory of Open Access Journals (Sweden)

    Christian Freese

    Full Text Available In the pathogenesis of Alzheimer's disease (AD the homeostasis of amyloid precursor protein (APP processing in the brain is impaired. The expression of the competing proteases ADAM10 (a disintegrin and metalloproteinase 10 and BACE-1 (beta site APP cleaving enzyme 1 is shifted in favor of the A-beta generating enzyme BACE-1. Acitretin--a synthetic retinoid-e.g., has been shown to increase ADAM10 gene expression, resulting in a decreased level of A-beta peptides within the brain of AD model mice and thus is of possible value for AD therapy. A striking challenge in evaluating novel therapeutically applicable drugs is the analysis of their potential to overcome the blood-brain barrier (BBB for central nervous system targeting. In this study, we established a novel cell-based bio-assay model to test ADAM10-inducing drugs for their ability to cross the BBB. We therefore used primary porcine brain endothelial cells (PBECs and human neuroblastoma cells (SH-SY5Y transfected with an ADAM10-promoter luciferase reporter vector in an indirect co-culture system. Acitretin served as a model substance that crosses the BBB and induces ADAM10 expression. We ensured that ADAM10-dependent constitutive APP metabolism in the neuronal cells was unaffected under co-cultivation conditions. Barrier properties established by PBECs were augmented by co-cultivation with SH-SY5Y cells and they remained stable during the treatment with acitretin as demonstrated by electrical resistance measurement and permeability-coefficient determination. As a consequence of transcellular acitretin transport measured by HPLC, the activity of the ADAM10-promoter reporter gene was significantly increased in co-cultured neuronal cells as compared to vehicle-treated controls. In the present study, we provide a new bio-assay system relevant for the study of drug targeting of AD. This bio-assay can easily be adapted to analyze other Alzheimer- or CNS disease-relevant targets in neuronal cells

  8. A novel blood-brain barrier co-culture system for drug targeting of Alzheimer's disease: establishment by using acitretin as a model drug.

    Science.gov (United States)

    Freese, Christian; Reinhardt, Sven; Hefner, Gudrun; Unger, Ronald E; Kirkpatrick, C James; Endres, Kristina

    2014-01-01

    In the pathogenesis of Alzheimer's disease (AD) the homeostasis of amyloid precursor protein (APP) processing in the brain is impaired. The expression of the competing proteases ADAM10 (a disintegrin and metalloproteinase 10) and BACE-1 (beta site APP cleaving enzyme 1) is shifted in favor of the A-beta generating enzyme BACE-1. Acitretin--a synthetic retinoid-e.g., has been shown to increase ADAM10 gene expression, resulting in a decreased level of A-beta peptides within the brain of AD model mice and thus is of possible value for AD therapy. A striking challenge in evaluating novel therapeutically applicable drugs is the analysis of their potential to overcome the blood-brain barrier (BBB) for central nervous system targeting. In this study, we established a novel cell-based bio-assay model to test ADAM10-inducing drugs for their ability to cross the BBB. We therefore used primary porcine brain endothelial cells (PBECs) and human neuroblastoma cells (SH-SY5Y) transfected with an ADAM10-promoter luciferase reporter vector in an indirect co-culture system. Acitretin served as a model substance that crosses the BBB and induces ADAM10 expression. We ensured that ADAM10-dependent constitutive APP metabolism in the neuronal cells was unaffected under co-cultivation conditions. Barrier properties established by PBECs were augmented by co-cultivation with SH-SY5Y cells and they remained stable during the treatment with acitretin as demonstrated by electrical resistance measurement and permeability-coefficient determination. As a consequence of transcellular acitretin transport measured by HPLC, the activity of the ADAM10-promoter reporter gene was significantly increased in co-cultured neuronal cells as compared to vehicle-treated controls. In the present study, we provide a new bio-assay system relevant for the study of drug targeting of AD. This bio-assay can easily be adapted to analyze other Alzheimer- or CNS disease-relevant targets in neuronal cells, as their

  9. Pathophysiology of Blood-Brain Barrier in Brain Injury in Cold and Hot Environments: Novel Drug Targets for Neuroprotection.

    Science.gov (United States)

    Sharma, Hari Shanker; Muresanu, Dafin F; Lafuente, José V; Nozari, Ala; Patnaik, Ranjana; Skaper, Stephen D; Sharma, Aruna

    2016-01-01

    The blood-brain barrier (BBB) plays a pivotal role in the maintenance of central nervous system function in health and disease. Thus, in almost all neurodegenerative, traumatic or metabolic insults BBB breakdown occurs, allowing entry of serum proteins into the brain fluid microenvironment with subsequent edema formation and cellular injury. Accordingly, pharmacological restoration of BBB function will lead to neurorepair. However, brain injury which occurs following blast, bullet wounds, or knife injury appears to initiate different sets of pathophysiological responses. Moreover, other local factors at the time of injury such as cold or elevated ambient temperatures could also impact the final outcome. Obviously, drug therapy applied to different kinds of brain trauma occurring at either cold or hot environments may respond differently. This is largely due to the fact that internal defense mechanisms of the brain, gene expression, release of neurochemicals and binding of drugs to specific receptors are affected by external ambient temperature changes. These factors may also affect BBB function and development of edema formation after brain injury. In this review, the effects of seasonal exposure to heat and cold on traumatic brain injury using different models i.e., concussive brain injury and cerebral cortical lesion, on BBB dysfunction in relation to drug therapy are discussed. Our observations clearly suggest that closed head injury and open brain injury are two different entities and the external hot or cold environments affect both of them remarkably. Thus, effective pharmacological therapeutic strategies should be designed with these views in mind, as military personnel often experience blunt or penetrating head injuries in either cold or hot environments.

  10. Mucus as a Barrier to Drug Delivery

    DEFF Research Database (Denmark)

    Bøgh, Marie; Nielsen, Hanne Mørck

    2015-01-01

    barrier to drug delivery. Current knowledge of mucus characteristics and barrier properties, as achieved by state-of-the-art methodologies, is the topic of this MiniReview emphasizing the gastrointestinal mucus and an overall focus on oral drug delivery. Cell culture-based in vitro models are well......, studies of peptide and protein drug diffusion in and through mucus and studies of mucus-penetrating nanoparticles are included to illustrate the mucus as a potentially important barrier to obtain sufficient bioavailability of orally administered drugs, and thus an important parameter to address...

  11. Magnetic targeted drug delivery

    Directory of Open Access Journals (Sweden)

    Timothy Wiedmann

    2009-10-01

    Full Text Available Lung cancer is the most common cause of death from cancer in both men and women. Treatment by intravenous or oral administration of chemotherapy agents results in serious and often treatment-limiting side effects. Delivery of drugs directly to the lung by inhalation of an aerosol holds the promise of achieving a higher concentration in the lung with lower blood levels. To further enhance the selective lung deposition, it may be possible to target deposition by using external magnetic fields to direct the delivery of drug coupled to magnetic particles. Moreover, alternating magnetic fields can be used to induce particle heating, which in turn controls the drug release rate with the appropriate thermal sensitive material.With this goal, superparamagetic nanoparticles (SPNP were prepared and characterized, and enhanced magnetic deposition was demonstrated in vitro and in vivo. SPNPs were also incorporated into a lipid-based/SPNP aerosol formulation, and drug release was shown to be controlled by thermal activation. Because of the inherent imaging potential of SPNPs, this use of nanotechnology offers the possibility of coupling the diagnosis of lung cancer to drug release, which perhaps will ultimately provide the “magic bullet” that Paul Ehrlich originally sought.

  12. Progress and perspectives on targeting nanoparticles for brain drug delivery

    Directory of Open Access Journals (Sweden)

    Huile Gao

    2016-07-01

    Full Text Available Due to the ability of the blood–brain barrier (BBB to prevent the entry of drugs into the brain, it is a challenge to treat central nervous system disorders pharmacologically. The development of nanotechnology provides potential to overcome this problem. In this review, the barriers to brain-targeted drug delivery are reviewed, including the BBB, blood–brain tumor barrier (BBTB, and nose-to-brain barrier. Delivery strategies are focused on overcoming the BBB, directly targeting diseased cells in the brain, and dual-targeted delivery. The major concerns and perspectives on constructing brain-targeted delivery systems are discussed.

  13. Targeted Delivery of Protein Drugs by Nanocarriers

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    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.

  14. NATURAL BARRIERS TARGETED THRUST FY 2004 PROJECTS

    Energy Technology Data Exchange (ETDEWEB)

    NA

    2005-07-27

    This booklet contains project descriptions of work performed by the Department of Energy (DOE), Office of Civilian Radioactive Waste Management (OCRWM), Office of Science and Technology and International's (OST&I) Natural Barriers Targeted Thrust during Fiscal Year (FY) 2004. The Natural Barriers Targeted Thrust is part of OST&I's Science and Technology Program which supports the OCRWM mission to manage and dispose of high-level radioactive waste and spent nuclear fuel in a manner that protects health, safety, and the environment; enhances national and energy security; and merits public confidence. In general, the projects described will continue beyond FY 2004 assuming that the technical work remains relevant to the proposed Yucca Mountain Repository and sufficient funding is made available to the Science and Technology Program.

  15. Target Oriented Drugs against Leishmania.

    Science.gov (United States)

    1980-01-31

    the leishmanial source. Leishmanial strains L32 Leishmania tropica LRC L32 L137 Leishmania tropica LRC L137 L52 Leishmania donovani LRC L52 These...RESOLUTION TEST CHAR] 0REPORT NUMBER I TARGET ORIENTED DRUGS AGAINST LEISHMANIA (First Annual Summary Report) 0URI ZEHAVI, PhD and JOSEPH EL-ON, PhD...GOVT ACCESSION NO. 3. RE PIENT.S CATALOG NUMBER A....*( - ) S. TYPE OF REPORT & PERIOD COVERED TARGET ORIENTED DRUGS AGAINST LEISHMANIA 6 FIRST

  16. Drug lag and key regulatory barriers in the emerging markets.

    Science.gov (United States)

    Wileman, Harriet; Mishra, Arun

    2010-04-01

    There have been numerous investigations targeted at identifying whether a drug lag exists in the mature markets of the US, EU and Japan. This work focuses on the emerging markets because of the potential they hold for the future of the pharmaceutical industry as a consequence of rapid economic and political development.The aims of this work are to ascertain whether a drug lag exists in the emerging markets and how it has changed over time from the 1960s to the 2000s. It will also highlight key regulatory barriers which may contribute to drug lag.The date of the marketing authorisation (MA) approval by the US Food and Drug Administration (FDA) was used as a reference point. A comparison against the company database regarding emerging market specific approval enabled the difference in time and thus the drug lag for that particular market to be calculated.This work concludes that the overall relative drug lag in the emerging markets has decreased over time and that there are seven key regulatory barriers which need to be targeted in order to make further improvements; 'Western Approval', local clinical development (LCD), Certificate of Pharmaceutical Product (CPP), Good Manufacturing Practice (GMP), pricing approval, document authentication and harmonisation.

  17. Evaluation and validation of drug targets

    Institute of Scientific and Technical Information of China (English)

    Guan-huaDU

    2004-01-01

    Drug target is one of the key factors for discovering and developing new drugs. To find and validate drug targets is a crucial technique required in drug discovery by the strategy of high throughput screening. Based on the knowledge of molecular biology, human genomics and proteomics, it has been predicted that 5000 to 10000 drug targets exist in human. So, it is important orocedure to evaluate and validate the drug targets.

  18. Nanoscale drug delivery systems and the blood–brain barrier

    Directory of Open Access Journals (Sweden)

    Alyautdin R

    2014-02-01

    comprehensively discusses the functional morphology of the BBB and the challenges that must be overcome by drug-delivery systems and elaborates on the potential targets, mechanisms, and formulations to improve drug delivery to the CNS.Keywords: apoE, blood–brain barrier, CNS, drug targeting, liposomes, nanoparticles

  19. Nanoscale drug delivery systems and the blood-brain barrier.

    Science.gov (United States)

    Alyautdin, Renad; Khalin, Igor; Nafeeza, Mohd Ismail; Haron, Muhammad Huzaimi; Kuznetsov, Dmitry

    2014-01-01

    The protective properties of the blood-brain barrier (BBB) are conferred by the intricate architecture of its endothelium coupled with multiple specific transport systems expressed on the surface of endothelial cells (ECs) in the brain's vasculature. When the stringent control of the BBB is disrupted, such as following EC damage, substances that are safe for peripheral tissues but toxic to neurons have easier access to the central nervous system (CNS). As a consequence, CNS disorders, including degenerative diseases, can occur independently of an individual's age. Although the BBB is crucial in regulating the biochemical environment that is essential for maintaining neuronal integrity, it limits drug delivery to the CNS. This makes it difficult to deliver beneficial drugs across the BBB while preventing the passage of potential neurotoxins. Available options include transport of drugs across the ECs through traversing occludins and claudins in the tight junctions or by attaching drugs to one of the existing transport systems. Either way, access must specifically allow only the passage of a particular drug. In general, the BBB allows small molecules to enter the CNS; however, most drugs with the potential to treat neurological disorders other than infections have large structures. Several mechanisms, such as modifications of the built-in pumping-out system of drugs and utilization of nanocarriers and liposomes, are among the drug-delivery systems that have been tested; however, each has its limitations and constraints. This review comprehensively discusses the functional morphology of the BBB and the challenges that must be overcome by drug-delivery systems and elaborates on the potential targets, mechanisms, and formulations to improve drug delivery to the CNS.

  20. Antibiotic drugs targeting bacterial RNAs

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    Weiling Hong

    2014-08-01

    Full Text Available RNAs have diverse structures that include bulges and internal loops able to form tertiary contacts or serve as ligand binding sites. The recent increase in structural and functional information related to RNAs has put them in the limelight as a drug target for small molecule therapy. In addition, the recognition of the marked difference between prokaryotic and eukaryotic rRNA has led to the development of antibiotics that specifically target bacterial rRNA, reduce protein translation and thereby inhibit bacterial growth. To facilitate the development of new antibiotics targeting RNA, we here review the literature concerning such antibiotics, mRNA, riboswitch and tRNA and the key methodologies used for their screening.

  1. NEW DRUG TARGETING TREATMENT - GLIVEC

    Institute of Scientific and Technical Information of China (English)

    SUN Xue-mei(孙雪梅); BRADY Ben

    2003-01-01

    This review evaluates the role of Glivec in the treatment of chronic myelogenous leukemia and other malignant tumors. Preclinical and clinical evidence showed that Glivec demonstrated a potent and specific inhibition on BCR-ABL positive leukemias and other malignant tumors in which overexpression of c-kit and PDGFR-β played a major role in their pathogenesis. Glivec has induced complete hematologic responses in up to 98% of patients evaluated in clinical trials. It's a very successful drug that supported the idea of targeted therapy through inhibition of tyrosine kinases. Although it's still in the early stages of clinical development and the resistance to Glivec remains to be a problem needed further study, a great deal has been learned from these research and observation. And with the increasing data, molecular targeting therapy will play much more important role in the treatment of malignant tumors. With the better understanding of the pathogenesis of malignant tumors, well-designed drugs targeting the specific molecular abnormalities with higher efficacy and lower side effect will benefit numerous patients with malignant tumors.

  2. Drug targeting through pilosebaceous route.

    Science.gov (United States)

    Chourasia, Rashmi; Jain, Sanjay K

    2009-10-01

    Local skin targeting is of interest for the pharmaceutical and the cosmetic industry. A topically applied substance has basically three possibilities to penetrate into the skin: transcellular, intercellular, and follicular. The transfollicular path has been largely ignored because hair follicles constitute only 0.1% of the total skin. The hair follicle is a skin appendage with a complex structure containing many cell types that produce highly specialised proteins. The hair follicle is in a continuous cycle: anagen is the hair growth phase, catagen the involution phase and telogen is the resting phase. Nonetheless, the hair follicle has great potential for skin treatment, owing to its deep extension into the dermis and thus provides much deeper penetration and absorption of compounds beneath the skin than seen with the transdermal route. In the case of skin diseases and of cosmetic products, delivery to sweat glands or to the pilosebaceous unit is essential for the effectiveness of the drug. Increased accumulation in the pilosebaceous unit could treat alopecia, acne and skin cancer more efficiently and improve the effect of cosmetic substances and nutrients. Therefore, we review herein various drug delivery systems, including liposomes, niosomes, microspheres, nanoparticles, nanoemulsions, lipid nanocarriers, gene therapy and discuss the results of recent researches. We also review the drugs which have been investigated for pilosebaceous delivery.

  3. Aquaporins as potential drug targets

    Institute of Scientific and Technical Information of China (English)

    Fang WANG; Xue-chao FENG; Yong-ming LI; Hong YANG; Tong-hui MA

    2006-01-01

    The aquaporins (AQP) are a family of integral membrane proteins that selectively transport water and,in some cases,small neutral solutes such as glycerol and urea.Thirteen mammalian AQP have been molecularly identified and localized to various epithelial,endothelial and other tissues.Phenotype studies of transgenic mouse models of AQP knockout,mutation,and in some cases humans with AQP mutations have demonstrated essential roles for AQP in mammalian physiology and pathophysiology,including urinary concentrating function,exocrine glandular fluid secretion,brain edema formation,regulation of intracranial and intraocular pressure,skin hydration,fat metabolism,tumor angiogenesis and cell migration.These studies suggest that AQP may be potential drug targets for not only new diuretic reagents for various forms of pathological water retention,but also targets for novel therapy of brain edema,inflammatory disease,glaucoma,obesity,and cancer.However,potent AQP modulators for in vivo application remain to be discovered.

  4. Antiepileptic drugs: newer targets and new drugs

    Directory of Open Access Journals (Sweden)

    Vihang S. Chawan

    2016-06-01

    Full Text Available Epilepsy is a common neurological disorder affecting 0.5-1% of the population in India. Majority of patients respond to currently available antiepileptic drugs (AEDs, but a small percentage of patients have shown poor and inadequate response to AEDs in addition to various side effects and drug interactions while on therapy. Thus there is a need to develop more effective AEDs in drug resistant epilepsy which have a better safety profile with minimal adverse effects. The United States food and drug administration (USFDA has approved eslicarbazepine acetate, ezogabine, perampanel and brivaracetam which have shown a promising future as better AEDs and drugs like ganaxolone, intranasal diazepam, ICA- 105665, valnoctamide, VX-765, naluzotan are in the pipeline. [Int J Basic Clin Pharmacol 2016; 5(3.000: 587-592

  5. Limited Efficiency of Drug Delivery to Specific Intracellular Organelles Using Subcellularly "Targeted" Drug Delivery Systems.

    Science.gov (United States)

    Maity, Amit Ranjan; Stepensky, David

    2016-01-01

    Many drugs have been designed to act on intracellular targets and to affect intracellular processes inside target cells. For the desired effects to be exerted, these drugs should permeate target cells and reach specific intracellular organelles. This subcellular drug targeting approach has been proposed for enhancement of accumulation of these drugs in target organelles and improved efficiency. This approach is based on drug encapsulation in drug delivery systems (DDSs) and/or their decoration with specific targeting moieties that are intended to enhance the drug/DDS accumulation in the intracellular organelle of interest. During recent years, there has been a constant increase in interest in DDSs targeted to specific intracellular organelles, and many different approaches have been proposed for attaining efficient drug delivery to specific organelles of interest. However, it appears that in many studies insufficient efforts have been devoted to quantitative analysis of the major formulation parameters of the DDSs disposition (efficiency of DDS endocytosis and endosomal escape, intracellular trafficking, and efficiency of DDS delivery to the target organelle) and of the resulting pharmacological effects. Thus, in many cases, claims regarding efficient delivery of drug/DDS to a specific organelle and efficient subcellular targeting appear to be exaggerated. On the basis of the available experimental data, it appears that drugs/DDS decoration with specific targeting residues can affect their intracellular fate and result in preferential drug accumulation within an organelle of interest. However, it is not clear whether these approaches will be efficient in in vivo settings and be translated into preclinical and clinical applications. Studies that quantitatively assess the mechanisms, barriers, and efficiencies of subcellular drug delivery and of the associated toxic effects are required to determine the therapeutic potential of subcellular DDS targeting.

  6. Barrier or carrier? Pulmonary surfactant and drug delivery.

    Science.gov (United States)

    Hidalgo, Alberto; Cruz, Antonio; Pérez-Gil, Jesús

    2015-09-01

    To consider the lung as a target for drug delivery and to optimise strategies directed at the pulmonary route, it is essential to consider the role of pulmonary surfactant, a thin lipid-protein film lining the respiratory surface of mammalian lungs. Membrane-based surfactant multilayers are essential for reducing the surface tension at the respiratory air-liquid interface to minimise the work of breathing. Different components of surfactant are also responsible for facilitating the removal of potentially pathological entities such as microorganisms, allergens or environmental pollutants and particles. Upon inhalation, drugs or nanoparticles first contact the surfactant layer, and these interactions critically affect their lifetime and fate in the airways. This review summarises the current knowledge on the possible role and effects of the pulmonary surfactant system in drug delivery strategies. It also summarises the evidence that suggests that pulmonary surfactant is far from being an insuperable barrier and could be used as an efficient shuttle for delivering hydrophobic and hydrophilic compounds deep into the lung and the organism.

  7. Properties of protein drug target classes.

    Directory of Open Access Journals (Sweden)

    Simon C Bull

    Full Text Available Accurate identification of drug targets is a crucial part of any drug development program. We mined the human proteome to discover properties of proteins that may be important in determining their suitability for pharmaceutical modulation. Data was gathered concerning each protein's sequence, post-translational modifications, secondary structure, germline variants, expression profile and drug target status. The data was then analysed to determine features for which the target and non-target proteins had significantly different values. This analysis was repeated for subsets of the proteome consisting of all G-protein coupled receptors, ion channels, kinases and proteases, as well as proteins that are implicated in cancer. Machine learning was used to quantify the proteins in each dataset in terms of their potential to serve as a drug target. This was accomplished by first inducing a random forest that could distinguish between its targets and non-targets, and then using the random forest to quantify the drug target likeness of the non-targets. The properties that can best differentiate targets from non-targets were primarily those that are directly related to a protein's sequence (e.g. secondary structure. Germline variants, expression levels and interactions between proteins had minimal discriminative power. Overall, the best indicators of drug target likeness were found to be the proteins' hydrophobicities, in vivo half-lives, propensity for being membrane bound and the fraction of non-polar amino acids in their sequences. In terms of predicting potential targets, datasets of proteases, ion channels and cancer proteins were able to induce random forests that were highly capable of distinguishing between targets and non-targets. The non-target proteins predicted to be targets by these random forests comprise the set of the most suitable potential future drug targets, and should therefore be prioritised when building a drug development programme.

  8. PS-109 Barriers and facilitators to implementing drug changes caused by drug tenders and shortages

    DEFF Research Database (Denmark)

    Rishøj, Rikke Mie; Christrup, Lona Louring; Clemmensen, Marianne H

    2015-01-01

    Background Drug tenders and shortages result in drug changes. International studies found that drug changes can adversely affect patient safety and the working procedures of healthcare professionals.1,2 The challenges of drug changes in Danish public hospitals have not previously been studied...... for drug identification during drug shortages were proposed. Conclusion This study identified different barriers and facilitators for implementing drug changes. The barriers and facilitators included specific features related to drugs, health care technology as well as to financial and organisational...... aspects. Future studies should focus on removal of barriers and development and implementation of appropriate facilitators which may indeed improve patient safety and the working procedures of healthcare professionals during drug changes....

  9. Automated High Throughput Drug Target Crystallography

    Energy Technology Data Exchange (ETDEWEB)

    Rupp, B

    2005-02-18

    The molecular structures of drug target proteins and receptors form the basis for 'rational' or structure guided drug design. The majority of target structures are experimentally determined by protein X-ray crystallography, which as evolved into a highly automated, high throughput drug discovery and screening tool. Process automation has accelerated tasks from parallel protein expression, fully automated crystallization, and rapid data collection to highly efficient structure determination methods. A thoroughly designed automation technology platform supported by a powerful informatics infrastructure forms the basis for optimal workflow implementation and the data mining and analysis tools to generate new leads from experimental protein drug target structures.

  10. [The new era of epithelium-targeted drug development].

    Science.gov (United States)

    Shimizu, Yoshimi; Nagase, Shotaro; Yagi, Kiyohito; Kondoh, Masuo

    2014-01-01

    Epithelium plays pivotal roles in biological barrier separating the inside of body and the outside environment. Ninety percent of malignant tumors are derived from epithelium. Most pathological microorganisms invade into the body from mucosal epithelium. Thus, epithelium is potential targets for drug development. Claudins (CLs), a family of tetra-transmembrane protein consisting of over 20 members, are structural and functional components of tight junction-seals in epithelium. Modulation of CL-seals enhanced mucosal absorption of drugs. CLs are often over-expressed in malignant tumors. CL-4 expression is increased in the epithelial cells covering the mucosal immune tissues. Very recently, CLs are also expected to be targets for traumatic brain injury and regenerative therapy. In this review, we overview the past, the present and the future of CLs-targeted drug development.

  11. Receptor-Mediated Drug Delivery Systems Targeting to Glioma

    Directory of Open Access Journals (Sweden)

    Shanshan Wang

    2015-12-01

    Full Text Available Glioma has been considered to be the most frequent primary tumor within the central nervous system (CNS. The complexity of glioma, especially the existence of the blood-brain barrier (BBB, makes the survival and prognosis of glioma remain poor even after a standard treatment based on surgery, radiotherapy, and chemotherapy. This provides a rationale for the development of some novel therapeutic strategies. Among them, receptor-mediated drug delivery is a specific pattern taking advantage of differential expression of receptors between tumors and normal tissues. The strategy can actively transport drugs, such as small molecular drugs, gene medicines, and therapeutic proteins to glioma while minimizing adverse reactions. This review will summarize recent progress on receptor-mediated drug delivery systems targeting to glioma, and conclude the challenges and prospects of receptor-mediated glioma-targeted therapy for future applications.

  12. Drug resistance mechanisms and novel drug targets for tuberculosis therapy.

    Science.gov (United States)

    Islam, Md Mahmudul; Hameed, H M Adnan; Mugweru, Julius; Chhotaray, Chiranjibi; Wang, Changwei; Tan, Yaoju; Liu, Jianxiong; Li, Xinjie; Tan, Shouyong; Ojima, Iwao; Yew, Wing Wai; Nuermberger, Eric; Lamichhane, Gyanu; Zhang, Tianyu

    2017-01-20

    Drug-resistant tuberculosis (TB) poses a significant challenge to the successful treatment and control of TB worldwide. Resistance to anti-TB drugs has existed since the beginning of the chemotherapy era. New insights into the resistant mechanisms of anti-TB drugs have been provided. Better understanding of drug resistance mechanisms helps in the development of new tools for the rapid diagnosis of drug-resistant TB. There is also a pressing need in the development of new drugs with novel targets to improve the current treatment of TB and to prevent the emergence of drug resistance in Mycobacterium tuberculosis. This review summarizes the anti-TB drug resistance mechanisms, furnishes some possible novel drug targets in the development of new agents for TB therapy and discusses the usefulness using known targets to develop new anti-TB drugs. Whole genome sequencing is currently an advanced technology to uncover drug resistance mechanisms in M. tuberculosis. However, further research is required to unravel the significance of some newly discovered gene mutations in their contribution to drug resistance.

  13. Inner ear barriers to nanomedicine-augmented drug delivery and imaging

    Directory of Open Access Journals (Sweden)

    Jing Zou

    2016-12-01

    Full Text Available There are several challenges to inner ear drug delivery and imaging due to the existence of tight biological barriers to the target structure and the dense bone surrounding it. Advances in imaging and nanomedicine may provide knowledge for overcoming the existing limitations to both the diagnosis and treatment of inner ear diseases. Novel techniques have improved the efficacy of drug delivery and targeting to the inner ear, as well as the quality and accuracy of imaging this structure. In this review, we will describe the pathways and biological barriers of the inner ear regarding drug delivery, the beneficial applications and limitations of the imaging techniques available for inner ear research, the behavior of engineered nanomaterials in inner ear applications, and future perspectives for nanomedicine-based inner ear imaging.

  14. Discovering drug targets through the web.

    Science.gov (United States)

    Wishart, David S

    2007-03-01

    Traditionally, drug-target discovery is a "wet-bench" experimental process, depending on carefully designed genetic screens, biochemical tests and cellular assays to identify proteins and genes that are associated with a particular disease or condition. However, recent advances in DNA sequencing, transcript profiling, protein identification and protein quantification are leading to a flood of genomic and proteomic data that is, or potentially could be, linked to disease data. The quantity of data generated by these high throughput methods is forcing scientists to re-think the way they do traditional drug-target discovery. In particular it is leading them more and more towards identifying potential drug targets using computers. In fact, drug-target identification is now being done as much on the desk-top as on the bench-top. This review focuses on describing how drug-target discovery can be done in silico (i.e. via computer) using a variety of bioinformatic resources that are freely available on the web. Specifically, it highlights a number of web-accessible sequence databases, automated genome annotation tools, text mining tools; and integrated drug/sequence databases that can be used to identify drug targets for both endogenous (genetic and epigenetic) diseases as well as exogenous (infectious) diseases.

  15. Drug Repurposing: Far Beyond New Targets for Old Drugs

    DEFF Research Database (Denmark)

    Oprea, Tudor; Mestres, J.

    2012-01-01

    Repurposing drugs requires finding novel therapeutic indications compared to the ones for which they were already approved. This is an increasingly utilized strategy for finding novel medicines, one that capitalizes on previous investments while derisking clinical activities. This approach is of ...... relevance to the disease in question and the intellectual property landscape. These activities go far beyond the identification of new targets for old drugs.......Repurposing drugs requires finding novel therapeutic indications compared to the ones for which they were already approved. This is an increasingly utilized strategy for finding novel medicines, one that capitalizes on previous investments while derisking clinical activities. This approach...... is of interest primarily because we continue to face significant gaps in the drug–target interactions matrix and to accumulate safety and efficacy data during clinical studies. Collecting and making publicly available as much data as possible on the target profile of drugs offer opportunities for drug...

  16. Wzy-dependent bacterial capsules as potential drug targets.

    Science.gov (United States)

    Ericsson, Daniel J; Standish, Alistair; Kobe, Bostjan; Morona, Renato

    2012-10-01

    The bacterial capsule is a recognized virulence factor in pathogenic bacteria. It likely works as an antiphagocytic barrier by minimizing complement deposition on the bacterial surface. With the continual rise of bacterial pathogens resistant to multiple antibiotics, there is an increasing need for novel drugs. In the Wzy-dependent pathway, the biosynthesis of capsular polysaccharide (CPS) is regulated by a phosphoregulatory system, whose main components consist of bacterial-tyrosine kinases (BY-kinases) and their cognate phosphatases. The ability to regulate capsule biosynthesis has been shown to be vital for pathogenicity, because different stages of infection require a shift in capsule thickness, making the phosphoregulatory proteins suitable as drug targets. Here, we review the role of regulatory proteins focusing on Streptococcus pneumoniae, Staphylococcus aureus, and Escherichia coli and discuss their suitability as targets in structure-based drug design.

  17. Drug targeting using solid lipid nanoparticles.

    Science.gov (United States)

    Rostami, Elham; Kashanian, Soheila; Azandaryani, Abbas H; Faramarzi, Hossain; Dolatabadi, Jafar Ezzati Nazhad; Omidfar, Kobra

    2014-07-01

    The present review aims to show the features of solid lipid nanoparticles (SLNs) which are at the forefront of the rapidly developing field of nanotechnology with several potential applications in drug delivery and research. Because of some unique features of SLNs such as their unique size dependent properties it offers possibility to develop new therapeutics. A common denominator of all these SLN-based platforms is to deliver drugs into specific tissues or cells in a pathological setting with minimal adverse effects on bystander cells. SLNs are capable to incorporate drugs into nanocarriers which lead to a new prototype in drug delivery which maybe used for drug targeting. Hence solid lipid nanoparticles hold great promise for reaching the goal of controlled and site specific drug delivery and hence attracted wide attention of researchers. This review presents a broad treatment of targeted solid lipid nanoparticles discussing their types such as antibody SLN, magnetic SLN, pH sensitive SLN and cationic SLN.

  18. NIOSOMES- A NOVEL DRUG CARRIER FOR DRUG TARGETING

    Directory of Open Access Journals (Sweden)

    A.KRISHNA SAILAJA

    2016-02-01

    Full Text Available Niosomes are vesicular drug delivery systems made of cholesterol and non ionic surfactants. Various novel drug delivery systems available for targeting of drugs include liposomes, nanoparticles, and resealed erythrocytes. Because of the instability and higher cost liposomes are less preferred over niosomes. The application of vesicular systems in cosmetics and for therapeutic purpose may offer several advantages for niosomes. They improve the therapeutic performance of the drug molecules by delayed clearance from the circulation, protecting the drug from biological environment and restricting effects to target cells. Niosomes have great drug delivery potential for targeted delivery of anti-cancer, anti-infective agents. Drug delivery potential of niosome can enhance by using novel concepts like proniosomes and aspasome. Niosomes also serve better aid in diagnostic imaging and as a vaccine adjuvant. Thus these areas need further exploration and research so as to bring out commercially available niosomal preparation. This article mainly focuses on the significance, advantages over other drug delivery systems, manufacturing methods, characterization methods, current research in niosomal drug delivery and their limitations.

  19. Mathematical modelling of magnetically targeted drug delivery

    Energy Technology Data Exchange (ETDEWEB)

    Grief, Andrew D. [Theoretical Mechanics, School of Mathematical Sciences, University of Nottingham, University Park, Nottingham NG7 2RD (United Kingdom)]. E-mail: andrew.grief@nottingham.ac.uk; Richardson, Giles [Theoretical Mechanics, School of Mathematical Sciences, University of Nottingham, University Park, Nottingham NG7 2RD (United Kingdom)]. E-mail: giles.richardson@nottingham.ac.uk

    2005-05-15

    A mathematical model for targeted drug delivery using magnetic particles is developed. This includes a diffusive flux of particles arising from interactions between erythrocytes in the microcirculation. The model is used to track particles in a vessel network. Magnetic field design is discussed and we show that it is impossible to specifically target internal regions using an externally applied field.

  20. Novel targeted bladder drug-delivery systems: a review

    Directory of Open Access Journals (Sweden)

    Zacchè MM

    2015-11-01

    Full Text Available Martino Maria Zacchè, Sushma Srikrishna, Linda Cardozo Department of Urogynaecology, King's College Hospital, London, UK Abstract: The objective of pharmaceutics is the development of drugs with increased efficacy and reduced side effects. Prolonged exposure of the diseased tissue to the drug is of crucial importance. Drug-delivery systems (DDSs have been introduced to control rate, time, and place of release. Drugs can easily reach the bladder through a catheter, while systemically administered agents may undergo extensive metabolism. Continuous urine filling and subsequent washout hinder intravesical drug delivery (IDD. Moreover, the low permeability of the urothelium, also described as the bladder permeability barrier, poses a major challenge in the development of the IDD. DDSs increase bioavailability of drugs, therefore improving therapeutic effect and patient compliance. This review focuses on novel DDSs to treat bladder conditions such as overactive bladder, interstitial cystitis, bladder cancer, and recurrent urinary tract infections. The rationale and strategies for both systemic and local delivery methods are discussed, with emphasis on new formulations of well-known drugs (oxybutynin, nanocarriers, polymeric hydrogels, intravesical devices, encapsulated DDSs, and gene therapy. We give an overview of current and future prospects of DDSs for bladder disorders, including nanotechnology and gene therapy. Keywords: drug targeting, drug-delivery system, bladder disorders

  1. Atypical GTPases as drug targets.

    Science.gov (United States)

    Soundararajan, Meera; Eswaran, Jeyanthy

    2012-01-01

    The Ras GTPases are the founding members of large Ras superfamily, which constitutes more than 150 of these important class of enzymes. These GTPases function as GDP-GTP-regulated binary switches that control many fundamental cellular processes. There are a number of GTPases that have been identified recently, which do not confine to this prototype termed as "atypical GTPases" but have proved to play a remarkable role in vital cellular functions. In this review, we provide an overview of the crucial physiological functions mediated by RGK and Centaurin class of multi domain atypical GTPases. Moreover, the recently available atypical GTPase structures of the two families, regulation, physiological functions and their critical roles in various diseases will be discussed. In summary, this review will highlight the emerging atypical GTPase family which allows us to understand novel regulatory mechanisms and thus providing new avenues for drug discovery programs.

  2. Nanobiotechnology-based drug delivery in brain targeting.

    Science.gov (United States)

    Dinda, Subas C; Pattnaik, Gurudutta

    2013-01-01

    Blood brain barrier (BBB) found to act as rate limiting factor in drug delivery to brain in combating the central nervous system (CNS) disorders. Such limiting physiological factors include the reticuloendothelial system and protein opsonization, which present across BBB, play major role in reducing the passage of drug. Several approaches employed to improve the drug delivery across the BBB. Nanoparticles (NP) are the solid colloidal particle ranges from 1 to 1000 nm in size utilized as career for drug delivery. At present NPs are found to play a significant advantage over the other methods of available drug delivery systems to deliver the drug across the BBB. Nanoparticles may be because of its size and functionalization characteristics able to penetrate and facilitate the drug delivery through the barrier. There are number of mechanisms and strategies found to be involved in this process, which are based on the type of nanomaterials used and its combination with therapeutic agents, such materials include liposomes, polymeric nanoparticles and non-viral vectors of nano-sizes for CNS gene therapy, etc. Nanotechnology is expected to reduce the need for invasive procedures for delivery of therapeutics to the CNS. Some devices such as implanted catheters and reservoirs however will still be needed to overcome the problems in effective drug delivery to the CNS. Nanomaterials are found to improve the safety and efficacy level of drug delivery devices in brain targeting. Nanoegineered devices are found to be delivering the drugs at cellular levels through nono-fluidic channels. Different drug delivery systems such as liposomes, microspheres, nanoparticles, nonogels and nonobiocapsules have been used to improve the bioavailability of the drug in the brain, but microchips and biodegradable polymeric nanoparticulate careers are found to be more effective therapeutically in treating brain tumor. The physiological approaches also utilized to improve the transcytosis capacity

  3. Fluid mechanics aspects of magnetic drug targeting.

    Science.gov (United States)

    Odenbach, Stefan

    2015-10-01

    Experiments and numerical simulations using a flow phantom for magnetic drug targeting have been undertaken. The flow phantom is a half y-branched tube configuration where the main tube represents an artery from which a tumour-supplying artery, which is simulated by the side branch of the flow phantom, branches off. In the experiments a quantification of the amount of magnetic particles targeted towards the branch by a magnetic field applied via a permanent magnet is achieved by impedance measurement using sensor coils. Measuring the targeting efficiency, i.e. the relative amount of particles targeted to the side branch, for different field configurations one obtains targeting maps which combine the targeting efficiency with the magnetic force densities in characteristic points in the flow phantom. It could be shown that targeting efficiency depends strongly on the magnetic field configuration. A corresponding numerical model has been set up, which allows the simulation of targeting efficiency for variable field configuration. With this simulation good agreement of targeting efficiency with experimental data has been found. Thus, the basis has been laid for future calculations of optimal field configurations in clinical applications of magnetic drug targeting. Moreover, the numerical model allows the variation of additional parameters of the drug targeting process and thus an estimation of the influence, e.g. of the fluid properties on the targeting efficiency. Corresponding calculations have shown that the non-Newtonian behaviour of the fluid will significantly influence the targeting process, an aspect which has to be taken into account, especially recalling the fact that the viscosity of magnetic suspensions depends strongly on the magnetic field strength and the mechanical load.

  4. Glycemic targets in hospital and barriers to attaining them.

    Science.gov (United States)

    Miller, David B

    2014-04-01

    The importance of glycemic control in hospitalized patients has been a relatively recent revelation. There is somewhat contradictory evidence concerning the optimal glycemic target in critically ill patients. There is only indirect evidence in non-critically ill patients. This article reviews the evidence for glycemic targets in hospitalized patients. It also investigates which hospital-based treatments can act as barriers to attaining optimal blood glucose levels in hospital and system barriers to attaining those optimal levels. The systematic approach to and evaluation of in-hospital diabetes management has a short history. The first large clinical trial, the DIGAMI trial of peri-myocardial infarction insulin therapy, was published in 1995 (1). The first guideline discussion of in-hospital diabetes management occurred briefly in 2003, more fully in 2008 and 2013 (2-4) by the Canadian Diabetes Association; in 2005 and annually since then by the American Diabetes Association (5,6). Recently, there have been many more publications on the topic. A recent PubMed search, limited to the last 5 years, "hospital" and "diabetes" as a Medical Subject Headings (MeSH) major topic, revealed more than 5000 English-language clinical trials (PubMed.gov; accessed 6 Oct 2013). Still, relatively little is certain about appropriate glycemic targets in hospital. This has left us, in 2014, with consensus recommendations only for glycemic targets in non-critically ill patients from both the Canadian Diabetes Association Clinical Practice Guidelines (4) and the American Diabetes Association Standards of Medical Care in Diabetes (6). This article reviews recommended glycemic targets in various in-hospital populations and the barriers to obtaining them.

  5. P-glycoprotein targeted nanoscale drug carriers

    KAUST Repository

    Li, Wengang

    2013-02-01

    Multi-drug resistance (MDR) is a trend whereby tumor cells exposed to one cytotoxic agent develop cross-resistance to a range of structurally and functionally unrelated compounds. P -glycoprotein (P -gp) efflux pump is one of the mostly studied drug carrying processes that shuttle the drugs out of tumor cells. Thus, P -gp inhibitors have attracted a lot of attention as they can stop cancer drugs from being pumped out of target cells with the consumption of ATP. Using quantitive structure activity relationship (QSAR), we have successfully synthesized a series of novel P -gp inhibitors. The obtained dihydropyrroloquinoxalines series were fully characterized and then tested against bacterial and tumor assays with over-expressed P -gps. All compounds were bioactive especially compound 1c that had enhanced antibacterial activity. Furthermore, these compounds were utilized as targeting vectors to direct drug delivery vehicles such as silica nanoparticles (SNPs) to cancerous Hela cells with over expressed P -gps. Cell uptake studies showed a successful accumulation of these decorated SNPs in tumor cells compared to undecorated SNPs. The results obtained show that dihydropyrroloquinoxalines constitute a promising drug candidate for targeting cancers with MDR. Copyright © 2013 American Scientific Publishers All rights reserved.

  6. Targeting nanoparticles across the blood-brain barrier with monoclonal antibodies.

    Science.gov (United States)

    Loureiro, Joana A; Gomes, Bárbara; Coelho, Manuel A N; do Carmo Pereira, Maria; Rocha, Sandra

    2014-04-01

    Development of therapeutics for brain disorders is one of the more difficult challenges to be overcome by the scientific community due to the inability of most molecules to cross the blood-brain barrier (BBB). Antibody-conjugated nanoparticles are drug carriers that can be used to target encapsulated drugs to the brain endothelial cells and have proven to be very promising. They significantly improve the accumulation of the drug in pathological sites and decrease the undesirable side effect of drugs in healthy tissues. We review the systems that have demonstrated promising results in crossing the BBB through receptor-mediated endocytic mechanisms for the treatment of neurodegenerative disorders such as Alzheimer's and Parkinson's disease.

  7. Targeting molecular networks for drug research

    Directory of Open Access Journals (Sweden)

    José Pedro Pinto

    2014-06-01

    Full Text Available The study of molecular networks has recently moved into the limelight of biomedical research. While it has certainly provided us with plenty of new insights into cellular mechanisms, the challenge now is how to modify or even restructure these networks. This is especially true for human diseases, which can be regarded as manifestations of distorted states of molecular networks. Of the possible interventions for altering networks, the use of drugs is presently the most feasible. In this mini-review, we present and discuss some exemplary approaches of how analysis of molecular interaction networks can contribute to pharmacology (e.g., by identifying new drug targets or prediction of drug side effects, as well as listing pointers to relevant resources and software to guide future research. We also outline recent progress in the use of drugs for in vitro reprogramming of cells, which constitutes an example par excellence for altering molecular interaction networks with drugs.

  8. Polymeric nanoparticles assembled with microfluidics for drug delivery across the blood-brain barrier

    Science.gov (United States)

    Tavares, M. R.; de Menezes, L. R.; do Nascimento, D. F.; Souza, D. H. S.; Reynaud, F.; Marques, M. F. V.; Tavares, M. I. B.

    2016-07-01

    The blood-brain barrier (BBB) is a challenge in the treatment of some diseases, since it prevents many drugs from reaching therapeutic concentrations in the brain. In this context, there is a growing interest in nanoparticles for drug delivery, since they are able to cross this barrier and target the brain. The use of polymeric materials in the development of these nanoparticles has been extensively studied. It has already been demonstrated that these nanosystems have the ability to cross the BBB, which allows effective drug release into the brain. Biodegradable polymers provide a great advantage in the development of nanosystems, but modifications of the nanoparticles' surface is essential. The traditional batch methods lack precise control over the processes of nucleation and growth, resulting in poor control over final properties of the nanoparticles. Therefore, microfluidics could be used to achieve a better production environment for the fabrication of nano- structured drug delivery systems. This study provides a brief review of: the BBB, the polymeric nanoparticles with the ability to overcome the barrier, the properties of the most used polymeric matrices, and the nanostructured drug delivery systems assembled with microfluidics.

  9. Barriers to Alzheimer disease drug discovery and development in the biotechnology industry.

    Science.gov (United States)

    Altstiel, L D

    2002-01-01

    The major barrier to Alzheimer disease (AD) drug discovery and development in the biotechnology industry is scale. Most biotechnology companies do not have the personnel or expertise to carry a drug from the bench to the market. Much effort in the industry has been directed toward the elucidation of molecular mechanisms of AD and the identification of new targets. Advances in biotechnology have generated new insights into disease mechanisms, increased the number of lead compounds, and accelerated biologic screening. The majority of costs associated with drug development are in clinical testing and development activities, many of which are driven by regulatory issues. For most biotechnology companies, the costs of such trials and the infrastructure necessary to support them are prohibitive. Another significant barrier is the definition of therapeutic benefit for AD drugs; Food and Drug Administration (FDA) precedent has established that a drug must show superiority to placebo on a performance-based test of cognition and a measure of global clinical function. This restrictive definition is biased toward drugs that enhance performance on memory-based tests. Newer AD drugs are targeted toward slowing disease progression; however, there is currently no accepted definition of what constitutes efficacy in disease progression. Despite these obstacles, the biotechnology industry has much to offer AD drug discovery and development. Biotechnology firms have already developed essential technology for AD drug development and will continue to do so. Biotechnology companies can move more quickly; of course, the trick is to move quickly in the right direction. Speed may offset some of the problems associated with lack of scale. Additionally, biotechnology companies can afford to address markets that may be too restricted for larger pharmaceutical companies. This advantage will have increasing importance, as therapies are developed to address subtypes of AD.

  10. Combinatorial approaches for the identification of brain drug delivery targets.

    Science.gov (United States)

    Stutz, Charles C; Zhang, Xiaobin; Shusta, Eric V

    2014-01-01

    The blood-brain barrier (BBB) represents a large obstacle for the treatment of central nervous system diseases. Targeting endogenous nutrient transporters that transcytose the BBB is one promising approach to selectively and noninvasively deliver a drug payload to the brain. The main limitations of the currently employed transcytosing receptors are their ubiquitous expression in the peripheral vasculature and the inherent low levels of transcytosis mediated by such systems. In this review, approaches designed to increase the repertoire of transcytosing receptors which can be targeted for the purpose of drug delivery are discussed. In particular, combinatorial protein libraries can be screened on BBB cells in vitro or in vivo to isolate targeting peptides or antibodies that can trigger transcytosis. Once these targeting reagents are discovered, the cognate BBB transcytosis system can be identified using techniques such as expression cloning or immunoprecipitation coupled with mass spectrometry. Continued technological advances in BBB genomics and proteomics, membrane protein manipulation, and in vitro BBB technology promise to further advance the capability to identify and optimize peptides and antibodies capable of mediating drug transport across the BBB.

  11. Emerging migraine treatments and drug targets

    DEFF Research Database (Denmark)

    Olesen, Jes; Ashina, Messoud

    2011-01-01

    . Tonabersat, a cortical spreading depression inhibitor, has shown efficacy in the prophylaxis of migraine with aura. Several new drug targets such as nitric oxide synthase, the 5-HT(1D) receptor, the prostanoid receptors EP(2) and EP(4), and the pituitary adenylate cyclase receptor PAC1 await development...

  12. Drug-induced regulation of target expression

    DEFF Research Database (Denmark)

    Iskar, Murat; Campillos, Monica; Kuhn, Michael;

    2010-01-01

    further newly identified drug-induced differential regulation of Lanosterol 14-alpha demethylase, Endoplasmin, DNA topoisomerase 2-alpha and Calmodulin 1. The feedback regulation in these and other targets is likely to be relevant for the success or failure of the molecular intervention....

  13. Amphotericin B formulations and drug targeting.

    Science.gov (United States)

    Torrado, J J; Espada, R; Ballesteros, M P; Torrado-Santiago, S

    2008-07-01

    Amphotericin B is a low-soluble polyene antibiotic which is able to self-aggregate. The aggregation state can modify its activity and pharmacokinetical characteristics. In spite of its high toxicity it is still widely employed for the treatment of systemic fungal infections and parasitic disease and different formulations are marketed. Some of these formulations, such as liposomal formulations, can be considered as classical examples of drug targeting. The pharmacokinetics, toxicity and activity are clearly dependent on the type of amphotericin B formulation. New drug delivery systems such as liposomes, nanospheres and microspheres can result in higher concentrations of AMB in the liver and spleen, but lower concentrations in kidney and lungs, so decreasing its toxicity. Moreover, the administration of these drug delivery systems can enhance the drug accessibility to organs and tissues (e.g., bone marrow) otherwise inaccessible to the free drug. During the last few years, new AMB formulations (AmBisome, Abelcet, and Amphotec) with an improved efficacy/toxicity ratio have been marketed. This review compares the different formulations of amphotericin B in terms of pharmacokinetics, toxicity and activity and discusses the possible drug targeting effect of some of these new formulations.

  14. Cell-penetrating peptides for drug delivery across membrane barriers

    DEFF Research Database (Denmark)

    Foged, Camilla; Nielsen, Hanne Moerck

    2008-01-01

    During the last decade, cell-penetrating peptides have been investigated for their ability to overcome the plasma membrane barrier of mammalian cells for the intracellular or transcellular delivery of cargoes as diverse as low molecular weight drugs, imaging agents, oligonucleotides, peptides......-penetrating peptides as transmembrane drug delivery agents, according to the recent literature, and discusses critical issues and future challenges in relation to fully understanding the fundamental principles of the cell-penetrating peptide-mediated membrane translocation of cargoes and the exploitation......, proteins and colloidal carriers such as liposomes and polymeric nanoparticles. Their ability to cross biological membranes in a non-disruptive way without apparent toxicity is highly desired for increasing drug bioavailability. This review provides an overview of the application of cell...

  15. New targets for drug discovery against malaria.

    Directory of Open Access Journals (Sweden)

    Guido Santos

    Full Text Available A mathematical model which predicts the intraerythrocytic stages of Plasmodium falciparum infection was developed using data from malaria-infected mice. Variables selected accounted for levels of healthy red blood cells, merozoite (Plasmodium asexual phase infected red blood cells, gametocyte (Plasmodium sexual phase infected red blood cells and a phenomenological variable which accounts for the mean activity of the immune system of the host. The model built was able to reproduce the behavior of three different scenarios of malaria. It predicts the later dynamics of malaria-infected humans well after the first peak of parasitemia, the qualitative response of malaria-infected monkeys to vaccination and the changes observed in malaria-infected mice when they are treated with antimalarial drugs. The mathematical model was used to identify new targets to be focused on drug design. Optimization methodologies were applied to identify five targets for minimizing the parasite load; four of the targets thus identified have never before been taken into account in drug design. The potential targets include: 1 increasing the death rate of the gametocytes, 2 decreasing the invasion rate of the red blood cells by the merozoites, 3 increasing the transformation of merozoites into gametocytes, 4 decreasing the activation of the immune system by the gametocytes, and finally 5 a combination of the previous target with decreasing the recycling rate of the red blood cells. The first target is already used in current therapies, whereas the remainders are proposals for potential new targets. Furthermore, the combined target (the simultaneous decrease of the activation of IS by gRBC and the decrease of the influence of IS on the recycling of hRBC is interesting, since this combination does not affect the parasite directly. Thus, it is not expected to generate selective pressure on the parasites, which means that it would not produce resistance in Plasmodium.

  16. Complementary Approaches to Existing Target Based Drug Discovery for Identifying Novel Drug Targets

    Directory of Open Access Journals (Sweden)

    Suhas Vasaikar

    2016-11-01

    Full Text Available In the past decade, it was observed that the relationship between the emerging New Molecular Entities and the quantum of R&D investment has not been favorable. There might be numerous reasons but few studies stress the introduction of target based drug discovery approach as one of the factors. Although a number of drugs have been developed with an emphasis on a single protein target, yet identification of valid target is complex. The approach focuses on an in vitro single target, which overlooks the complexity of cell and makes process of validation drug targets uncertain. Thus, it is imperative to search for alternatives rather than looking at success stories of target-based drug discovery. It would be beneficial if the drugs were developed to target multiple components. New approaches like reverse engineering and translational research need to take into account both system and target-based approach. This review evaluates the strengths and limitations of known drug discovery approaches and proposes alternative approaches for increasing efficiency against treatment.

  17. Targeted proteins for diabetes drug design

    Science.gov (United States)

    Doan Trang Nguyen, Ngoc; Thi Le, Ly

    2012-03-01

    Type 2 diabetes mellitus is a common metabolism disorder characterized by high glucose in the bloodstream, especially in the case of insulin resistance and relative insulin deficiency. Nowadays, it is very common in middle-aged people and involves such dangerous symptoms as increasing risk of stroke, obesity and heart failure. In Vietnam, besides the common treatment of insulin injection, some herbal medication is used but no unified optimum remedy for the disease yet exists and there is no production of antidiabetic drugs in the domestic market yet. In the development of nanomedicine at the present time, drug design is considered as an innovative tool for researchers to study the mechanisms of diseases at the molecular level. The aim of this article is to review some common protein targets involved in type 2 diabetes, offering a new idea for designing new drug candidates to produce antidiabetic drugs against type 2 diabetes for Vietnamese people.

  18. Barriers to the Preclinical Development of Therapeutics that Target Aging Mechanisms

    Science.gov (United States)

    Burd, Christin E.; Gill, Matthew S.; Niedernhofer, Laura J.; Robbins, Paul D.; Austad, Steven N.; Barzilai, Nir

    2016-01-01

    Through the progress of basic science research, fundamental mechanisms that contribute to age-related decline are being described with increasing depth and detail. Although these efforts have identified new drug targets and compounds that extend life span in model organisms, clinical trials of therapeutics that target aging processes remain scarce. Progress in aging research is hindered by barriers associated with the translation of basic science discoveries into the clinic. This report summarizes discussions held at a 2014 Geroscience Network retreat focused on identifying hurdles that currently impede the preclinical development of drugs targeting fundamental aging processes. From these discussions, it was evident that aging researchers have varied perceptions of the ideal preclinical pipeline. To forge a clear and cohesive path forward, several areas of controversy must first be resolved and new tools developed. Here, we focus on five key issues in preclinical drug development (drug discovery, lead compound development, translational preclinical biomarkers, funding, and integration between researchers and clinicians), expanding upon discussions held at the Geroscience Retreat and suggesting areas for further research. By bringing these findings to the attention of the aging research community, we hope to lay the foundation for a concerted preclinical drug development pipeline. PMID:27535964

  19. Strategies to improve intracellular drug delivery by targeted liposomes

    NARCIS (Netherlands)

    Fretz, M.M.

    2007-01-01

    Biotechnological advances increased the number of novel macromolecular drugs and new drug targets. The latter are mostly found intracellular. Unfortunately, most of the new macromolecular drugs rely on drug delivery tools for their intracellular delivery because their unfavourable physicochemical pr

  20. Targeted blood-to-brain drug delivery --10 key development criteria.

    Science.gov (United States)

    Gaillard, Pieter J; Visser, Corine C; Appeldoorn, Chantal C M; Rip, Jaap

    2012-09-01

    Drug delivery to the brain remains challenging due to the presence of the blood-brain barrier. In this review, 10 key development criteria are presented that are important for successful drug development to treat CNS diseases by targeted drug delivery systems. Although several routes of delivery are being investigated, such as intranasal delivery, direct injections into the brain or CSF, and transient opening of the blood-brain barrier, the focus of this review is on physiological strategies aiming to target endogenous transport mechanisms. Examples from literature, focusing on targeted drug delivery systems that are being commercially developed, will be discussed to illustrate the 10 key development criteria. The first four criteria apply to the targeting of the blood-brain barrier: (1) a proven inherently safe receptor biology, (2) a safe and human applicable ligand, (3) receptor specific binding, and (4) applicable for acute and chronic indications. Next to an efficient and safe targeting strategy, as captured in key criteria 1 to 4, a favorable pharmacokinetic profile is also important (key criterion 5). With regard to the drug carriers, two criteria are important: (6) no modification of active ingredient and (7) able to carry various classes of molecules. The final three criteria apply to the development of a drug from lab to clinic: (8) low costs and straightforward manufacturing, (9) activity in all animal models, and (10) strong intellectual property (IP) protection. Adhering to these 10 key development criteria will allow for a successful brain drug development.

  1. Prediction of potential drug targets based on simple sequence properties

    Directory of Open Access Journals (Sweden)

    Lai Luhua

    2007-09-01

    Full Text Available Abstract Background During the past decades, research and development in drug discovery have attracted much attention and efforts. However, only 324 drug targets are known for clinical drugs up to now. Identifying potential drug targets is the first step in the process of modern drug discovery for developing novel therapeutic agents. Therefore, the identification and validation of new and effective drug targets are of great value for drug discovery in both academia and pharmaceutical industry. If a protein can be predicted in advance for its potential application as a drug target, the drug discovery process targeting this protein will be greatly speeded up. In the current study, based on the properties of known drug targets, we have developed a sequence-based drug target prediction method for fast identification of novel drug targets. Results Based on simple physicochemical properties extracted from protein sequences of known drug targets, several support vector machine models have been constructed in this study. The best model can distinguish currently known drug targets from non drug targets at an accuracy of 84%. Using this model, potential protein drug targets of human origin from Swiss-Prot were predicted, some of which have already attracted much attention as potential drug targets in pharmaceutical research. Conclusion We have developed a drug target prediction method based solely on protein sequence information without the knowledge of family/domain annotation, or the protein 3D structure. This method can be applied in novel drug target identification and validation, as well as genome scale drug target predictions.

  2. Drug Delivery Systems, CNS Protection, and the Blood Brain Barrier

    Directory of Open Access Journals (Sweden)

    Ravi Kant Upadhyay

    2014-01-01

    Full Text Available Present review highlights various drug delivery systems used for delivery of pharmaceutical agents mainly antibiotics, antineoplastic agents, neuropeptides, and other therapeutic substances through the endothelial capillaries (BBB for CNS therapeutics. In addition, the use of ultrasound in delivery of therapeutic agents/biomolecules such as proline rich peptides, prodrugs, radiopharmaceuticals, proteins, immunoglobulins, and chimeric peptides to the target sites in deep tissue locations inside tumor sites of brain has been explained. In addition, therapeutic applications of various types of nanoparticles such as chitosan based nanomers, dendrimers, carbon nanotubes, niosomes, beta cyclodextrin carriers, cholesterol mediated cationic solid lipid nanoparticles, colloidal drug carriers, liposomes, and micelles have been discussed with their recent advancements. Emphasis has been given on the need of physiological and therapeutic optimization of existing drug delivery methods and their carriers to deliver therapeutic amount of drug into the brain for treatment of various neurological diseases and disorders. Further, strong recommendations are being made to develop nanosized drug carriers/vehicles and noninvasive therapeutic alternatives of conventional methods for better therapeutics of CNS related diseases. Hence, there is an urgent need to design nontoxic biocompatible drugs and develop noninvasive delivery methods to check posttreatment clinical fatalities in neuropatients which occur due to existing highly toxic invasive drugs and treatment methods.

  3. Nanowired Drug Delivery Across the Blood-Brain Barrier in Central Nervous System Injury and Repair.

    Science.gov (United States)

    Sharma, Aruna; Menon, Preeti; Muresanu, Dafin F; Ozkizilcik, Asya; Tian, Z Ryan; Lafuente, José V; Sharma, Hari S

    2016-01-01

    The blood-brain barrier (BBB) is a physiological regulator of transport of essential items from blood to brain for the maintenance of homeostasis of the central nervous system (CNS) within narrow limits. The BBB is also responsible for export of harmful or metabolic products from brain to blood to keep the CNS fluid microenvironment healthy. However, noxious insults to the brain caused by trauma, ischemia or environmental/chemical toxins alter the BBB function to small as well as large molecules e.g., proteins. When proteins enter the CNS fluid microenvironment, development of brain edema occurs due to altered osmotic balance between blood and brain. On the other hand, almost all neurodegenerative diseases and traumatic insults to the CNS and subsequent BBB dysfunction lead to edema formation and cell injury. To treat these brain disorders suitable drug therapy reaching their brain targets is needed. However, due to edema formation or only a focal disruption of the BBB e.g., around brain tumors, many drugs are unable to reach their CNS targets in sufficient quantity. This results in poor therapeutic outcome. Thus, new technology such as nanodelivery is needed for drugs to reach their CNS targets and be effective. In this review, use of nanowires as a possible novel tool to enhance drug delivery into the CNS in various disease models is discussed based on our investigations. These data show that nanowired delivery of drugs may have superior neuroprotective ability to treat several CNS diseases effectively indicating their role in future therapeutic strategies.

  4. Crossing the Blood-Brain Barrier: Recent Advances in Drug Delivery to the Brain.

    Science.gov (United States)

    Patel, Mayur M; Patel, Bhoomika M

    2017-02-01

    CNS disorders are on the rise despite advancements in our understanding of their pathophysiological mechanisms. A major hurdle to the treatment of these disorders is the blood-brain barrier (BBB), which serves as an arduous janitor to protect the brain. Many drugs are being discovered for CNS disorders, which, however fail to enter the market because of their inability to cross the BBB. This is a pronounced challenge for the pharmaceutical fraternity. Hence, in addition to the discovery of novel entities and drug candidates, scientists are also developing new formulations of existing drugs for brain targeting. Several approaches have been investigated to allow therapeutics to cross the BBB. As the molecular structure of the BBB is better elucidated, several key approaches for brain targeting include physiological transport mechanisms such as adsorptive-mediated transcytosis, inhibition of active efflux pumps, receptor-mediated transport, cell-mediated endocytosis, and the use of peptide vectors. Drug-delivery approaches comprise delivery from microspheres, biodegradable wafers, and colloidal drug-carrier systems (e.g., liposomes, nanoparticles, nanogels, dendrimers, micelles, nanoemulsions, polymersomes, exosomes, and quantum dots). The current review discusses the latest advancements in these approaches, with a major focus on articles published in 2015 and 2016. In addition, we also cover the alternative delivery routes, such as intranasal and convection-enhanced diffusion methods, and disruption of the BBB for brain targeting.

  5. Malaria heat shock proteins: drug targets that chaperone other drug targets.

    Science.gov (United States)

    Pesce, E-R; Cockburn, I L; Goble, J L; Stephens, L L; Blatch, G L

    2010-06-01

    Ongoing research into the chaperone systems of malaria parasites, and particularly of Plasmodium falciparum, suggests that heat shock proteins (Hsps) could potentially be an excellent class of drug targets. The P. falciparum genome encodes a vast range and large number of chaperones, including 43 Hsp40, six Hsp70, and three Hsp90 proteins (PfHsp40s, PfHsp70s and PfHsp90s), which are involved in a number of fundamental cellular processes including protein folding and assembly, protein translocation, signal transduction and the cellular stress response. Despite the fact that Hsps are relatively conserved across different species, PfHsps do exhibit a considerable number of unique structural and functional features. One PfHsp90 is thought to be sufficiently different to human Hsp90 to allow for selective targeting. PfHsp70s could potentially be used as drug targets in two ways: either by the specific inhibition of Hsp70s by small molecule modulators, as well as disruption of the interactions between Hsp70s and co-chaperones such as the Hsp70/Hsp90 organising protein (Hop) and Hsp40s. Of the many PfHsp40s present on the parasite, there are certain unique or essential members which are considered to have good potential as drug targets. This review critically evaluates the potential of Hsps as malaria drug targets, as well as the use of chaperones as aids in the heterologous expression of other potential malarial drug targets.

  6. Neurological disorders and therapeutics targeted to surmount the blood–brain barrier

    Directory of Open Access Journals (Sweden)

    Kanwar JR

    2012-07-01

    Full Text Available Jagat R Kanwar, Bhasker Sriramoju, Rupinder K KanwarNanomedicine Laboratory of Immunology and Molecular Biomedical Research, Centre for Biotechnology and Interdisciplinary Biosciences, Institute for Frontier Materials (IFM, Deakin University, Waurn Ponds, Victoria, AustraliaAbstract: We are now in an aging population, so neurological disorders, particularly the neurodegenerative diseases, are becoming more prevalent in society. As per the epidemiological studies, Europe alone suffers 35% of the burden, indicating an alarming rate of disease progression. Further, treatment for these disorders is a challenging area due to the presence of the tightly regulated blood–brain barrier and its unique ability to protect the brain from xenobiotics. Conventional therapeutics, although effective, remain critically below levels of optimum therapeutic efficacy. Hence, methods to overcome the blood–brain barrier are currently a focus of research. Nanotechnological applications are gaining paramount importance in addressing this question, and yielding some promising results. This review addresses the pathophysiology of the more common neurological disorders and novel drug candidates, along with targeted nanoparticle applications for brain delivery.Keywords: blood–brain barrier, neurological diseases, brain delivery, targeted nanoparticles

  7. Focused ultrasound-mediated drug delivery through the blood-brain barrier.

    Science.gov (United States)

    Burgess, Alison; Shah, Kairavi; Hough, Olivia; Hynynen, Kullervo

    2015-05-01

    Despite recent advances in blood-brain barrier (BBB) research, it remains a significant hurdle for the pharmaceutical treatment of brain diseases. Focused ultrasound (FUS) is one method to transiently increase permeability of the BBB to promote drug delivery to specific brain regions. An introduction to the BBB and a brief overview of the methods, which can be used to circumvent the BBB to promote drug delivery, is provided. In particular, we discuss the advantages and limitations of FUS technology and the efficacy of FUS-mediated drug delivery in models of disease. MRI for targeting and evaluating FUS treatments, combined with administration of microbubbles, allows for transient, reproducible BBB opening. The integration of a real-time acoustic feedback controller has improved treatment safety. Successful clinical translation of FUS has the potential to transform the treatment of brain disease worldwide without requiring the development of new pharmaceutical agents.

  8. Emerging migraine treatments and drug targets

    DEFF Research Database (Denmark)

    Olesen, Jes; Ashina, Messoud

    2011-01-01

    Migraine has a 1-year prevalence of 10% and high socioeconomic costs. Despite recent drug developments, there is a huge unmet need for better pharmacotherapy. In this review we discuss promising anti-migraine strategies such as calcitonin gene-related peptide (CGRP) receptor antagonists and 5......-hydroxytrypamine (5-HT)(1F) receptor agonists, which are in late-stage development. Nitric oxide antagonists are also in development. New forms of administration of sumatriptan might improve efficacy and reduce side effects. Botulinum toxin A has recently been approved for the prophylaxis of chronic migraine....... Tonabersat, a cortical spreading depression inhibitor, has shown efficacy in the prophylaxis of migraine with aura. Several new drug targets such as nitric oxide synthase, the 5-HT(1D) receptor, the prostanoid receptors EP(2) and EP(4), and the pituitary adenylate cyclase receptor PAC1 await development...

  9. New drugs and treatment targets in psoriasis.

    Science.gov (United States)

    Kofoed, Kristian; Skov, Lone; Zachariae, Claus

    2015-02-01

    In recent years, the increased understanding of the pathophysiology of psoriasis has resulted in several new treatments. The success of ustekinumab proved the importance of the IL-23/T helper cell 17 axis in psoriatic diseases. Several new biologics targeting this axis will reach the clinic in the next years. Biologics are costly, require injections, and some patients experience tacaphylaxis, thus, the development of orally available, small-molecule inhibitors is desirable. Among small-molecules under investigation are A3 adenosine receptor agonists, Janus kinase inhibitors, and phosphodiesterase inhibitors. We review published clinical trials, and conference abstracts presented during the last years, concerned with new drugs under development for the treatment of psoriasis. In conclusion, our psoriasis armamentarium will be filled with several new effective therapeutic options the coming years. We need to be aware of the limitations of drug safety data when selecting new novel treatments. Monitoring and clinical registries are still important tools.

  10. Medicinal chemistry based approaches and nanotechnology-based systems to improve CNS drug targeting and delivery.

    Science.gov (United States)

    Vlieghe, Patrick; Khrestchatisky, Michel

    2013-05-01

    The central nervous system (CNS) is protected by various barriers, which regulate nervous tissue homeostasis and control the selective and specific uptake, efflux, and metabolism of endogenous and exogenous molecules. Among these barriers is the blood-brain barrier (BBB), a physical and physiological barrier that filters very efficiently and selectively the entry of compounds from the blood to the brain and protects nervous tissue from harmful substances and infectious agents present in the bloodstream. The BBB also prevents the entry of potential drugs. As a result, various drug targeting and delivery strategies are currently being developed to enhance the transport of drugs from the blood to the brain. Following a general introduction, we briefly overview in this review article the fundamental physiological properties of the BBB. Then, we describe current strategies to bypass the BBB (i.e., invasive methods, alternative approaches, and temporary opening) and to cross it (i.e., noninvasive approaches). This section is followed by a chapter addressing the chemical and technological solutions developed to cross the BBB. A special emphasis is given to prodrug-targeting approaches and targeted nanotechnology-based systems, two promising strategies for BBB targeting and delivery of drugs to the brain.

  11. NSAIDs: Old Drugs Reveal New Anticancer Targets

    Directory of Open Access Journals (Sweden)

    Gary A. Piazza

    2010-05-01

    Full Text Available There is compelling evidence that nonsteroidal anti-inflammatory drugs (NSAIDs and cyclooxygenase-2 selective inhibitors have antineoplastic activity, but toxicity from cyclooxygenase (COX inhibition and the suppression of physiologically important prostaglandins limits their use for cancer chemoprevention. Previous studies as reviewed here suggest that the mechanism for their anticancer properties does not require COX inhibition, but instead involves an off-target effect. In support of this possibility, recent molecular modeling studies have shown that the NSAID sulindac can be chemically modified to selectively design out its COX-1 and COX-2 inhibitory activity. Unexpectedly, certain derivatives that were synthesized based on in silico modeling displayed increased potency to inhibit tumor cell growth. Other experiments have shown that sulindac can inhibit phosphodiesterase to increase intracellular cyclic GMP levels and that this activity is closely associated with its ability to selectively induce apoptosis of tumor cells. Together, these studies suggest that COX-independent mechanisms can be targeted to develop safer and more efficacious drugs for cancer chemoprevention.

  12. Phage display:development of nanocarriers for targeted drug delivery to the brain

    Institute of Scientific and Technical Information of China (English)

    Babak Bakhshinejad; Marzieh Karimi; Mohammad Khalaj-Kondori

    2015-01-01

    The blood brain barrier represents a formidable obstacle for the transport of most systemati-cally administered neurodiagnostics and neurotherapeutics to the brain. Phage display is a high throughput screening strategy that can be used for the construction of nanomaterial peptide libraries. These libraries can be screened for ifnding brain targeting peptide ligands. Surface func-tionalization of a variety of nanocarriers with these brain homing peptides is a sophisticated way to develop nanobiotechnology-based drug delivery platforms that are able to cross the blood brain barrier. These efifcient drug delivery systems raise our hopes for the diagnosis and treatment of various brain disorders in the future.

  13. Optimizing drugs to reach treatment targets for children and adolescents living with HIV

    Directory of Open Access Journals (Sweden)

    Martina Penazzato

    2015-12-01

    Full Text Available Introduction: As the global community makes progress towards the 90-90-90 targets by 2020, a key challenge is ensuring that antiretroviral drugs for children and adolescents are suitable to the context of resource-limited settings. Drug optimization aims to support the expanded use of more simplified, less toxic drug regimens with high barriers to drug resistance that require minimal clinical monitoring while maintaining therapeutic efficacy. This manuscript summarizes the progress made and outlines further critical steps required to ensure that the right drugs are available to start children and adolescents on treatment and to keep them virologically suppressed. Discussion: Building upon previous work in drug optimization, several important steps were taken in 2014 to ensure alignment between WHO dosing recommendations and the requirements of regulatory bodies, to accelerate drug development, to reduce intellectual property barriers to generic production of combined formulations and rationalize drug selection in countries. The priority for the future is to improve access to antiretroviral therapy (ART at the two ends of the paediatric age spectrum – infants and adolescents – where the treatment gap is greatest, and optimize drug sequencing with better use of available medicines for second- and third-line ART. Future efforts in this area will require continuous collaboration and coordination, and the promotion of innovative approaches to accelerate access to new drugs and formulations. Conclusions: While significant progress has been made, additional efforts are needed to ensure that treatment targets are reached by 2020.

  14. New Drugs and Treatment Targets in Psoriasis

    DEFF Research Database (Denmark)

    Kofoed, Kristian; Skov, Lone; Zachariae, Claus

    2015-01-01

    In recent years, the increased understanding of the pathophysiology of psoriasis has resulted in several new treatments. The success of ustekinumab proved the importance of the IL-23/T helper cell 17 axis in psoriatic diseases. Several new biologics targeting this axis will reach the clinic...... in the next years. Biologics are costly, require injections, and some patients experience tacaphylaxis, thus, the development of orally available, small-molecule inhibitors is desirable. Among small-molecules under investigation are A3 adenosine receptor agonists, Janus kinase inhibitors......, and phosphodiesterase inhibitors. We review published clinical trials, and conference abstracts presented during the last years, concerned with new drugs under development for the treatment of psoriasis. In conclusion, our psoriasis armamentarium will be filled with several new effective therapeutic options the coming...

  15. The drug target genes show higher evolutionary conservation than non-target genes.

    Science.gov (United States)

    Lv, Wenhua; Xu, Yongdeng; Guo, Yiying; Yu, Ziqi; Feng, Guanglong; Liu, Panpan; Luan, Meiwei; Zhu, Hongjie; Liu, Guiyou; Zhang, Mingming; Lv, Hongchao; Duan, Lian; Shang, Zhenwei; Li, Jin; Jiang, Yongshuai; Zhang, Ruijie

    2016-01-26

    Although evidence indicates that drug target genes share some common evolutionary features, there have been few studies analyzing evolutionary features of drug targets from an overall level. Therefore, we conducted an analysis which aimed to investigate the evolutionary characteristics of drug target genes. We compared the evolutionary conservation between human drug target genes and non-target genes by combining both the evolutionary features and network topological properties in human protein-protein interaction network. The evolution rate, conservation score and the percentage of orthologous genes of 21 species were included in our study. Meanwhile, four topological features including the average shortest path length, betweenness centrality, clustering coefficient and degree were considered for comparison analysis. Then we got four results as following: compared with non-drug target genes, 1) drug target genes had lower evolutionary rates; 2) drug target genes had higher conservation scores; 3) drug target genes had higher percentages of orthologous genes and 4) drug target genes had a tighter network structure including higher degrees, betweenness centrality, clustering coefficients and lower average shortest path lengths. These results demonstrate that drug target genes are more evolutionarily conserved than non-drug target genes. We hope that our study will provide valuable information for other researchers who are interested in evolutionary conservation of drug targets.

  16. Dynamics of target-mediated drug disposition.

    Science.gov (United States)

    Peletier, Lambertus A; Gabrielsson, Johan

    2009-12-08

    We present a mathematical analysis of the basic model underlying target-mediated drug disposition (TMDD) in which a ligand is supplied through an initial bolus or through a constant rate infusion and forms a complex with a receptor (target), which is supplied and removed continuously. Ligand and complex may be eliminated according to first-order processes. We assume that the total receptor pool (free and bound) is constant in time and we give a geometrical description of the evolution of the concentrations of ligand, receptor and receptor-ligand complex which offers a transparent way to compare the full model with simpler models such as the quasi-steady-state (QSS) model, the quasi-equilibrium (QE) model and the empirical Michaelis-Menten (MM) model; we also give precise conditions on the parameters in the TMDD model for the validity of these reduced models. We relate characteristic properties of time courses to parameter regimes and, in particular, we identify and explain non-monotone dependence of the time-to-steady-state on the infusion rate. Finally, we discuss how the volume of the central compartment may be overestimated because of singular initial behaviour of the time course of the ligand concentration.

  17. Targeted and reversible blood-retinal barrier disruption via focused ultrasound and microbubbles.

    Directory of Open Access Journals (Sweden)

    Juyoung Park

    Full Text Available The blood-retinal barrier (BRB prevents most systemically-administered drugs from reaching the retina. This study investigated whether burst ultrasound applied with a circulating microbubble agent can disrupt the BRB, providing a noninvasive method for the targeted delivery of systemically administered drugs to the retina. To demonstrate the efficacy and reversibility of such a procedure, five overlapping targets around the optic nerve head were sonicated through the cornea and lens in 20 healthy male Sprague-Dawley rats using a 690 kHz focused ultrasound transducer. For BRB disruption, 10 ms bursts were applied at 1 Hz for 60 s with different peak rarefactional pressure amplitudes (0.81, 0.88 and 1.1 MPa. Each sonication was combined with an IV injection of a microbubble ultrasound contrast agent (Definity. To evaluate BRB disruption, an MRI contrast agent (Magnevist was injected IV immediately after the last sonication, and serial T1-weighted MR images were acquired up to 30 minutes. MRI contrast enhancement into the vitreous humor near targeted area was observed for all tested pressure amplitudes, with more signal enhancement evident at the highest pressure amplitude. At 0.81 MPa, BRB disruption was not detected 3 h post sonication, after an additional MRI contrast injection. A day after sonication, the eyes were processed for histology of the retina. At the two lower exposure levels (0.81 and 0.88 MPa, most of the sonicated regions were indistinguishable from the control eyes, although a few tiny clusters of extravasated erythrocytes (petechaie were observed. More severe retinal damage was observed at 1.1 MPa. These results demonstrate that focused ultrasound and microbubbles can offer a noninvasive and targeted means to transiently disrupt the BRB for ocular drug delivery.

  18. Drug target identification using side-effect similarity

    DEFF Research Database (Denmark)

    Campillos, Monica; Kuhn, Michael; Gavin, Anne-Claude;

    2008-01-01

    Targets for drugs have so far been predicted on the basis of molecular or cellular features, for example, by exploiting similarity in chemical structure or in activity across cell lines. We used phenotypic side-effect similarities to infer whether two drugs share a target. Applied to 746 marketed...... drugs, a network of 1018 side effect-driven drug-drug relations became apparent, 261 of which are formed by chemically dissimilar drugs from different therapeutic indications. We experimentally tested 20 of these unexpected drug-drug relations and validated 13 implied drug-target relations by in vitro...... binding assays, of which 11 reveal inhibition constants equal to less than 10 micromolar. Nine of these were tested and confirmed in cell assays, documenting the feasibility of using phenotypic information to infer molecular interactions and hinting at new uses of marketed drugs....

  19. Identifying drug-target proteins based on network features

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    Proteins rarely function in isolation inside and outside cells, but operate as part of a highly intercon- nected cellular network called the interaction network. Therefore, the analysis of the properties of drug-target proteins in the biological network is especially helpful for understanding the mechanism of drug action in terms of informatics. At present, no detailed characterization and description of the topological features of drug-target proteins have been available in the human protein-protein interac- tion network. In this work, by mapping the drug-targets in DrugBank onto the interaction network of human proteins, five topological indices of drug-targets were analyzed and compared with those of the whole protein interactome set and the non-drug-target set. The experimental results showed that drug-target proteins have higher connectivity and quicker communication with each other in the PPI network. Based on these features, all proteins in the interaction network were ranked. The results showed that, of the top 100 proteins, 48 are covered by DrugBank; of the remaining 52 proteins, 9 are drug-target proteins covered by the TTD, Matador and other databases, while others have been dem- onstrated to be drug-target proteins in the literature.

  20. Identifying drug-target proteins based on network features

    Institute of Scientific and Technical Information of China (English)

    ZHU MingZhu; GAO Lei; LI Xia; LIU ZhiCheng

    2009-01-01

    Proteins rarely function in isolation Inside and outside cells, but operate as part of a highly Intercon-nected cellular network called the interaction network. Therefore, the analysis of the properties of drug-target proteins in the biological network is especially helpful for understanding the mechanism of drug action In terms of informatice. At present, no detailed characterization and description of the topological features of drug-target proteins have been available in the human protein-protein interac-tion network. In this work, by mapping the drug-targets in DrugBank onto the interaction network of human proteins, five topological indices of drug-targets were analyzed and compared with those of the whole protein interactome set and the non-drug-target set. The experimental results showed that drug-target proteins have higher connectivity and quicker communication with each other in the PPI network. Based on these features, all proteins In the interaction network were ranked. The results showed that, of the top 100 proteins, 48 are covered by DrugBank; of the remaining 52 proteins, 9 are drug-target proteins covered by the TTD, Matador and other databases, while others have been dem-onstrated to be drug-target proteins in the literature.

  1. "Targeted disruption of the epithelial-barrier by Helicobacter pylori"

    OpenAIRE

    Wroblewski Lydia E; Peek Richard M

    2011-01-01

    Abstract Helicobacter pylori colonizes the human gastric epithelium and induces chronic gastritis, which can lead to gastric cancer. Through cell-cell contacts the gastric epithelium forms a barrier to protect underlying tissue from pathogenic bacteria; however, H. pylori have evolved numerous strategies to perturb the integrity of the gastric barrier. In this review, we summarize recent research into the mechanisms through which H. pylori disrupts intercellular junctions and disrupts the gas...

  2. Unilateral Opening of Rat Blood-Brain Barrier Assisted by Diagnostic Ultrasound Targeted Microbubbles Destruction

    Directory of Open Access Journals (Sweden)

    Yali Xu

    2016-01-01

    Full Text Available Objective. Blood-brain barrier (BBB is a key obstacle that prevents the medication from blood to the brain. Microbubble-enhanced cavitation by focused ultrasound can open the BBB and proves to be valuable in the brain drug delivery. The study aimed to explore the feasibility, efficacy, and safety of unilateral opening of BBB using diagnostic ultrasound targeted microbubbles destruction in rats. Methods. A transtemporal bone irradiation of diagnostic ultrasound and intravenous injection of lipid-coated microbubbles were performed at unilateral hemisphere. Pathological changes were monitored. Evans Blue extravasation grades, extraction from brain tissue, and fluorescence optical density were quantified. Lanthanum nitrate was traced by transmission electron microscopy. Results. After diagnostic ultrasound mediated microbubbles destruction, Evans Blue extravasation and fluorescence integrated optical density were significantly higher in the irradiated hemisphere than the contralateral side (all p<0.01. Erythrocytes extravasations were demonstrated in the ultrasound-exposed hemisphere (4±1, grade 2 while being invisible in the control side. Lanthanum nitrate tracers leaked through interendothelial cleft and spread to the nerve fiber existed in the irradiation side. Conclusions. Transtemporal bone irradiation under DUS mediated microbubble destruction provides us with a more accessible, safer, and higher selective BBB opening approach in rats, which is advantageous in brain targeted drugs delivery.

  3. Deep-Learning-Based Drug-Target Interaction Prediction.

    Science.gov (United States)

    Wen, Ming; Zhang, Zhimin; Niu, Shaoyu; Sha, Haozhi; Yang, Ruihan; Yun, Yonghuan; Lu, Hongmei

    2017-03-13

    Identifying interactions between known drugs and targets is a major challenge in drug repositioning. In silico prediction of drug-target interaction (DTI) can speed up the expensive and time-consuming experimental work by providing the most potent DTIs. In silico prediction of DTI can also provide insights about the potential drug-drug interaction and promote the exploration of drug side effects. Traditionally, the performance of DTI prediction depends heavily on the descriptors used to represent the drugs and the target proteins. In this paper, to accurately predict new DTIs between approved drugs and targets without separating the targets into different classes, we developed a deep-learning-based algorithmic framework named DeepDTIs. It first abstracts representations from raw input descriptors using unsupervised pretraining and then applies known label pairs of interaction to build a classification model. Compared with other methods, it is found that DeepDTIs reaches or outperforms other state-of-the-art methods. The DeepDTIs can be further used to predict whether a new drug targets to some existing targets or whether a new target interacts with some existing drugs.

  4. Anti-malarial Drug Design by Targeting Apicoplasts: New Perspectives

    Directory of Open Access Journals (Sweden)

    Avinaba Mukherjee

    2016-03-01

    Full Text Available Objectives: Malaria has been a major global health problem in recent times with increasing mortality. Current treatment methods include parasiticidal drugs and vaccinations. However, resistance among malarial parasites to the existing drugs has emerged as a significant area of concern in anti-malarial drug design. Researchers are now desperately looking for new targets to develop anti-malarials drug which is more target specific. Malarial parasites harbor a plastid-like organelle known as the ‘apicoplast’, which is thought to provide an exciting new outlook for the development of drugs to be used against the parasite. This review elaborates on the current state of development of novel compounds targeted againstemerging malaria parasites. Methods: The apicoplast, originates by an endosymbiotic process, contains a range of metabolic pathways and housekeeping processes that differ from the host body and thereby presents ideal strategies for anti-malarial drug therapy. Drugs are designed by targeting the unique mechanism of the apicoplasts genetic machinery. Several anabolic and catabolic processes, like fatty acid, isopenetyl diphosphate and heme synthess in this organelle, have also been targeted by drugs. Results: Apicoplasts offer exciting opportunities for the development of malarial treatment specific drugs have been found to act by disrupting this organelle’s function, which wouldimpede the survival of the parasite. Conclusion: Recent advanced drugs, their modes of action, and their advantages in the treatment of malaria by using apicoplasts as a target are discussed in this review which thought to be very useful in desigining anti-malarial drugs. Targetting the genetic machinery of apicoplast shows a great advantange regarding anti-malarial drug design. Critical knowledge of these new drugs would give a healthier understanding for deciphering the mechanism of action of anti-malarial drugs when targeting apicoplasts to overcome drug

  5. Target based drug design - a reality in virtual sphere.

    Science.gov (United States)

    Verma, Saroj; Prabhakar, Yenamandra S

    2015-01-01

    The target based drug design approaches are a series of computational procedures, including visualization tools, to support the decision systems of drug design/discovery process. In the essence of biological targets shaping the potential lead/drug molecules, this review presents a comprehensive position of different components of target based drug design which include target identification, protein modeling, molecular dynamics simulations, binding/catalytic sites identification, docking, virtual screening, fragment based strategies, substructure treatment of targets in tackling drug resistance, in silico ADMET, structural vaccinology, etc along with the key issues involved therein and some well investigated case studies. The concepts and working of these procedures are critically discussed to arouse interest and to advance the drug research.

  6. Assessing drug target association using semantic linked data.

    Directory of Open Access Journals (Sweden)

    Bin Chen

    Full Text Available The rapidly increasing amount of public data in chemistry and biology provides new opportunities for large-scale data mining for drug discovery. Systematic integration of these heterogeneous sets and provision of algorithms to data mine the integrated sets would permit investigation of complex mechanisms of action of drugs. In this work we integrated and annotated data from public datasets relating to drugs, chemical compounds, protein targets, diseases, side effects and pathways, building a semantic linked network consisting of over 290,000 nodes and 720,000 edges. We developed a statistical model to assess the association of drug target pairs based on their relation with other linked objects. Validation experiments demonstrate the model can correctly identify known direct drug target pairs with high precision. Indirect drug target pairs (for example drugs which change gene expression level are also identified but not as strongly as direct pairs. We further calculated the association scores for 157 drugs from 10 disease areas against 1683 human targets, and measured their similarity using a [Formula: see text] score matrix. The similarity network indicates that drugs from the same disease area tend to cluster together in ways that are not captured by structural similarity, with several potential new drug pairings being identified. This work thus provides a novel, validated alternative to existing drug target prediction algorithms. The web service is freely available at: http://chem2bio2rdf.org/slap.

  7. Assessing drug target association using semantic linked data.

    Science.gov (United States)

    Chen, Bin; Ding, Ying; Wild, David J

    2012-01-01

    The rapidly increasing amount of public data in chemistry and biology provides new opportunities for large-scale data mining for drug discovery. Systematic integration of these heterogeneous sets and provision of algorithms to data mine the integrated sets would permit investigation of complex mechanisms of action of drugs. In this work we integrated and annotated data from public datasets relating to drugs, chemical compounds, protein targets, diseases, side effects and pathways, building a semantic linked network consisting of over 290,000 nodes and 720,000 edges. We developed a statistical model to assess the association of drug target pairs based on their relation with other linked objects. Validation experiments demonstrate the model can correctly identify known direct drug target pairs with high precision. Indirect drug target pairs (for example drugs which change gene expression level) are also identified but not as strongly as direct pairs. We further calculated the association scores for 157 drugs from 10 disease areas against 1683 human targets, and measured their similarity using a [Formula: see text] score matrix. The similarity network indicates that drugs from the same disease area tend to cluster together in ways that are not captured by structural similarity, with several potential new drug pairings being identified. This work thus provides a novel, validated alternative to existing drug target prediction algorithms. The web service is freely available at: http://chem2bio2rdf.org/slap.

  8. IGF-1 receptor targeted nanoparticles for image-guided therapy of stroma-rich and drug resistant human cancer

    Science.gov (United States)

    Zhou, Hongyu; Qian, Weiping; Uckun, Fatih M.; Zhou, Zhiyang; Wang, Liya; Wang, Andrew; Mao, Hui; Yang, Lily

    2016-05-01

    Low drug delivery efficiency and drug resistance from highly heterogeneous cancer cells and tumor microenvironment represent major challenges in clinical oncology. Growth factor receptor, IGF-1R, is overexpressed in both human tumor cells and tumor associated stromal cells. The level of IGF-1R expression is further up-regulated in drug resistant tumor cells. We have developed IGF-1R targeted magnetic iron oxide nanoparticles (IONPs) carrying multiple anticancer drugs into human tumors. This IGF-1R targeted theranostic nanoparticle delivery system has an iron core for non-invasive MR imaging, amphiphilic polymer coating to ensure the biocompatibility as well as for drug loading and conjugation of recombinant human IGF-1 as targeting molecules. Chemotherapy drugs, Doxorubicin (Dox), was encapsulated into the polymer coating and/or conjugated to the IONP surface by coupling with the carboxyl groups. The ability of IGF1R targeted theranostic nanoparticles to penetrate tumor stromal barrier and enhance tumor cell killing has been demonstrated in human pancreatic cancer patient tissue derived xenograft (PDX) models. Repeated systemic administrations of those IGF-1R targeted theranostic IONP carrying Dox led to breaking the tumor stromal barrier and improved therapeutic effect. Near infrared (NIR) optical and MR imaging enabled noninvasive monitoring of nanoparticle-drug delivery and therapeutic responses. Our results demonstrated that IGF-1R targeted nanoparticles carrying multiple drugs are promising combination therapy approaches for image-guided therapy of stroma-rich and drug resistant human cancer, such as pancreatic cancer.

  9. Identification of Multiple Cryptococcal Fungicidal Drug Targets by Combined Gene Dosing and Drug Affinity Responsive Target Stability Screening

    Directory of Open Access Journals (Sweden)

    Yoon-Dong Park

    2016-08-01

    Full Text Available Cryptococcus neoformans is a pathogenic fungus that is responsible for up to half a million cases of meningitis globally, especially in immunocompromised individuals. Common fungistatic drugs, such as fluconazole, are less toxic for patients but have low efficacy for initial therapy of the disease. Effective therapy against the disease is provided by the fungicidal drug amphotericin B; however, due to its high toxicity and the difficulty in administering its intravenous formulation, it is imperative to find new therapies targeting the fungus. The antiparasitic drug bithionol has been recently identified as having potent fungicidal activity. In this study, we used a combined gene dosing and drug affinity responsive target stability (GD-DARTS screen as well as protein modeling to identify a common drug binding site of bithionol within multiple NAD-dependent dehydrogenase drug targets. This combination genetic and proteomic method thus provides a powerful method for identifying novel fungicidal drug targets for further development.

  10. Hydrodynamic modeling of ferrofluid flow in magnetic targeting drug delivery

    Institute of Scientific and Technical Information of China (English)

    LIU Han-dan; XU Wei; WANG Shi-gang; KE Zun-ji

    2008-01-01

    Among the proposed techniques for delivering drugs to specific locations within human body, magnetic drug targeting prevails due to its non-invasive character and its high targeting efficiency. Magnetic targeting drug delivery is a method of carrying drug-loaded magnetic nanoparticles to a target tissue target under the applied magnetic field. This method increases the drug concentration in the target while reducing the adverse side-effects. Although there have been some theoretical analyses for magnetic drug targeting, very few researchers have addressed the hydrodynamic models of magnetic fluids in the blood vessel. A mathematical model is presented to describe the hydrodynamics of ferrofluids as drug carriers flowing in a blood vessel under the applied magnetic field. In this model, magnetic force and asymmetrical force are added, and an angular momentum equation of magnetic nanoparticles in the applied magnetic field is modeled. Engineering approximations are achieved by retaining the physically most significant items in the model due to the mathematical complexity of the motion equations. Numerical simulations are performed to obtain better insight into the theoretical model with computational fluid dynamics. Simulation results demonstrate the important parameters leading to adequate drug delivery to the target site depending on the magnetic field intensity, which coincident with those of animal experiments. Results of the analysis provide important information and suggest strategies for improving delivery in clinical application.

  11. Computational and Pharmacological Target of Neurovascular Unit for Drug Design and Delivery.

    Science.gov (United States)

    Islam, Md Mirazul; Mohamed, Zahurin

    2015-01-01

    The blood-brain barrier (BBB) is a dynamic and highly selective permeable interface between central nervous system (CNS) and periphery that regulates the brain homeostasis. Increasing evidences of neurological disorders and restricted drug delivery process in brain make BBB as special target for further study. At present, neurovascular unit (NVU) is a great interest and highlighted topic of pharmaceutical companies for CNS drug design and delivery approaches. Some recent advancement of pharmacology and computational biology makes it convenient to develop drugs within limited time and affordable cost. In this review, we briefly introduce current understanding of the NVU, including molecular and cellular composition, physiology, and regulatory function. We also discuss the recent technology and interaction of pharmacogenomics and bioinformatics for drug design and step towards personalized medicine. Additionally, we develop gene network due to understand NVU associated transporter proteins interactions that might be effective for understanding aetiology of neurological disorders and new target base protective therapies development and delivery.

  12. Computational and Pharmacological Target of Neurovascular Unit for Drug Design and Delivery

    Directory of Open Access Journals (Sweden)

    Md. Mirazul Islam

    2015-01-01

    Full Text Available The blood-brain barrier (BBB is a dynamic and highly selective permeable interface between central nervous system (CNS and periphery that regulates the brain homeostasis. Increasing evidences of neurological disorders and restricted drug delivery process in brain make BBB as special target for further study. At present, neurovascular unit (NVU is a great interest and highlighted topic of pharmaceutical companies for CNS drug design and delivery approaches. Some recent advancement of pharmacology and computational biology makes it convenient to develop drugs within limited time and affordable cost. In this review, we briefly introduce current understanding of the NVU, including molecular and cellular composition, physiology, and regulatory function. We also discuss the recent technology and interaction of pharmacogenomics and bioinformatics for drug design and step towards personalized medicine. Additionally, we develop gene network due to understand NVU associated transporter proteins interactions that might be effective for understanding aetiology of neurological disorders and new target base protective therapies development and delivery.

  13. Nanoparticle-mediated brain drug delivery: Overcoming blood-brain barrier to treat neurodegenerative diseases.

    Science.gov (United States)

    Saraiva, Cláudia; Praça, Catarina; Ferreira, Raquel; Santos, Tiago; Ferreira, Lino; Bernardino, Liliana

    2016-08-10

    The blood-brain barrier (BBB) is a vital boundary between neural tissue and circulating blood. The BBB's unique and protective features control brain homeostasis as well as ion and molecule movement. Failure in maintaining any of these components results in the breakdown of this specialized multicellular structure and consequently promotes neuroinflammation and neurodegeneration. In several high incidence pathologies such as stroke, Alzheimer's (AD) and Parkinson's disease (PD) the BBB is impaired. However, even a damaged and more permeable BBB can pose serious challenges to drug delivery into the brain. The use of nanoparticle (NP) formulations able to encapsulate molecules with therapeutic value, while targeting specific transport processes in the brain vasculature, may enhance drug transport through the BBB in neurodegenerative/ischemic disorders and target relevant regions in the brain for regenerative processes. In this review, we will discuss BBB composition and characteristics and how these features are altered in pathology, namely in stroke, AD and PD. Additionally, factors influencing an efficient intravenous delivery of polymeric and inorganic NPs into the brain as well as NP-related delivery systems with the most promising functional outcomes will also be discussed.

  14. Target-based drug discovery for human African trypanosomiasis: selection of molecular target and chemical matter.

    Science.gov (United States)

    Gilbert, Ian H

    2014-01-01

    Target-based approaches for human African trypanosomiasis (HAT) and related parasites can be a valuable route for drug discovery for these diseases. However, care needs to be taken in selection of both the actual drug target and the chemical matter that is developed. In this article, potential criteria to aid target selection are described. Then the physiochemical properties of typical oral drugs are discussed and compared to those of known anti-parasitics.

  15. Targeted drug-carrying bacteriophages as antibacterial nanomedicines.

    Science.gov (United States)

    Yacoby, Iftach; Bar, Hagit; Benhar, Itai

    2007-06-01

    While the resistance of bacteria to traditional antibiotics is a major public health concern, the use of extremely potent antibacterial agents is limited by their lack of selectivity. As in cancer therapy, antibacterial targeted therapy could provide an opportunity to reintroduce toxic substances to the antibacterial arsenal. A desirable targeted antibacterial agent should combine binding specificity, a large drug payload per binding event, and a programmed drug release mechanism. Recently, we presented a novel application of filamentous bacteriophages as targeted drug carriers that could partially inhibit the growth of Staphylococcus aureus bacteria. This partial success was due to limitations of drug-loading capacity that resulted from the hydrophobicity of the drug. Here we present a novel drug conjugation chemistry which is based on connecting hydrophobic drugs to the phage via aminoglycoside antibiotics that serve as solubility-enhancing branched linkers. This new formulation allowed a significantly larger drug-carrying capacity of the phages, resulting in a drastic improvement in their performance as targeted drug-carrying nanoparticles. As an example for a potential systemic use for potent agents that are limited for topical use, we present antibody-targeted phage nanoparticles that carry a large payload of the hemolytic antibiotic chloramphenicol connected through the aminoglycoside neomycin. We demonstrate complete growth inhibition toward the pathogens Staphylococcus aureus, Streptococcus pyogenes, and Escherichia coli with an improvement in potency by a factor of approximately 20,000 compared to the free drug.

  16. Magnetic polymer nanospheres for anticancer drug targeting

    Energy Technology Data Exchange (ETDEWEB)

    JurIkova, A; Csach, K; Koneracka, M; Zavisova, V; Tomasovicova, N; Lancz, G; Kopcansky, P; Timko, M; Miskuf, J [Institute of Experimental Physics, Slovak Academy of Sciences, 040 01 Kosice (Slovakia); Muckova, M, E-mail: akasard@saske.s [Hameln rds a.s., 900 01 Modra (Slovakia)

    2010-01-01

    Poly(D,L-lactide-co-glycolide) polymer (PLGA) nanospheres loaded with biocom-patible magnetic fluid as a magnetic carrier and anticancer drug Taxol were prepared by the modified nanoprecipitation method with size of 200-250 nm in diameter. The PLGA polymer was utilized as a capsulation material due to its biodegradability and biocompatibility. Taxol as an important anticancer drug was chosen for its significant role against a wide range of tumours. Thermal properties of the drug-polymer system were characterized using thermal analysis methods. It was determined the solubility of Taxol in PLGA nanospheres. Magnetic properties investigated using SQUID magnetometry showed superparamagnetism of the prepared magnetic polymer nanospheres.

  17. Drug efflux pump deficiency and drug target resistance masking in growing bacteria

    Science.gov (United States)

    Fange, David; Nilsson, Karin; Tenson, Tanel; Ehrenberg, Måns

    2009-01-01

    Recent experiments have shown that drug efflux pump deficiency not only increases the susceptibility of pathogens to antibiotics, but also seems to “mask” the effects of mutations, that decrease the affinities of drugs to their intracellular targets, on the growth rates of drug-exposed bacteria. That is, in the presence of drugs, the growth rates of drug-exposed WT and target mutated strains are the same in a drug efflux pump deficient background, but the mutants grow faster than WT in a drug efflux pump proficient background. Here, we explain the mechanism of target resistance masking and show that it occurs in response to drug efflux pump inhibition among pathogens with high-affinity drug binding targets, low cell-membrane drug-permeability and insignificant intracellular drug degradation. We demonstrate that target resistance masking is fundamentally linked to growth-bistability, i.e., the existence of 2 different steady state growth rates for one and the same drug concentration in the growth medium. We speculate that target resistance masking provides a hitherto unknown mechanism for slowing down the evolution of target resistance among pathogens. PMID:19416855

  18. Nanoemulsion-based intranasal drug delivery system of saquinavir mesylate for brain targeting.

    Science.gov (United States)

    Mahajan, Hitendra S; Mahajan, Milind S; Nerkar, Pankaj P; Agrawal, Anshuman

    2014-03-01

    The central nervous system (CNS) is an immunological privileged sanctuary site-providing reservoir for HIV-1 virus. Current anti-HIV drugs, although effective in reducing plasma viral levels, cannot eradicate the virus completely from the body. The low permeability of anti-HIV drugs across the blood-brain barrier (BBB) leads to insufficient delivery. Therefore, developing a novel approaches enhancing the CNS delivery of anti-HIV drugs are required for the treatment of neuro-AIDS. The aim of this study was to develop intranasal nanoemulsion (NE) for enhanced bioavailability and CNS targeting of saquinavir mesylate (SQVM). SQVM is a protease inhibitor which is a poorly soluble drug widely used as antiretroviral drug, with oral bioavailability is about 4%. The spontaneous emulsification method was used to prepare drug-loaded o/w nanoemulsion, which was characterized by droplet size, zeta potential, pH, drug content. Moreover, ex-vivo permeation studies were performed using sheep nasal mucosa. The optimized NE showed a significant increase in drug permeation rate compared to the plain drug suspension (PDS). Cilia toxicity study on sheep nasal mucosa showed no significant adverse effect of SQVM-loaded NE. Results of in vivo biodistribution studies show higher drug concentration in brain after intranasal administration of NE than intravenous delivered PDS. The higher percentage of drug targeting efficiency (% DTE) and nose-to-brain drug direct transport percentage (% DTP) for optimized NE indicated effective CNS targeting of SQVM via intranasal route. Gamma scintigraphy imaging of the rat brain conclusively demonstrated transport of drug in the CNS at larger extent after intranasal administration as NE.

  19. Evaluation of Giardia lamblia thioredoxin reductase as drug activating enzyme and as drug target

    Directory of Open Access Journals (Sweden)

    David Leitsch

    2016-12-01

    Our results constitute first direct evidence for the notion that TrxR is an activator of metronidazole and furazolidone but rather question that it is a relevant drug target of presently used antigiardial drugs.

  20. Hemozoin Formation as a Target for Antimalarial Drug Design

    Science.gov (United States)

    2005-02-01

    AD Award Number: DAMD17-03-1-0030 TITLE: Hemozoin Formation as a Target for Antimalarial Drug Design PRINCIPAL INVESTIGATOR: Michael K. Riscoe, Ph.D...Formation as a Target for Antimalarial Drug Design DAMD17-03-1-0030 6. A UTHOR(S) Michael K. Riscoe, Ph.D. 7. PERFORMING ORGANIZA TION NAME(S) AND ADDRESS...Report: by Principal Investigator - Michael K. Riscoe, Ph.D. DAMD1 7-03-1-0030: "Hemozoin Formation as a Target for Antimalarial Drug Design " INTRODUCTION

  1. Chemical proteomics: terra incognita for novel drug target profiling

    Institute of Scientific and Technical Information of China (English)

    Fuqiang Huang; Boya Zhang; Shengtao Zhou; Xia Zhao; Ce Bian; Yuquan Wei

    2012-01-01

    The growing demand for new therapeutic strategies in the medical and pharmaceutic fields has resulted in a pressing need for novel druggable targets.Paradoxically,however,the targets of certain drugs that are already widely used in clinical practice have largely not been annotated.Because the pharmacologic effects of a drug can only be appreciated when its interactions with cellular components are clearly delineated,an integrated deconvolution of drug-target interactions for each drug is necessary.The emerging field of chemical proteomics represents a powerful mass spectrometry (MS)-based affinity chromatography approach for identifying proteome-wide small molecule-protein interactions and mapping these interactions to signaling and metabolic pathways.This technique could comprehensively characterize drug targets,profile the toxicity of known drugs,and identify possible off-target activities.With the use of this technique,candidate drug molecules could be optimized,and predictable side effects might consequently be avoided.Herein,we provide a holistic overview of the major chemical proteomic approaches and highlight recent advances in this area as well as its potential applications in drug discovery.

  2. Chemical signatures and new drug targets for gametocytocidal drug development

    Science.gov (United States)

    Sun, Wei; Tanaka, Takeshi Q.; Magle, Crystal T.; Huang, Wenwei; Southall, Noel; Huang, Ruili; Dehdashti, Seameen J.; McKew, John C.; Williamson, Kim C.; Zheng, Wei

    2014-01-01

    Control of parasite transmission is critical for the eradication of malaria. However, most antimalarial drugs are not active against P. falciparum gametocytes, responsible for the spread of malaria. Consequently, patients can remain infectious for weeks after the clearance of asexual parasites and clinical symptoms. Here we report the identification of 27 potent gametocytocidal compounds (IC50 malaria transmission-blocking reagents.

  3. Targeted therapies for malignant gliomas: novel agents, same barrier

    NARCIS (Netherlands)

    Lin, F.

    2013-01-01

    Malignant gliomas are common and devastating brain malignancies. Despite this extensive treatment the mean overall survival is still only 14.6 months and more effective treatments are urgently needed. Targeted therapy holds the promise for the new generation of chemotherapy due to the selectively ta

  4. A review on target drug delivery:magnetic microspheres

    Institute of Scientific and Technical Information of China (English)

    Amit Chandna; Deepa Batra; Satinder Kakar; Ramandeep Singh

    2013-01-01

    Novel drug delivery system aims to deliver the drug at a rate directed by the needs of the body during the period of treatment, and target the active entity to the site of action.A number of novel drug delivery systems have emerged encompassing various routes of administration, to achieve controlled and targeted drug delivery, magnetic micro carriers being one of them. Magnetic microsphere is newer approach in pharmaceutical field.Magnetic microspheres as an alternative to traditional radiation methods which use highly penetrating radiation that is absorbed throughout the body.Its use is limited by toxicity and side effects.The aim of the specific targeting is to enhance the efficiency of drug delivery & at the same time to reduce the toxicity & side effects.This kind of delivery system is very much important which localises the drug to the disease site.In this larger amount of freely circulating drug can be replaced by smaller amount of magnetically targeted drug.Magnetic carriers receive magnetic responses to a magnetic field from incorporated materials that are used for magnetic microspheres are chitosan, dextran etc. magnetic microspheres can be prepared from a variety of carrier material. One of the most utilized is serum albumin from human or other appropriate species.Drug release from albumin microspheres can be sustained or controlled by various stabilization procedures generally involving heat or chemical cross-linking of the protein carrier matrix.

  5. Enhanced cellular transport and drug targeting using dendritic nanostructures

    Science.gov (United States)

    Kannan, R. M.; Kolhe, Parag; Kannan, Sujatha; Lieh-Lai, Mary

    2003-03-01

    Dendrimers and hyperbranched polymers possess highly branched architectures, with a large number of controllable, tailorable, peripheral' functionalities. Since the surface chemistry of these materials can be modified with relative ease, these materials have tremendous potential in targeted drug delivery. The large density of end groups can also be tailored to create enhanced affinity to targeted cells, and can also encapsulate drugs and deliver them in a controlled manner. We are developing tailor-modified dendritic systems for drug delivery. Synthesis, drug/ligand conjugation, in vitro cellular and in vivo drug delivery, and the targeting efficiency to the cell are being studied systematically using a wide variety of experimental tools. Results on PAMAM dendrimers and polyol hyperbranched polymers suggest that: (1) These materials complex/encapsulate a large number of drug molecules and release them at tailorable rates; (2) The drug-dendrimer complex is transported very rapidly through a A549 lung epithelial cancel cell line, compared to free drug, perhaps by endocytosis. The ability of the drug-dendrimer-ligand complexes to target specific asthma and cancer cells is currently being explored using in vitro and in vivo animal models.

  6. TargetNet: a web service for predicting potential drug-target interaction profiling via multi-target SAR models

    Science.gov (United States)

    Yao, Zhi-Jiang; Dong, Jie; Che, Yu-Jing; Zhu, Min-Feng; Wen, Ming; Wang, Ning-Ning; Wang, Shan; Lu, Ai-Ping; Cao, Dong-Sheng

    2016-05-01

    Drug-target interactions (DTIs) are central to current drug discovery processes and public health fields. Analyzing the DTI profiling of the drugs helps to infer drug indications, adverse drug reactions, drug-drug interactions, and drug mode of actions. Therefore, it is of high importance to reliably and fast predict DTI profiling of the drugs on a genome-scale level. Here, we develop the TargetNet server, which can make real-time DTI predictions based only on molecular structures, following the spirit of multi-target SAR methodology. Naïve Bayes models together with various molecular fingerprints were employed to construct prediction models. Ensemble learning from these fingerprints was also provided to improve the prediction ability. When the user submits a molecule, the server will predict the activity of the user's molecule across 623 human proteins by the established high quality SAR model, thus generating a DTI profiling that can be used as a feature vector of chemicals for wide applications. The 623 SAR models related to 623 human proteins were strictly evaluated and validated by several model validation strategies, resulting in the AUC scores of 75-100 %. We applied the generated DTI profiling to successfully predict potential targets, toxicity classification, drug-drug interactions, and drug mode of action, which sufficiently demonstrated the wide application value of the potential DTI profiling. The TargetNet webserver is designed based on the Django framework in Python, and is freely accessible at http://targetnet.scbdd.com.

  7. TargetNet: a web service for predicting potential drug-target interaction profiling via multi-target SAR models.

    Science.gov (United States)

    Yao, Zhi-Jiang; Dong, Jie; Che, Yu-Jing; Zhu, Min-Feng; Wen, Ming; Wang, Ning-Ning; Wang, Shan; Lu, Ai-Ping; Cao, Dong-Sheng

    2016-05-01

    Drug-target interactions (DTIs) are central to current drug discovery processes and public health fields. Analyzing the DTI profiling of the drugs helps to infer drug indications, adverse drug reactions, drug-drug interactions, and drug mode of actions. Therefore, it is of high importance to reliably and fast predict DTI profiling of the drugs on a genome-scale level. Here, we develop the TargetNet server, which can make real-time DTI predictions based only on molecular structures, following the spirit of multi-target SAR methodology. Naïve Bayes models together with various molecular fingerprints were employed to construct prediction models. Ensemble learning from these fingerprints was also provided to improve the prediction ability. When the user submits a molecule, the server will predict the activity of the user's molecule across 623 human proteins by the established high quality SAR model, thus generating a DTI profiling that can be used as a feature vector of chemicals for wide applications. The 623 SAR models related to 623 human proteins were strictly evaluated and validated by several model validation strategies, resulting in the AUC scores of 75-100 %. We applied the generated DTI profiling to successfully predict potential targets, toxicity classification, drug-drug interactions, and drug mode of action, which sufficiently demonstrated the wide application value of the potential DTI profiling. The TargetNet webserver is designed based on the Django framework in Python, and is freely accessible at http://targetnet.scbdd.com .

  8. Drug targeting to tumors using HPMA copolymers

    NARCIS (Netherlands)

    Lammers, T.G.G.M.

    2009-01-01

    Copolymers based on N-(2-hydroxypropyl)methacrylamide (HPMA) are prototypic and well-characterized polymeric drug carriers that have been broadly implemented in the delivery of anticancer agents. HPMA copolymers circulate for prolonged periods of time, and by means of the Enhance Permeability and Re

  9. Leveraging big data to transform target selection and drug discovery

    Science.gov (United States)

    Butte, AJ

    2016-01-01

    The advances of genomics, sequencing, and high throughput technologies have led to the creation of large volumes of diverse datasets for drug discovery. Analyzing these datasets to better understand disease and discover new drugs is becoming more common. Recent open data initiatives in basic and clinical research have dramatically increased the types of data available to the public. The past few years have witnessed successful use of big data in many sectors across the whole drug discovery pipeline. In this review, we will highlight the state of the art in leveraging big data to identify new targets, drug indications, and drug response biomarkers in this era of precision medicine. PMID:26659699

  10. Mitochondrial drug targets in neurodegenerative diseases.

    Science.gov (United States)

    Lee, Jiyoun

    2016-02-01

    Growing evidence suggests that mitochondrial dysfunction is the main culprit in neurodegenerative diseases. Given the fact that mitochondria participate in diverse cellular processes, including energetics, metabolism, and death, the consequences of mitochondrial dysfunction in neuronal cells are inevitable. In fact, new strategies targeting mitochondrial dysfunction are emerging as potential alternatives to current treatment options for neurodegenerative diseases. In this review, we focus on mitochondrial proteins that are directly associated with mitochondrial dysfunction. We also examine recently identified small molecule modulators of these mitochondrial targets and assess their potential in research and therapeutic applications.

  11. Development of a blood-brain barrier model in a membrane-based microchip for characterization of drug permeability and cytotoxicity for drug screening.

    Science.gov (United States)

    Shao, Xiaojian; Gao, Dan; Chen, Yongli; Jin, Feng; Hu, Guangnan; Jiang, Yuyang; Liu, Hongxia

    2016-08-31

    Since most of the central nervous system (CNS) drug candidates show poor permeability across the blood-brain barrier (BBB), development of a reliable platform for permeability assay will greatly accelerate drug discovery. Herein, we constructed a microfluidic BBB model to mimic drug delivery into the brain to induce cytotoxicity at target cells. To reconstitute the in vivo BBB properties, human cerebral microvessel endothelial cells (hCMEC/D3) were dynamically cultured in a membrane-based microchannel. Sunitinib, a model drug, was then delivered into the microchannel and forced to permeate through the BBB model. The permeated amount was directly quantified by an electrospray ionization quadrupole time-of-flight mass spectrometer (ESI-Q-TOF MS) after on-chip SPE (μSPE) pretreatment. Moreover, the permeated drug was incubated with glioma cells (U251) cultured inside agarose gel in the downstream to investigate drug-induced cytotoxicity. The resultant permeability of sunitinib was highly correlated with literature reported value, and it only required 30 min and 5 μL of sample solution for each permeation experiment. Moreover, after 48 h of treatment, the survival rate of U251 cells cultured in 3D scaffolds was nearly 6% higher than that in 2D, which was in accordance with the previously reported results. These results demonstrate that this platform provides a valid tool for drug permeability and cytotoxicity assays which have great value for the research and development of CNS drugs.

  12. Using Click Chemistry to Identify Potential Drug Targets in Plasmodium

    Science.gov (United States)

    2015-04-01

    AWARD NUMBER: W81XWH-13-1-0429 TITLE: Using "Click Chemistry" to Identify Potential Drug Targets in Plasmodium PRINCIPAL INVESTIGATOR: Dr. Purnima...SUBTITLE Sa. CONTRACT NUMBER W81XWH-1 3-1-0429 Using "Click Chemistry" to Identify Potential Drug Targets in Plasmodium 5b. GRANT NUMBER 5c. PROGRAM...Release; Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT Sporozo ite infection of the liver is the first obl igate step of the Plasmodium

  13. Using Click Chemistry to Identify Potential Drug Targets in Plasmodium

    Science.gov (United States)

    2016-06-01

    AWARD NUMBER: W81XWH-13-1-0429 TITLE: Using "Click Chemistry " to Identify Potential Drug Targets in Plasmodium PRINCIPAL INVESTIGATOR...29Mar2016 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER W81XWH-13-1-0429 Using click chemistry to identify potential drug targets in Plasmodium 5b...Al-Tsp derivatives begins. Two classes of Tsp derivatives (Al-Tsp) are appropriate for click chemistry (Fig. 1). Class I derivatives carry a

  14. Advanced drug delivery and targeting technologies for the ocular diseases

    OpenAIRE

    Barar, Jaleh; AGHANEJAD, Ayuob; Fathi, Marziyeh; Omidi, Yadollah

    2016-01-01

    Introduction: Ocular targeted therapy has enormously been advanced by implementation of new methods of drug delivery and targeting using implantable drug delivery systems (DDSs) or devices (DDDs), stimuli-responsive advanced biomaterials, multimodal nanomedicines, cell therapy modalities and medical bioMEMs. These technologies tackle several ocular diseases such as inflammation-based diseases (e.g., scleritis, keratitis, uveitis, iritis, conjunctivitis, chorioretinitis, choroiditis, retinitis...

  15. Brain targeted transcranial route of drug delivery of diazepam

    OpenAIRE

    2006-01-01

    The term transcranial route means the brain targeted transfer of drug molecules across the cranium through the layers of the skin and skin appendages of the head, arteries and veins of the skin of the head, the cranial bones along with the diploe, the cranial bone sutures, the meninges and specifically through the emissary veins. The administration of drugs through the scalp in ayurvedic system for the diseases associated with the brain was evaluated with a view to develop a novel targeted ro...

  16. Drug targeting to tumors using HPMA copolymers

    OpenAIRE

    Lammers, T.G.G.M.

    2009-01-01

    Copolymers based on N-(2-hydroxypropyl)methacrylamide (HPMA) are prototypic and well-characterized polymeric drug carriers that have been broadly implemented in the delivery of anticancer agents. HPMA copolymers circulate for prolonged periods of time, and by means of the Enhance Permeability and Retention (EPR) effect, they localize to tumors both effectively and selectively. As a consequence, the concentrations of attached active agents in tumors can be increased, and their accumulation in ...

  17. CNIO cancer conference: targeted search for anticancer drugs.

    Science.gov (United States)

    Fischer, Peter M

    2003-06-01

    The topics discussed at the conference covered many aspects of cancer research, from the genetic search for new targets, target validation and drug discovery, all the way to preclinical and clinical development of oncology drugs. Here the presentations on new metabolic, angiogenic, cell cycle and other molecular targets, as well as recent developments with experimental drugs with action on some of these targets, are summarised. Particular emphasis is placed on the emerging realisation that changes in the metabolic phenotype lie at the heart of cellular transformation. New insights into the biological links between cancer cell metabolism and the balance between survival and death signalling are likely to lead to the identification of a new category of anticancer targets.

  18. REVIEW ON ADVANCES IN COLON TARGETED DRUG DELIVERY SYSTEM

    Directory of Open Access Journals (Sweden)

    Sunena Sethi, SL Harikumar* and Nirmala

    2012-09-01

    Full Text Available The colon is the terminal part of the GIT which has gained in recent years as a potential site for delivery of various novel therapeutic drugs, i.e. peptides. However, colon is rich in microflora which can be used to target the drug release in the colon. Colon is a site where both local and systemic drug delivery can take place. Local delivery allows the topical treatment of inflammatory bowel disease. If drug can be targeted directly into the colon, treatment can become more effective and side effects can be minimized. These systemic side effects can be minimized by primary approaches for CDDS (Colon specific drug delivery namely prodrugs, pH and time dependent systems and microbially triggered system which gained limited success and have limitations as compared with recently new CDDS namely pressure controlled colon delivery capsules (PCDCS, CODESTM (Novel colon targeted delivery system osmotic controlled drug delivery system, Pulsincap system, time clock system, chronotropic system. This review is to understand the pharmaceutical approaches to colon targeted drug delivery systems for better therapeutic action without compromising on drug degradation (or its low bioavailability.

  19. Targeted drug delivery to the brain using magnetic nanoparticles.

    Science.gov (United States)

    Thomsen, Louiza Bohn; Thomsen, Maj Schneider; Moos, Torben

    2015-01-01

    Brain capillary endothelial cells denote the blood-brain barrier (BBB), and conjugation of nanoparticles with antibodies that target molecules expressed by these endothelial cells may facilitate their uptake and transport into the brain. Magnetic nanoparticles can be encapsulated in liposomes and carry large molecules with therapeutic potential, for example, siRNA, cDNA and polypeptides. An additional approach to enhance the transport of magnetic nanoparticles across the BBB is the application of extracranially applied magnetic force. Stepwise targeting of magnetic nanoparticles to brain capillary endothelial cells followed by transport through the BBB using magnetic force may prove a novel mechanism for targeted therapy of macromolecules to the brain.

  20. The calculated genetic barrier for antiretroviral drug resistance substitutions is largely similar for different HIV-1 subtypes

    NARCIS (Netherlands)

    Vijver, D.A. van de; Wensing, A.M.J.; Angarano, G.; Asjo, B.; Balotta, C.; Camacho, R.; Chaix, M.; Costagliola, D.; De Luca, A.; Derdelinckx, I.; Grossman, Z.; Hamouda, O.; Hatzakis, A.; Hemmer, R.; Hoepelman, A.I.M.; Horban, A.; Korn, K.; Kücherer, C.; Leitner, T.; Loveday, C.; MacRae, E.; Maljkovic, I.; Mendoza, C. de; Meyer, L.; Nielsen, C.; Op de Coul, E.L.M.; Omaasen, V.; Paraskevis, D.; Perrin, L.; Puchhammer-Stöckl, E.; Salminen, M.; Schmit, J.; Scheider, F.; Schuurman, R.; Soriano, V.; Stanczak, G.; Stanojevic, M.; Vandamme, A.; Laethem, K. van; Violin, M.; Wilde, K.; Yerly, S.; Zazzi, M.; Boucher, C.A.B.

    2006-01-01

    The genetic barrier, defined as the number of mutations required to overcome drug-selective pressure, is an important factor for the development of HIV drug resistance. Because of high variability between subtypes, particular HIV-1 subtypes could have different genetic barriers for drug resistance s

  1. Prediction of drug-target interactions for drug repositioning only based on genomic expression similarity.

    Directory of Open Access Journals (Sweden)

    Kejian Wang

    Full Text Available Small drug molecules usually bind to multiple protein targets or even unintended off-targets. Such drug promiscuity has often led to unwanted or unexplained drug reactions, resulting in side effects or drug repositioning opportunities. So it is always an important issue in pharmacology to identify potential drug-target interactions (DTI. However, DTI discovery by experiment remains a challenging task, due to high expense of time and resources. Many computational methods are therefore developed to predict DTI with high throughput biological and clinical data. Here, we initiatively demonstrate that the on-target and off-target effects could be characterized by drug-induced in vitro genomic expression changes, e.g. the data in Connectivity Map (CMap. Thus, unknown ligands of a certain target can be found from the compounds showing high gene-expression similarity to the known ligands. Then to clarify the detailed practice of CMap based DTI prediction, we objectively evaluate how well each target is characterized by CMap. The results suggest that (1 some targets are better characterized than others, so the prediction models specific to these well characterized targets would be more accurate and reliable; (2 in some cases, a family of ligands for the same target tend to interact with common off-targets, which may help increase the efficiency of DTI discovery and explain the mechanisms of complicated drug actions. In the present study, CMap expression similarity is proposed as a novel indicator of drug-target interactions. The detailed strategies of improving data quality by decreasing the batch effect and building prediction models are also effectively established. We believe the success in CMap can be further translated into other public and commercial data of genomic expression, thus increasing research productivity towards valid drug repositioning and minimal side effects.

  2. Synthetic LDL as targeted drug delivery vehicle

    Science.gov (United States)

    Forte, Trudy M.; Nikanjam, Mina

    2012-08-28

    The present invention provides a synthetic LDL nanoparticle comprising a lipid moiety and a synthetic chimeric peptide so as to be capable of binding the LDL receptor. The synthetic LDL nanoparticle of the present invention is capable of incorporating and targeting therapeutics to cells expressing the LDL receptor for diseases associated with the expression of the LDL receptor such as central nervous system diseases. The invention further provides methods of using such synthetic LDL nanoparticles.

  3. Targeting autophagic pathways for cancer drug discovery

    Institute of Scientific and Technical Information of China (English)

    Bo Liu; Jin-Ku Bao; Jin-Ming Yang; Yan Cheng

    2013-01-01

    Autophagy,an evolutionarily conserved lysosomal degradation process,has drawn an increasing amount of attention in recent years for its role in a variety of human diseases,such as cancer.Notably,autophagy plays an important role in regulating several survival and death signaling pathways that determine cell fate in cancer.To date,substantial evidence has demonstrated that some key autophagic mediators,such as autophagy-related genes (ATGs),PI3K,mTOR,p53,and Beclin-1,may play crucial roles in modulating autophagic activity in cancer initiation and progression.Because autophagy-modulating agents such as rapamycin and chloroquine have already been used clinically to treat cancer,it is conceivable that targeting autophagic pathways may provide a new opportunity for discovery and development of more novel cancer therapeutics.With a deeper understanding of the regulatory mechanisms governing autophagy,we will have a better opportunity to facilitate the exploitation of autophagy as a target for therapeutic intervention in cancer.This review discusses the current status of targeting autophagic pathways as a potential cancer therapy.

  4. Identification of New Drug Targets in Multi-Drug Resistant Bacterial Infections

    Science.gov (United States)

    2012-10-01

    COVERED 26 September 2011 25 September 2012 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Identification of New Drug Targets in Multi-Drug Resistant...will be necessary for the fragment based screening and subsequent design of new drug lead compounds. To accompany and validate the structural studies

  5. Perceptions of drugs benefits and barriers to quit by undergraduate health students

    OpenAIRE

    HENRIQUÉZ, Patricia Cid; Carvalho,Ana Maria Pimenta

    2008-01-01

    Several studies have exposed the consumption of drugs by undergraduate students in the health area, who are supposed to be examples of behavior and health educators. This descriptive correlation study aimed to relate the benefits of tobacco consumption and barriers to quit according to the perception of undergraduate students. Eighty third-year students, in three different courses, answered a self-applied questionnaire. The studied variables were: consumption conditions, barriers and benefits...

  6. Drug targeting systems for cancer therapy: nanotechnological approach.

    Science.gov (United States)

    Tigli Aydin, R Seda

    2015-01-01

    Progress in cancer treatment remains challenging because of the great nature of tumor cells to be drug resistant. However, advances in the field of nanotechnology have enabled the delivery of drugs for cancer treatment by passively and actively targeting to tumor cells with nanoparticles. Dramatic improvements in nanotherapeutics, as applied to cancer, have rapidly accelerated clinical investigations. In this review, drug-targeting systems using nanotechnology and approved and clinically investigated nanoparticles for cancer therapy are discussed. In addition, the rationale for a nanotechnological approach to cancer therapy is emphasized because of its promising advances in the treatment of cancer patients.

  7. Large-scale Direct Targeting for Drug Repositioning and Discovery

    Science.gov (United States)

    Zheng, Chunli; Guo, Zihu; Huang, Chao; Wu, Ziyin; Li, Yan; Chen, Xuetong; Fu, Yingxue; Ru, Jinlong; Ali Shar, Piar; Wang, Yuan; Wang, Yonghua

    2015-01-01

    A system-level identification of drug-target direct interactions is vital to drug repositioning and discovery. However, the biological means on a large scale remains challenging and expensive even nowadays. The available computational models mainly focus on predicting indirect interactions or direct interactions on a small scale. To address these problems, in this work, a novel algorithm termed weighted ensemble similarity (WES) has been developed to identify drug direct targets based on a large-scale of 98,327 drug-target relationships. WES includes: (1) identifying the key ligand structural features that are highly-related to the pharmacological properties in a framework of ensemble; (2) determining a drug’s affiliation of a target by evaluation of the overall similarity (ensemble) rather than a single ligand judgment; and (3) integrating the standardized ensemble similarities (Z score) by Bayesian network and multi-variate kernel approach to make predictions. All these lead WES to predict drug direct targets with external and experimental test accuracies of 70% and 71%, respectively. This shows that the WES method provides a potential in silico model for drug repositioning and discovery. PMID:26155766

  8. Network output controllability-based method for drug target identification.

    Science.gov (United States)

    Wu, Lin; Shen, Yichao; Li, Min; Wu, Fang-Xiang

    2015-03-01

    Biomolecules do not perform their functions alone, but interactively with one another to form so called biomolecular networks. It is well known that a complex disease stems from the malfunctions of corresponding biomolecular networks. Therefore, one of important tasks is to identify drug targets from biomolecular networks. In this study, the drug target identification is formulated as a problem of finding steering nodes in biomolecular networks while the concept of network output controllability is applied to the problem of drug target identification. By applying control signals to these steering nodes, the biomolecular networks are expected to be transited from one state to another. A graph-theoretic algorithm has been proposed to find a minimum set of steering nodes in biomolecular networks which can be a potential set of drug targets. Application results of the method to real biomolecular networks show that identified potential drug targets are in agreement with existing research results. This indicates that the method can generate testable predictions and provide insights into experimental design of drug discovery.

  9. A Review of Computational Methods for Predicting Drug Targets.

    Science.gov (United States)

    Huang, Guohua; Yan, Fengxia; Tan, Duoduo

    2016-11-14

    Drug discovery and development is not only a time-consuming and labor-intensive process but also full of risk. Identifying targets of small molecules helps evaluate safety of drugs and find new therapeutic applications. The biotechnology measures a wide variety of properties related to drug and targets from different perspectives, thus generating a large body of data. This undoubtedly provides a solid foundation to explore relationships between drugs and targets. A large number of computational techniques have recently been developed for drug target prediction. In this paper, we summarize these computational methods and classify them into structure-based, molecular activity-based, side-effect-based and multi-omics-based predictions according to the used data for inference. The multi-omics-based methods are further grouped into two types: classifier-based and network-based predictions. Furthermore,the advantages and limitations of each type of methods are discussed. Finally, we point out the future directions of computational predictions for drug targets.

  10. Targeted drug delivery using genetically engineered diatom biosilica.

    Science.gov (United States)

    Delalat, Bahman; Sheppard, Vonda C; Rasi Ghaemi, Soraya; Rao, Shasha; Prestidge, Clive A; McPhee, Gordon; Rogers, Mary-Louise; Donoghue, Jacqueline F; Pillay, Vinochani; Johns, Terrance G; Kröger, Nils; Voelcker, Nicolas H

    2015-11-10

    The ability to selectively kill cancerous cell populations while leaving healthy cells unaffected is a key goal in anticancer therapeutics. The use of nanoporous silica-based materials as drug-delivery vehicles has recently proven successful, yet production of these materials requires costly and toxic chemicals. Here we use diatom microalgae-derived nanoporous biosilica to deliver chemotherapeutic drugs to cancer cells. The diatom Thalassiosira pseudonana is genetically engineered to display an IgG-binding domain of protein G on the biosilica surface, enabling attachment of cell-targeting antibodies. Neuroblastoma and B-lymphoma cells are selectively targeted and killed by biosilica displaying specific antibodies sorbed with drug-loaded nanoparticles. Treatment with the same biosilica leads to tumour growth regression in a subcutaneous mouse xenograft model of neuroblastoma. These data indicate that genetically engineered biosilica frustules may be used as versatile 'backpacks' for the targeted delivery of poorly water-soluble anticancer drugs to tumour sites.

  11. NASAL ROUTE: A NOVELISTIC APPROACH FOR TARGETED DRUG DELIVERY TO CNS

    Directory of Open Access Journals (Sweden)

    Choudhary Rakhi

    2013-03-01

    Full Text Available Drug delivery through nasal route has attracted the interest of scientific community as it has been potentially explored as an alternative route for the administration of vaccines and biomolecules such as proteins, peptides and non-peptide drugs that are susceptible to enzymatic or acidic degradation and first-pass hepatic metabolism. The nasal mucosa is one of the most permeable and highly vascularised sites for drug administration ensuring rapid absorption and onset of therapeutic action. Intranasal administration is a non-invasive route for drug delivery, which is widely used for the local treatment of rhinitis or nasal polyposis. Since drugs can be absorbed into the systemic circulation through the nasal mucosa, this route may also be used in a range of acute or chronic conditions requiring considerable systemic exposure. In addition it minimizes the lag time associated with oral drug delivery and offers non-invasiveness, self medication, patient comfort and patient compliance which are hurdled in intravenous drug therapy. The objective of this review is to provide an anatomical, histological and physiological overview of nose, absorption enhancers, barriers related to nasal drug delivery, physicochemical, biological and formulation related factors affecting nasal drug delivery system and its advantages. It also highlights research approaches on brain targeting through nasal cavity.

  12. Coating nanoparticles with cell membranes for targeted drug delivery.

    Science.gov (United States)

    Gao, Weiwei; Zhang, Liangfang

    2015-01-01

    Targeted delivery allows drug molecules to preferentially accumulate at the sites of action and thus holds great promise to improve therapeutic index. Among various drug-targeting approaches, nanoparticle-based delivery systems offer some unique strengths and have achieved exciting preclinical and clinical results. Herein, we aim to provide a review on the recent development of cell membrane-coated nanoparticle system, a new class of biomimetic nanoparticles that combine both the functionalities of cellular membranes and the engineering flexibility of synthetic nanomaterials for effective drug delivery and novel therapeutics. This review is particularly focused on novel designs of cell membrane-coated nanoparticles as well as their underlying principles that facilitate the purpose of drug targeting. Three specific areas are highlighted, including: (i) cell membrane coating to prolong nanoparticle circulation, (ii) cell membrane coating to achieve cell-specific targeting and (iii) cell membrane coating for immune system targeting. Overall, cell membrane-coated nanoparticles have emerged as a novel class of targeted nanotherapeutics with strong potentials to improve on drug delivery and therapeutic efficacy for treatment of various diseases.

  13. Improved nanoparticles preparation and drug release for liver targeted delivery

    Directory of Open Access Journals (Sweden)

    Qiao Weili

    2009-05-01

    Full Text Available "nTargeted delivery of drugs and proteins to liver can be achieved via asialoglycoprotein receptor, which can recognize and combine the galactose- and N-acetygalatosamine-terminated glycoproteins. Glycosyl is usually conjugated with drugs directly to fabricate prodrugs or with nanoparticles encapsulated drugs via forming covalent bonds, while the covalent bonds may lead to some shortages for drug release. Therefore, we have a hypothesis that we can prepare nanoparticles for efficient targeting by glycosylation using galactosylated poly (L-glutamic acid (Gal-PLGA as a carrier to entrap the model drugs in nanoparticles core physically rather than forming covalent drug conjugation. The means of incorporation of drug in nanoparticles may improve drug release to maintain its activity, raise its therapeutic index and diminish the adverse effect. Based on previous researches, it is achievable to obtain nanoparticles that we hypothesize to prepare. Due to their nanometer-size and galactosyl, the nanoparticles may be a potential delivery system for passive and active targeting to liver parenchymal cells for therapy of hepatitis and liver cancer.

  14. How do antimalarial drugs reach their intracellular targets?

    Directory of Open Access Journals (Sweden)

    Katherine eBasore

    2015-05-01

    Full Text Available Drugs represent the primary treatment available for human malaria, as caused by Plasmodium spp. Currently approved drugs and antimalarial drug leads generally work against parasite enzymes or activities within infected erythrocytes. To reach their specific targets, these chemicals must cross at least three membranes beginning with the host cell membrane. Uptake at each membrane may involve partitioning and diffusion through the lipid bilayer or facilitated transport through channels or carriers. Here, we review the features of available antimalarials and examine whether transporters may be required for their uptake. Our computational analysis suggests that most antimalarials have high intrinsic membrane permeability, obviating the need for uptake via transporters; a subset of compounds appear to require facilitated uptake. We also review parasite and host transporters that may contribute to drug uptake. Broad permeability channels at the erythrocyte and parasitophorous vacuolar membranes of infected cells relax permeability constraints on antimalarial drug design; however, this uptake mechanism is prone to acquired resistance as the parasite may alter channel activity to reduce drug uptake. A better understanding of how antimalarial drugs reach their intracellular targets is critical to prioritizing drug leads for antimalarial development and may reveal new targets for therapeutic intervention.

  15. Novel colon targeted drug delivery system using natural polymers

    Directory of Open Access Journals (Sweden)

    Ravi V

    2008-01-01

    Full Text Available A novel colon targeted tablet formulation was developed using pectin as carrier and diltiazem HCl and indomethacin as model drugs. The tablets were coated with inulin followed by shellac and were evaluated for average weight, hardness and coat thickness. In vitro release studies for prepared tablets were carried out for 2 h in pH 1.2 HCl buffer, 3 h in pH 7.4 phosphate buffer and 6 h in simulated colonic fluid. The drug release from the coated systems was monitored using UV/Vis spectroscopy. In vitro studies revealed that the tablets coated with inulin and shellac have limited the drug release in stomach and small intestinal environment and released maximum amount of drug in the colonic environment. The study revealed that polysaccharides as carriers and inulin and shellac as a coating material can be used effectively for colon targeting of both water soluble and insoluble drugs.

  16. Targeting efflux pumps to overcome antifungal drug resistance.

    Science.gov (United States)

    Holmes, Ann R; Cardno, Tony S; Strouse, J Jacob; Ivnitski-Steele, Irena; Keniya, Mikhail V; Lackovic, Kurt; Monk, Brian C; Sklar, Larry A; Cannon, Richard D

    2016-08-01

    Resistance to antifungal drugs is an increasingly significant clinical problem. The most common antifungal resistance encountered is efflux pump-mediated resistance of Candida species to azole drugs. One approach to overcome this resistance is to inhibit the pumps and chemosensitize resistant strains to azole drugs. Drug discovery targeting fungal efflux pumps could thus result in the development of azole-enhancing combination therapy. Heterologous expression of fungal efflux pumps in Saccharomyces cerevisiae provides a versatile system for screening for pump inhibitors. Fungal efflux pumps transport a range of xenobiotics including fluorescent compounds. This enables the use of fluorescence-based detection, as well as growth inhibition assays, in screens to discover compounds targeting efflux-mediated antifungal drug resistance. A variety of medium- and high-throughput screens have been used to identify a number of chemical entities that inhibit fungal efflux pumps.

  17. Cytotoxicity of liver targeted drug-loaded alginate nanoparticles

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    In this study, novel liver targeted doxorubicin (DOX) loaded alginate (ALG) nanoparticles were prepared by CaCl2 crosslinking method. Glycyrrhetinic acid (GA, a liver targeted molecule) modified alginate (GA-ALG) was synthesized in a heterogeneous system, and the structure of GA-ALG and the substitu-tion degree of GA were analyzed by 1H NMR, FT-IR and elemental analysis. The drug release profile under the simulated physiological condition and cytotoxicity experiments of drug-loaded GA-ALG nanoparticles were carried out in vitro. Transmission electron micrographs (TEM) and dynamic light scattering (DLS) analysis showed that drug-loaded GA-ALG nanoparticles have spherical shape structure with the mean hydrodynamic diameter around 214 ± 11 nm. The drug release was shown to last 20 days, and the MTT assay suggested that drug-loaded GA-ALG nanoparticles had a distinct kill-ing effect on 7703 hepatocellular carcinoma cells.

  18. Cytotoxicity of liver targeted drug-loaded aiginate nanoparticles

    Institute of Scientific and Technical Information of China (English)

    ZHANG ChuangNian; WANG Wei; WANG ChunHong; TIAN Qin; HUANG Wei; YUAN Zhi; CHEN XueSi

    2009-01-01

    In this study,novel liver targeted doxorubicin (DOX) loaded alginate (ALG) nanoparticles were prepared by CaCl2 crosslinking method.Glycyrrhetinic acid (GA,a liver targeted molecule) modified alginate (GA-ALG) was synthesized in a heterogeneous system,and the structure of GA-ALG and the substitution degree of GA were analyzed by 1H NMR,FT-IR and elemental analysis.The drug release profile under the simulated physiological condition and cytotoxicity experiments of drug-loaded GA-ALG nanoparticles were carried out in vitro.Transmission electron micrographs (TEM) and dynamic light scattering (DLS) analysis showed that drug-loaded GA-ALG nanoparticles have spherical shape structure with the mean hydrodynamic diameter around 214±11 nm.The drug release was shown to last 20 days,and the MTT assay suggested that drug-loaded GA-ALG nanoparticles had a distinct killing effect on 7703 hepatocellular carcinoma cells.

  19. Meningococcal disease and future drug targets

    DEFF Research Database (Denmark)

    Colding, Hanne; Hartzen, S H; Penkowa, Milena;

    2011-01-01

    Neisseria meningitidis (N. meningitidis) causes sepsis, epidemic meningitis, and sometimes also meningoencephalitis. Despite early antibiotic treatment, mortality and morbidity remain significant. We present recent studies on meningococcal disease with focus on the pathophysiology caused by bacte......Neisseria meningitidis (N. meningitidis) causes sepsis, epidemic meningitis, and sometimes also meningoencephalitis. Despite early antibiotic treatment, mortality and morbidity remain significant. We present recent studies on meningococcal disease with focus on the pathophysiology caused......-host interactions are key determinants of the clinical course and risk of fatal outcome. Accordingly, successful treatment of severe meningococcal disease requires not only antibiotics but also adjuvants targeting the released endotoxins and the host immune/inflammatory responses. This review highlights the most...

  20. Drug treatment and novel drug target against Cryptosporidium

    Directory of Open Access Journals (Sweden)

    Gargala G.

    2008-09-01

    Full Text Available Cryptosporidiosis emergence triggered the screening of many compounds for potential anti-cryptosporidial activity in which the majority were ineffective. The outbreak of cryptosporidiosis which occurred in Milwaukee in 1993 was not only the first significant emergence of Cryptosporidium spp. as a major human pathogen but also a huge waterborne outbreak thickening thousands of people from a major city in North America. Since then, outbreaks of cryptosporidiosis are regularly occurring throughout the world. New drugs against this parasite became consequently urgently needed. Among the most commonly used treatments against cryptosporidiosis are paromomycin, and azithromycin, which are partially effective. Nitazoxanide (NTZ’s effectiveness was demonstrated in vitro, and in vivo using several animal models and finally in clinical trials. It significantly shortened the duration of diarrhea and decreased mortality in adults and in malnourished children. NTZ is not effective without an appropriate immune response. In AIDS patients, combination therapy restoring immunity along with antimicrobial treatment of Cryptosporidium infection is necessary. Recent investigations focused on the potential of molecular-based immunotherapy against this parasite. Others tested the effects of probiotic bacteria, but were unable to demonstrate eradication of C. parvum. New synthetic isoflavone derivatives demonstrated excellent activity against C. parvum in vitro and in a gerbil model of infection. Newly synthesized nitroor non nitro- thiazolide compounds, derived from NTZ, have been recently shown to be at least as effective as NTZ against C. parvum in vitro development and are promising new therapeutic agents.

  1. Drug Elucidation: Invertebrate Genetics Sheds New Light on the Molecular Targets of CNS Drugs

    Directory of Open Access Journals (Sweden)

    Donard S. Dwyer

    2014-07-01

    Full Text Available Many important drugs approved to treat common human diseases were discovered by serendipity, without a firm understanding of their modes of action. As a result, the side effects and interactions of these medications are often unpredictable, and there is limited guidance for improving the design of next-generation drugs. Here, we review the innovative use of simple model organisms, especially Caenorhabditis elegans, to gain fresh insights into the complex biological effects of approved CNS medications. Whereas drug discovery involves the identification of new drug targets and lead compounds/biologics, and drug development spans preclinical testing to FDA approval, drug elucidation refers to the process of understanding the mechanisms of action of marketed drugs by studying their novel effects in model organisms. Drug elucidation studies have revealed new pathways affected by antipsychotic drugs, e.g., the insulin signaling pathway, a trace amine receptor and a nicotinic acetylcholine receptor. Similarly, novel targets of antidepressant drugs and lithium have been identified in C. elegans, including lipid-binding/transport proteins and the SGK-1 signaling pathway, respectively. Elucidation of the mode of action of anesthetic agents has shown that anesthesia can involve mitochondrial targets, leak currents and gap junctions. The general approach reviewed in this article has advanced our knowledge about important drugs for CNS disorders and can guide future drug discovery efforts.

  2. Drug transport into the mammalian brain: the nasal pathway and its specific metabolic barrier.

    Science.gov (United States)

    Minn, Alain; Leclerc, Séverine; Heydel, Jean-Marie; Minn, Anne-Laure; Denizcot, Claire; Cattarelli, Martine; Netter, Patrick; Gradinaru, Daniela

    2002-06-01

    It is generally accepted that the rate of entry into and distribution of drugs and other xenobiotics within the central nervous system (CNS) depends on the particular anatomy of the brain microvessels forming the blood-brain barrier (BBB), and of the choroid plexus forming the blood-cerebrospinal fluid barrier (CSF), which possess tight junctions preventing the passage of most polar substances. Drug entry to the CNS also depends on the physicochemical properties of the substances, which can be metabolised during this transport to pharmacologically inactive, non-penetrating polar products. Finally, the entry of drugs may be prevented by multiple complex specialized carriers, which are able to catalyse the active transport of numerous drugs and xenobiotics out of the CNS. Nasal delivery is currently considered as an efficient tool for systemic administration of drugs that are poorly absorbed via the oral route, and increasing evidence suggests that numerous drugs and potentially toxic xenobiotics can reach the CNS by this route. This short review summarizes recent knowledge on factors controlling the nasal pathway, focusing on drug metabolising enzymes in olfactory mucosa, olfactory bulb and brain, which should constitute a CNS metabolic barrier.

  3. The sodium channel as a target for local anesthetic drugs

    Directory of Open Access Journals (Sweden)

    Harry A Fozzard

    2011-11-01

    Full Text Available Na channels are the source of excitatory currents for the nervous system and muscle. They are the target for a class of drugs called local anesthetics (LA, which have been used for local and regional anesthesia and for excitatory dysfunction problems such as epilepsy and cardiac arrhythmia. LA drugs are prototypes for new analgesic drugs. The LA drug binding site has been localized to the inner pore of the channel, where drugs interact mainly with a phenylalanine in domain IV S6. Drug affinity is both voltage- and use-dependent. Voltage-dependency is the result of changes in the conformation of the inner pore during channel activation and opening, allowing high energy interaction of drugs with the phenylalanine. LA drugs also reduce the gating current of Na channels, which represents the movement of charged residues in the voltage sensors. Specifically, drug binding to phenylalanine locks the domain III S4 in its outward (activated position, and slows recovery of the domain IV S4. Although strongly affecting gating, LA drugs almost certainly also block by steric occlusion of the pore. Molecular definition of the binding and blocking interactions may help in new drug development.

  4. Genomes2Drugs: identifies target proteins and lead drugs from proteome data.

    LENUS (Irish Health Repository)

    Toomey, David

    2009-01-01

    BACKGROUND: Genome sequencing and bioinformatics have provided the full hypothetical proteome of many pathogenic organisms. Advances in microarray and mass spectrometry have also yielded large output datasets of possible target proteins\\/genes. However, the challenge remains to identify new targets for drug discovery from this wealth of information. Further analysis includes bioinformatics and\\/or molecular biology tools to validate the findings. This is time consuming and expensive, and could fail to yield novel drugs if protein purification and crystallography is impossible. To pre-empt this, a researcher may want to rapidly filter the output datasets for proteins that show good homology to proteins that have already been structurally characterised or proteins that are already targets for known drugs. Critically, those researchers developing novel antibiotics need to select out the proteins that show close homology to any human proteins, as future inhibitors are likely to cross-react with the host protein, causing off-target toxicity effects later in clinical trials. METHODOLOGY\\/PRINCIPAL FINDINGS: To solve many of these issues, we have developed a free online resource called Genomes2Drugs which ranks sequences to identify proteins that are (i) homologous to previously crystallized proteins or (ii) targets of known drugs, but are (iii) not homologous to human proteins. When tested using the Plasmodium falciparum malarial genome the program correctly enriched the ranked list of proteins with known drug target proteins. CONCLUSIONS\\/SIGNIFICANCE: Genomes2Drugs rapidly identifies proteins that are likely to succeed in drug discovery pipelines. This free online resource helps in the identification of potential drug targets. Importantly, the program further highlights proteins that are likely to be inhibited by FDA-approved drugs. These drugs can then be rapidly moved into Phase IV clinical studies under \\'change-of-application\\' patents.

  5. Process Modeling of Ferrofluids Flowfor Magnetic Targeting Drug Delivery

    Institute of Scientific and Technical Information of China (English)

    LIU Handan; WANG Shigang; XU Wei

    2009-01-01

    Among the proposed techniques for delivering drugs to specific sites within the human body, magnetic targeting drug delivery surpasses due to its non-invasive character and its high targeting efficiency. Although there have been some analyses theoretically for magnetic drug targeting, very few researchers have addressed the hydrodynamic models of magnetic fluids in the blood vessel of human body. This paper presents a mathematical model to describe the hydrodynamics of ferrofluids as drug carriers flowing in a blood vessel under the applied magnetic field. A 3D flow field of magnetic particles in a blood vessel model is numerically simulated in order to further understand clinical application of magnetic targeting drug delivery. Simulation results show that magnetic nanoparticles can be enriched in a target region depending on the applied magnetic field intensity. Magnetic resonance imaging conftrms the enrichment of ferrofluids in a desired body tissue of Sprague-Dawley rats. The simulation results coincide with those animal experiments. Results of the analysis provide the important information and can suggest strategies for improving delivery in favor of the clinical application.

  6. Magnetic Nanoparticles as Intraocular Drug Delivery System to Target Retinal Pigmented Epithelium (RPE

    Directory of Open Access Journals (Sweden)

    Martina Giannaccini

    2014-01-01

    Full Text Available One of the most challenging efforts in drug delivery is the targeting of the eye. The eye structure and barriers render this organ poorly permeable to drugs. Quite recently the entrance of nanoscience in ocular drug delivery has improved the penetration and half-life of drugs, especially in the anterior eye chamber, while targeting the posterior chamber is still an open issue. The retina and the retinal pigment epithelium/choroid tissues, located in the posterior eye chamber, are responsible for the majority of blindness both in childhood and adulthood. In the present study, we used magnetic nanoparticles (MNPs as a nanotool for ocular drug delivery that is capable of specific localization in the retinal pigmented epithelium (RPE layer. We demonstrate that, following intraocular injection in Xenopus embryos, MNPs localize specifically in RPE where they are retained for several days. The specificity of the localization did not depend on particle size and surface properties of the MNPs used in this work. Moreover, through similar experiments in zebrafish, we demonstrated that the targeting of RPE by the nanoparticles is not specific for the Xenopus species.

  7. Cardiotoxic drugs Herceptin and doxorubicin inhibit cardiac microvascular endothelial cell barrier formation resulting in increased drug permeability

    Directory of Open Access Journals (Sweden)

    Emma L. Wilkinson

    2016-10-01

    Full Text Available Cardiotoxicity induced by anti-cancer therapeutics is a severe, and potentially fatal, adverse reaction of the heart in response to certain drugs. Current in vitro approaches to assess cardiotoxicity have focused on analysing cardiomyocytes. More recently it has become apparent that non-cardiomyocyte cells of the heart can potentially contribute to cardiotoxicity. Herceptin and doxorubicin are known to induce cardiotoxicity in the clinic. The effect of these drugs on the endothelial tight junction barrier was tested by analysing tight junction formation and zona occludens-1 (ZO-1 levels, revealing that Herceptin and doxorubicin are able to induce barrier perturbment and decrease barrier function in human cardiac microvascular endothelial cells (HCMECs leading to increased permeability. Herceptin treatment had no effect on the tight junction barrier function in human dermal and human brain microvascular endothelial cells. HCMECs showed detectable levels of HER2 compared with the other endothelial cells suggesting that Herceptin binding to HER2 in these cells may interfere with tight junction formation. Our data suggests that doxorubicin and Herceptin can affect tight junction formation in the cardiac microvasculature leading to increased drug permeability and adverse effects on the cardiac myocytes.

  8. Large-scale prediction of drug-target interactions using protein sequences and drug topological structures

    Energy Technology Data Exchange (ETDEWEB)

    Cao Dongsheng [Research Center of Modernization of Traditional Chinese Medicines, Central South University, Changsha 410083 (China); Liu Shao [Xiangya Hospital, Central South University, Changsha 410008 (China); Xu Qingsong [School of Mathematical Sciences and Computing Technology, Central South University, Changsha 410083 (China); Lu Hongmei; Huang Jianhua [Research Center of Modernization of Traditional Chinese Medicines, Central South University, Changsha 410083 (China); Hu Qiannan [Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (Wuhan University), Ministry of Education, and Wuhan University School of Pharmaceutical Sciences, Wuhan 430071 (China); Liang Yizeng, E-mail: yizeng_liang@263.net [Research Center of Modernization of Traditional Chinese Medicines, Central South University, Changsha 410083 (China)

    2012-11-08

    Highlights: Black-Right-Pointing-Pointer Drug-target interactions are predicted using an extended SAR methodology. Black-Right-Pointing-Pointer A drug-target interaction is regarded as an event triggered by many factors. Black-Right-Pointing-Pointer Molecular fingerprint and CTD descriptors are used to represent drugs and proteins. Black-Right-Pointing-Pointer Our approach shows compatibility between the new scheme and current SAR methodology. - Abstract: The identification of interactions between drugs and target proteins plays a key role in the process of genomic drug discovery. It is both consuming and costly to determine drug-target interactions by experiments alone. Therefore, there is an urgent need to develop new in silico prediction approaches capable of identifying these potential drug-target interactions in a timely manner. In this article, we aim at extending current structure-activity relationship (SAR) methodology to fulfill such requirements. In some sense, a drug-target interaction can be regarded as an event or property triggered by many influence factors from drugs and target proteins. Thus, each interaction pair can be represented theoretically by using these factors which are based on the structural and physicochemical properties simultaneously from drugs and proteins. To realize this, drug molecules are encoded with MACCS substructure fingerings representing existence of certain functional groups or fragments; and proteins are encoded with some biochemical and physicochemical properties. Four classes of drug-target interaction networks in humans involving enzymes, ion channels, G-protein-coupled receptors (GPCRs) and nuclear receptors, are independently used for establishing predictive models with support vector machines (SVMs). The SVM models gave prediction accuracy of 90.31%, 88.91%, 84.68% and 83.74% for four datasets, respectively. In conclusion, the results demonstrate the ability of our proposed method to predict the drug-target

  9. Designing Novel Nanoformulations Targeting Glutamate Transporter Excitatory Amino Acid Transporter 2: Implications in Treating Drug Addiction.

    Science.gov (United States)

    Rao, Pss; Yallapu, Murali M; Sari, Youssef; Fisher, Paul B; Kumar, Santosh

    Chronic drug abuse is associated with elevated extracellular glutamate concentration in the brain reward regions. Deficit of glutamate clearance has been identified as a contributing factor that leads to enhanced glutamate concentration following extended drug abuse. Importantly, normalization of glutamate level through induction of glutamate transporter 1 (GLT1)/ excitatory amino acid transporter 2 (EAAT2) expression has been described in several in vivo studies. GLT1 upregulators including ceftriaxone, a beta-lactam antibiotic, have been effective in attenuating drug-seeking and drug-consumption behavior in rodent models. However, potential obstacles toward clinical translation of GLT1 (EAAT2) upregulators as treatment for drug addiction might include poor gastrointestinal absorption, serious peripheral adverse effects, and/or suboptimal CNS concentrations. Given the growing success of nanotechnology in targeting CNS ailments, nanoformulating known GLT1 (EAAT2) upregulators for selective uptake across the blood brain barrier presents an ideal therapeutic approach for treating drug addiction. In this review, we summarize the results obtained with promising GLT1 (EAAT2) inducing compounds in animal models recapitulating drug addiction. Additionally, the various nanoformulations that can be employed for selectively increasing the CNS bioavailability of GLT1 (EAAT2) upregulators are discussed. Finally, the applicability of GLT1 (EAAT2) induction via central delivery of drug-loaded nanoformulations is described.

  10. Computational design of nanoparticle drug delivery systems for selective targeting.

    Science.gov (United States)

    Duncan, Gregg A; Bevan, Michael A

    2015-10-01

    Ligand-functionalized nanoparticles capable of selectively binding to diseased versus healthy cell populations are attractive for improved efficacy of nanoparticle-based drug and gene therapies. However, nanoparticles functionalized with high affinity targeting ligands may lead to undesired off-target binding to healthy cells. In this work, Monte Carlo simulations were used to quantitatively determine net surface interactions, binding valency, and selectivity between targeted nanoparticles and cell surfaces. Dissociation constant, KD, and target membrane protein density, ρR, are explored over a range representative of healthy and cancerous cell surfaces. Our findings show highly selective binding to diseased cell surfaces can be achieved with multiple, weaker affinity targeting ligands that can be further optimized by varying the targeting ligand density, ρL. Using the approach developed in this work, nanomedicines can be optimally designed for exclusively targeting diseased cells and tissues.

  11. Targeted drug delivery by ultrasound-triggered margination of microbubbles

    CERN Document Server

    Guckenberger, Achim

    2016-01-01

    The ideal agent for targeted drug delivery should stay away from the biochemically active walls of the blood vessels during circulation. However, upon reaching its target it should attain a near-wall position. Though seemingly contradictory, we show that coated microbubbles (ultrasound contrast agents) possess precisely these two properties. Using numerical simulations we find that application of a localized ultrasound pulse at the target organ triggers their rapid migration from the vessel center toward the endothelial wall. This ultrasound-triggered margination is due to hydrodynamic interactions between the red blood cells and the oscillating bubbles. Importantly, we find that the effect is very robust, existing even if the duration in the stiff state is five times lower than the opposing time in the soft state. Our results might also explain why recent in-vivo studies found strongly enhanced drug uptake by co-administration of microbubbles with classical drug delivery agents.

  12. Multifunctional Nanoparticles for Drug Delivery Applications Imaging, Targeting, and Delivery

    CERN Document Server

    Prud'homme, Robert

    2012-01-01

    This book clearly demonstrates the progression of nanoparticle therapeutics from basic research to applications. Unlike other books covering nanoparticles used in medical applications, Multifunctional Nanoparticles for Drug Delivery Applications presents the medical challenges that can be reduced or even overcome by recent advances in nanoscale drug delivery. Each chapter highlights recent progress in the design and engineering of select multifunctional nanoparticles with topics covering targeting, imaging, delivery, diagnostics, and therapy.

  13. Current strategies for targeted delivery of bio-active drug molecules in the treatment of brain tumor.

    Science.gov (United States)

    Garg, Tarun; Bhandari, Saurav; Rath, Goutam; Goyal, Amit K

    2015-12-01

    Brain tumor is one of the most challenging diseases to treat. The major obstacle in the specific drug delivery to brain is blood-brain barrier (BBB). Mostly available anti-cancer drugs are large hydrophobic molecules which have limited permeability via BBB. Therefore, it is clear that the protective barriers confining the passage of the foreign particles into the brain are the main impediment for the brain drug delivery. Hence, the major challenge in drug development and delivery for the neurological diseases is to design non-invasive nanocarrier systems that can assist controlled and targeted drug delivery to the specific regions of the brain. In this review article, our major focus to treat brain tumor by study numerous strategies includes intracerebral implants, BBB disruption, intraventricular infusion, convection-enhanced delivery, intra-arterial drug delivery, intrathecal drug delivery, injection, catheters, pumps, microdialysis, RNA interference, antisense therapy, gene therapy, monoclonal/cationic antibodies conjugate, endogenous transporters, lipophilic analogues, prodrugs, efflux transporters, direct conjugation of antitumor drugs, direct targeting of liposomes, nanoparticles, solid-lipid nanoparticles, polymeric micelles, dendrimers and albumin-based drug carriers.

  14. Nanoparticles laden in situ gelling system for ocular drug targeting

    Directory of Open Access Journals (Sweden)

    Divya Kumar

    2013-01-01

    Full Text Available Designing an ophthalmic drug delivery system is one of the most difficult challenges for the researchers. The anatomy and physiology of eye create barriers like blinking which leads to the poor retention time and penetration of drug moiety. Some conventional ocular drug delivery systems show shortcomings such as enhanced pre-corneal elimination, high variability in efficiency, and blurred vision. To overcome these problems, several novel drug delivery systems such as liposomes, nanoparticles, hydrogels, and in situ gels have been developed. In situ-forming hydrogels are liquid upon instillation and undergo phase transition in the ocular cul-de-sac to form viscoelastic gel and this provides a response to environmental changes. In the past few years, an impressive number of novel temperature, pH, and ion-induced in situ-forming systems have been reported for sustain ophthalmic drug delivery. Each system has its own advantages and drawbacks. Thus, a combination of two drug delivery systems, i.e., nanoparticles and in situ gel, has been developed which is known as nanoparticle laden in situ gel. This review describes every aspects of this novel formulation, which present the readers an exhaustive detail and might contribute to research and development.

  15. The Role of Carrier Geometry in Overcoming Biological Barriers to Drug Delivery.

    Science.gov (United States)

    Jordan, Carolyn; Shuvaev, Vladimir V; Bailey, Mark; Muzykantov, Vladimir R; Dziubla, Thomas D

    2016-01-01

    For a variety of diseases, effective therapy is severely limited or rendered impossible due to an inability to deliver medications to the intended sites of action. Multiple barriers exist through the body, which have evolved over time to limit the migration of foreign compounds from entering the tissues. Turning toward biology as inspiration, it has been the general goal of drug delivery to create carrier strategies that mimic, in part, features of bacteria/ viruses that allow them overcome these barriers. By packaging drugs into nano and micron scale vehicles, it should be possible to completely change the biodistribution and residence times of pharmaceutically active compounds. Recently, due to advances in formulation technologies, it has become possible to control not just the material selection, surface chemistry, and/or size, but also the overall geometry and plasticity of the drug carriers. These approaches aid in the formulation of nonspherical particles such as, discs, rods, and even unique structures such as cubes and nanodiamonds. The adjustment of size and shape can be used for the aid or prevention in cellular uptake and also to overcome the vascular and mucosal barrier. In this review, we present a summary of some approaches used to control carrier shape and the impact these geometries have upon drug transport across biological barriers.

  16. Identifying problematic drugs based on the characteristics of their targets

    Directory of Open Access Journals (Sweden)

    Tiago Jose eDa Silva Lopes

    2015-09-01

    Full Text Available Identifying promising compounds during the early stages of drug development is a major challenge for both academia and the pharmaceutical industry. The difficulties are even more pronounced when we consider multi-target pharmacology, where the compounds often target more than one protein, or multiple compounds are used together. Here, we address this problem by using machine learning and network analysis to process sequence and interaction data from human proteins to identify promising compounds. We used this strategy to identify properties that make certain proteins more likely to cause harmful effects when targeted; such proteins usually have domains commonly found throughout the human proteome. Additionally, since currently marketed drugs hit multiple targets simultaneously, we combined the information from individual proteins to devise a score that quantifies the likelihood of a compound being harmful to humans. This approach enabled us to distinguish between approved and problematic drugs with an accuracy of 60%¬–70%. Moreover, our approach can be applied as soon as candidate drugs are available, as demonstrated with predictions for more than 5000 experimental drugs. These resources are available at http://sourceforge.net/projects/psin/.

  17. Nanoparticle mediated P-glycoprotein silencing for improved drug delivery across the blood-brain barrier: a siRNA-chitosan approach.

    Directory of Open Access Journals (Sweden)

    Jostein Malmo

    Full Text Available The blood-brain barrier (BBB, composed of tightly organized endothelial cells, limits the availability of drugs to therapeutic targets in the central nervous system. The barrier is maintained by membrane bound efflux pumps efficiently transporting specific xenobiotics back into the blood. The efflux pump P-glycoprotein (P-gp, expressed at high levels in brain endothelial cells, has several drug substrates. Consequently, siRNA mediated silencing of the P-gp gene is one possible strategy how to improve the delivery of drugs to the brain. Herein, we investigated the potential of siRNA-chitosan nanoparticles in silencing P-gp in a BBB model. We show that the transfection of rat brain endothelial cells mediated effective knockdown of P-gp with subsequent decrease in P-gp substrate efflux. This resulted in increased cellular delivery and efficacy of the model drug doxorubicin.

  18. A smart multifunctional drug delivery nanoplatform for targeting cancer cells

    Science.gov (United States)

    Hoop, M.; Mushtaq, F.; Hurter, C.; Chen, X.-Z.; Nelson, B. J.; Pané, S.

    2016-06-01

    Wirelessly guided magnetic nanomachines are promising vectors for targeted drug delivery, which have the potential to minimize the interaction between anticancer agents and healthy tissues. In this work, we propose a smart multifunctional drug delivery nanomachine for targeted drug delivery that incorporates a stimuli-responsive building block. The nanomachine consists of a magnetic nickel (Ni) nanotube that contains a pH-responsive chitosan hydrogel in its inner cavity. The chitosan inside the nanotube serves as a matrix that can selectively release drugs in acidic environments, such as the extracellular space of most tumors. Approximately a 2.5 times higher drug release from Ni nanotubes at pH = 6 is achieved compared to that at pH = 7.4. The outside of the Ni tube is coated with gold. A fluorescein isothiocyanate (FITC) labeled thiol-ssDNA, a biological marker, was conjugated on its surface by thiol-gold click chemistry, which enables traceability. The Ni nanotube allows the propulsion of the device by means of external magnetic fields. As the proposed nanoarchitecture integrates different functional building blocks, our drug delivery nanoplatform can be employed for carrying molecular drug conjugates and for performing targeted combinatorial therapies, which can provide an alternative and supplementary solution to current drug delivery technologies.Wirelessly guided magnetic nanomachines are promising vectors for targeted drug delivery, which have the potential to minimize the interaction between anticancer agents and healthy tissues. In this work, we propose a smart multifunctional drug delivery nanomachine for targeted drug delivery that incorporates a stimuli-responsive building block. The nanomachine consists of a magnetic nickel (Ni) nanotube that contains a pH-responsive chitosan hydrogel in its inner cavity. The chitosan inside the nanotube serves as a matrix that can selectively release drugs in acidic environments, such as the extracellular space of

  19. Quantitative modeling of selective lysosomal targeting for drug design

    DEFF Research Database (Denmark)

    Trapp, Stefan; Rosania, G.; Horobin, R.W.;

    2008-01-01

    Lysosomes are acidic organelles and are involved in various diseases, the most prominent is malaria. Accumulation of molecules in the cell by diffusion from the external solution into cytosol, lysosome and mitochondrium was calculated with the Fick–Nernst–Planck equation. The cell model considers....... This demonstrates that the cell model can be a useful tool for the design of effective lysosome-targeting drugs with minimal off-target interactions....

  20. Getting into the brain: liposome-based strategies for effective drug delivery across the blood-brain barrier.

    Science.gov (United States)

    Vieira, Débora B; Gamarra, Lionel F

    This review summarizes articles that have been reported in literature on liposome-based strategies for effective drug delivery across the blood-brain barrier. Due to their unique physicochemical characteristics, liposomes have been widely investigated for their application in drug delivery and in vivo bioimaging for the treatment and/or diagnosis of neurological diseases, such as Alzheimer's, Parkinson's, stroke, and glioma. Several strategies have been used to deliver drug and/or imaging agents to the brain. Covalent ligation of such macromolecules as peptides, antibodies, and RNA aptamers is an effective method for receptor-targeting liposomes, which allows their blood-brain barrier penetration and/or the delivery of their therapeutic molecule specifically to the disease site. Additionally, methods have been employed for the development of liposomes that can respond to external stimuli. It can be concluded that the development of liposomes for brain delivery is still in its infancy, although these systems have the potential to revolutionize the ways in which medicine is administered.

  1. [Development of drug delivery systems for targeting to macrophages].

    Science.gov (United States)

    Chono, Sumio

    2007-09-01

    Drug delivery systems (DDS) using liposomes as drug carriers for targeting to macrophages have been developed for the treatment of diseases that macrophages are related to their progress. Initially, DDS for the treatment of atherosclerosis are described. The influence of particle size on the drug delivery to atherosclerotic lesions that macrophages are richly present and antiatherosclerotic effects following intravenous administration of liposomes containing dexamethasone (DXM-liposomes) was investigated in atherogenic mice. Both the drug delivery efficacy of DXM-liposomes (particle size, 200 nm) to atherosclerotic lesions and their antiatherosclerotic effects were greater than those of 70 and 500 nm. These results indicate that there is an optimal particle size for drug delivery to atherosclerotic lesions. DDS for the treatment of respiratory infections are then described. The influence of particle size and surface mannosylation on the drug delivery to alveolar macrophages (AMs) and antibacterial effects following pulmonary administration of liposomes containing ciprofloxacin (CPFX-liposomes) was investigated in rats. The drug delivery efficacy of CPFX-liposomes to AMs was particle size-dependent over the range 100-1000 nm and then became constant at over 1000 nm. These results indicate that the most effective size is 1000 nm. Both the drug delivery efficacy of mannosylated CPFX-liposomes (particle size, 1000 nm) to AMs and their antibacterial effects were significantly greater than those of unmodified CPFX-liposomes. These results indicate that the surface mannosylation is useful method for drug delivery to AMs. This review provides useful information to help in the development of novel pharmaceutical formulations aimed at drug targeting to macrophages.

  2. Potential of magnetic nanoparticles for targeted drug delivery

    Directory of Open Access Journals (Sweden)

    Yang HW

    2012-08-01

    Full Text Available Hung-Wei Yang,1,2 Mu-Yi Hua,1 Hao-Li Liu,3 Chiung-Yin Huang,2 Kuo-Chen Wei21Molecular Medicine Research Center, Department of Chemical and Materials Engineering, Chang Gung University, 2Department of Neurosurgery, Chang Gung University and Memorial Hospital, 3Department of Electrical Engineering, Chang Gung University, Taoyuan, TaiwanAbstract: Nanoparticles (NPs play an important role in the molecular diagnosis, treatment, and monitoring of therapeutic outcomes in various diseases. Their nanoscale size, large surface area, unique capabilities, and negligible side effects make NPs highly effective for biomedical applications such as cancer therapy, thrombolysis, and molecular imaging. In particular, nontoxic superparamagnetic magnetic NPs (MNPs with functionalized surface coatings can conjugate chemotherapeutic drugs or be used to target ligands/proteins, making them useful for drug delivery, targeted therapy, magnetic resonance imaging, transfection, and cell/protein/DNA separation. To optimize the therapeutic efficacy of MNPs for a specific application, three issues must be addressed. First, the efficacy of magnetic targeting/guidance is dependent on particle magnetization, which can be controlled by adjusting the reaction conditions during synthesis. Second, the tendency of MNPs to aggregate limits their therapeutic use in vivo; surface modifications to produce high positive or negative charges can reduce this tendency. Finally, the surface of MNPs can be coated with drugs which can be rapidly released after injection, resulting in targeting of low doses of the drug. Drugs therefore need to be conjugated to MNPs such that their release is delayed and their thermal stability enhanced. This chapter describes the creation of nanocarriers with a high drug-loading capacity comprised of a high-magnetization MNP core and a shell of aqueous, stable, conducting polyaniline derivatives and their applications in cancer therapy. It further summarizes some

  3. A conceptual framework for the identification of candidate drugs and drug targets in acute promyelocytic leukemia

    DEFF Research Database (Denmark)

    Marstrand, T T; Borup, R; Willer, A

    2010-01-01

    regulation, and (ii) the identification of candidate drugs and drug targets for therapeutic interventions. Significantly, our study provides a conceptual framework that can be applied to any subtype of AML and cancer in general to uncover novel information from published microarray data sets at low cost...

  4. Drug loading, dispersion stability, and therapeutic efficacy in targeted drug delivery with carbon nanotubes

    OpenAIRE

    Heister, E; Neves, V.; Lamprecht, C.; Silva, SRP; Coley, HM; Mcfadden, J.

    2012-01-01

    We have designed a drug delivery system for the anti-cancer drugs doxorubicin and mitoxantrone based on carbon nanotubes, which is stable under biological conditions, allows for sustained release, and promotes selectivity through an active targeting scheme. Carbon nanotubes are particularly promising for this area of application due to their high surface area, allowing for high drug loading, and their unique interaction with cellular membranes. We have taken a systematic approach to PEG conju...

  5. Injectable nanomaterials for drug delivery: carriers, targeting moieties, and therapeutics.

    Science.gov (United States)

    Webster, David M; Sundaram, Padma; Byrne, Mark E

    2013-05-01

    Therapeutics such as nucleic acids, proteins/peptides, vaccines, anti-cancer, and other drugs have disadvantages of low bio-availability, rapid clearance, and high toxicity. Thus, there is a significant need for the development of efficient delivery methods and carriers. Injectable nanocarriers have received much attention due to their vast range of structures and ability to contain multiple functional groups, both within the bulk material and on the surface of the particles. Nanocarriers may be tailored to control drug release and/or increase selective cell targeting, cellular uptake, drug solubility, and circulation time, all of which lead to a more efficacious delivery and action of therapeutics. The focus of this review is injectable, targeted nanoparticle drug delivery carriers highlighting the diversity of nanoparticle materials and structures as well as highlighting current therapeutics and targeting moieties. Structures and materials discussed include liposomes, polymersomes, dendrimers, cyclodextrin-containing polymers (CDPs), carbon nanotubes (CNTs), and gold nanoparticles. Additionally, current clinical trial information and details such as trial phase, treatment, active drug, carrier sponsor, and clinical trial identifier for different materials and structures are presented and discussed.

  6. Nanofabricated biomimetic structures for smart targeting and drug delivery

    NARCIS (Netherlands)

    Dudia, Alma; Kanger, Johannes S.; Subramaniam, Vinod

    2005-01-01

    We present a new approach to hybrid artificial cells (AC) designed for specific targeting and active drug delivery by combining an impermeable non-biological scaffold with an artificial bilayer lipid membrane (BLM) that supports the functioning bio-molecules required to provide AC functionality. We

  7. Current and future drug targets in weight management

    NARCIS (Netherlands)

    Witkamp, R.F.

    2011-01-01

    Obesity will continue to be one of the leading causes of chronic disease unless the ongoing rise in the prevalence of this condition is reversed. Accumulating morbidity figures and a shortage of effective drugs have generated substantial research activity with several molecular targets being investi

  8. Mitochondrial chaperones may be targets for anti-cancer drugs

    Science.gov (United States)

    Scientists at NCI have found that a mitochondrial chaperone protein, TRAP1, may act indirectly as a tumor suppressor as well as a novel target for developing anti-cancer drugs. Chaperone proteins, such as TRAP1, help other proteins adapt to stress, but sc

  9. Spherons as a drug target in Alzheimer's disease.

    Science.gov (United States)

    Averback, P

    1998-10-01

    Spherons are unique brain entities that are causally linked to the amyloid plaques (SPs [senile plaques]) of Alzheimer's disease (AD). SPs are the quantitatively major tissue abnormality of AD. Spherons increase in size (but not in number) gradually throughout life until they reach a size range where they burst and form SPs. Drugs targeted at attenuating the process of spheron transformation into SPs are a logical approach to AD therapy. There are 20 criteria of validity for an SP causal entity that are satisfied by spherons-and no more than a few of these 20 criteria are satisfied by any other known hypothesis. These criteria of validity are reviewed, in addition to common difficulties in understanding spheron theory and a number of common-sense considerations in AD therapeutic research. Spheron-based drug therapy in AD potentially can retard the process of spheron bursting and subsequent plaque formation by: 1) blocking the formation of SPs; 2) reducing the size of SPs; 3) delaying spheron breakdown; and 4) retarding spheron growth. Isolated spherons from human brain are intact human drug targets and can be used as human in vitro or in vivo screening targets. The paramount importance of spherons as a target for drug therapy in AD is emphasized by considering that regardless of any other type of real or potential therapy, there still already exists in every middle-aged adult a full population of spherons in the brain, filled with more than enough amyloid to bring about full-blown AD.

  10. Glial cells as drug targets : What does it take?

    NARCIS (Netherlands)

    Moller, Thomas; Boddeke, Hendrikus W. G. M.

    2016-01-01

    The last two decades have brought a significant increase in our understanding of glial biology and glial contribution to CNS disease. Yet, despite the fact that glial cells make up the majority of CNS cells, no drug specifically targeting glial cells is on the market. Given the long development time

  11. Folate receptor targeted liposomes encapsulating anti-cancer drugs.

    Science.gov (United States)

    Chaudhury, Anumita; Das, Surajit

    2015-01-01

    Among all available lipid based nanoparticulate systems, the success of liposomal drug delivery system is evident by the number of liposomal products available in the market or under advanced stages of preclinical and clinical trials. Liposome has the ability to deliver chemotherapeutic agents to the targeted tissues or even inside the cancerous cells by enhanced intracellular penetration or improved tumour targeting. In the last decade, folate receptor mediated tumour targeting has emerged as an attractive alternative method of active targeting of cancer cells through liposomes due to its numerous advantages over other targeting methods. Folate receptors, also known as folate binding proteins, allow the binding and internalization of folate or folic acid into the cells by a method called folate receptor mediated endocytosis. They have restricted presence in normal cells and are mostly expressed during malignant transformation. In this review article, folate receptor targeting capability of liposomes has been described. This review article has focussed on the different cancer drugs which have been encapsulated in folate receptor targeted liposomes and their in vitro as well as in vivo efficacies in several tumour models.

  12. Glycoprotein mucin molecular brush on cancer cell surface acting as mechanical barrier against drug delivery

    Science.gov (United States)

    Wang, Xin; Shah, Aalok A.; Campbell, Robert B.; Wan, Kai-tak

    2010-12-01

    Uptake of cytotoxic drugs by typical tumor cells is limited by the dense dendritic network of oligosaccharide mucin chains that forms a mechanical barrier. Atomic force microscopy is used to directly measure the force needed to pierce the mucin layer to reach the cell surface. Measurements are analyzed by de Gennes' steric reptation theory. Multidrug resistant ovarian tumor cells shows significantly larger penetration load compared to the wide type. A pool of pancreatic, lung, colorectal, and breast cells are also characterized. The chemotherapeutic agent, benzyl-α-GalNac, for inhibiting glycosylation is shown to be effective in reducing the mechanical barrier.

  13. Leishmaniasis:Current status of available drugs and new potential drug targets

    Institute of Scientific and Technical Information of China (English)

    Nisha Singh; Manish Kumar; Rakesh Kumar Singh

    2012-01-01

    The control ofLeishmania infection relies primarily on chemotherapy till date. Resistance to pentavalent antimonials, which have been the recommended drugs to treat cutaneous and visceral leishmaniasis, is now widespread in Indian subcontinents. New drug formulations like amphotericinB, its lipid formulations, and miltefosine have shown great efficacy to treat leishmaniasis but their high cost and therapeutic complications limit their usefulness. In addition, irregular and inappropriate uses of these second line drugs in endemic regions like state of Bihar, India threaten resistance development in the parasite. In context to the limited drug options and unavailability of either preventive or prophylactic candidates, there is a pressing need to develop true antileishmanial drugs to reduce the disease burden of this debilitating endemic disease. Notwithstanding significant progress of leishmanial research during last few decades, identification and characterization of novel drugs and drug targets are far from satisfactory. This review will initially describe current drug regimens and later will provide an overview on few important biochemical and enzymatic machineries that could be utilized as putative drug targets for generation of true antileishmanial drugs.

  14. Cancer targeted therapeutics: From molecules to drug delivery vehicles.

    Science.gov (United States)

    Liu, Daxing; Auguste, Debra T

    2015-12-10

    The pitfall of all chemotherapeutics lies in drug resistance and the severe side effects experienced by patients. One way to reduce the off-target effects of chemotherapy on healthy tissues is to alter the biodistribution of drug. This can be achieved in two ways: Passive targeting utilizes shape, size, and surface chemistry to increase particle circulation and tumor accumulation. Active targeting employs either chemical moieties (e.g. peptides, sugars, aptamers, antibodies) to selectively bind to cell membranes or responsive elements (e.g. ultrasound, magnetism, light) to deliver its cargo within a local region. This article will focus on the systemic administration of anti-cancer agents and their ability to home to tumors and, if relevant, distant metastatic sites.

  15. The tuberculosis drug discovery and development pipeline and emerging drug targets.

    Science.gov (United States)

    Mdluli, Khisimuzi; Kaneko, Takushi; Upton, Anna

    2015-01-29

    The recent accelerated approval for use in extensively drug-resistant and multidrug-resistant-tuberculosis (MDR-TB) of two first-in-class TB drugs, bedaquiline and delamanid, has reinvigorated the TB drug discovery and development field. However, although several promising clinical development programs are ongoing to evaluate new TB drugs and regimens, the number of novel series represented is few. The global early-development pipeline is also woefully thin. To have a chance of achieving the goal of better, shorter, safer TB drug regimens with utility against drug-sensitive and drug-resistant disease, a robust and diverse global TB drug discovery pipeline is key, including innovative approaches that make use of recently acquired knowledge on the biology of TB. Fortunately, drug discovery for TB has resurged in recent years, generating compounds with varying potential for progression into developable leads. In parallel, advances have been made in understanding TB pathogenesis. It is now possible to apply the lessons learned from recent TB hit generation efforts and newly validated TB drug targets to generate the next wave of TB drug leads. Use of currently underexploited sources of chemical matter and lead-optimization strategies may also improve the efficiency of future TB drug discovery. Novel TB drug regimens with shorter treatment durations must target all subpopulations of Mycobacterium tuberculosis existing in an infection, including those responsible for the protracted TB treatment duration. This review summarizes the current TB drug development pipeline and proposes strategies for generating improved hits and leads in the discovery phase that could help achieve this goal.

  16. Peptide-22 and Cyclic RGD Functionalized Liposomes for Glioma Targeting Drug Delivery Overcoming BBB and BBTB.

    Science.gov (United States)

    Chen, Cuitian; Duan, Ziqing; Yuan, Yan; Li, Ruixiang; Pang, Liang; Liang, Jianming; Xu, Xinchun; Wang, Jianxin

    2017-02-22

    Chemotherapy outcomes for the treatment of glioma remain unsatisfied due to the inefficient drug transport across BBB/BBTB and poor drug accumulation in the tumor site. Nanocarriers functionalized with different targeting ligands are considered as one of the most promising alternatives. However, few studies were reported to compare the targeting efficiency of the ligands and develop nanoparticles to realize BBB/BBTB crossing and brain tumor targeting simultaneously. In this study, six peptide-based ligands (Angiopep-2, T7, Peptide-22, c(RGDfK), D-SP5 and Pep-1), widely used for brain delivery, were selected to decorate liposomes, respectively, so as to compare their targeting ability to BBB or BBTB. Based on the in vitro cellular uptake results on BCECs and HUVECs, Peptide-22 and c(RGDfK) were picked to construct a BBB/BBTB dual-crossing, glioma-targeting liposomal drug delivery system c(RGDfK)/Pep-22-DOX-LP. In vitro cellular uptake demonstrated that the synergetic effect of c(RGDfK) and Peptide-22 could significantly increase the internalization of liposomes on U87 cells. In vivo imaging further verified that c(RGDfK)/Pep-22-LP exhibited higher brain tumor distribution than single ligand modified liposomes. The median survival time of glioma-bearing mice treated with c(RGDfK)/Pep-22-DOX-LP (39.5 days) was significantly prolonged than those treated with free doxorubicin or other controls. In conclusion, the c(RGDfK) and Peptide-22 dual-modified liposome was constructed based on the targeting ability screening of various ligands. The system could effectively overcome BBB/BBTB barriers, target to tumor cells and inhibit the growth of glioma, which proved its potential for improving the efficacy of chemotherapeutics for glioma therapy.

  17. Mechanistic models enable the rational use of in vitro drug-target binding kinetics for better drug effects in patients.

    NARCIS (Netherlands)

    Witte, W.E.; Wong, Y.C.; Nederpelt, I.; Heitman, L.H.; Danhof, M.; Graaf, van der P.H.; Gilissen, R.A.; de, Lange E.C.

    2016-01-01

    INTRODUCTION Drug-target binding kinetics are major determinants of the time course of drug action for several drugs, as clearly described for the irreversible binders omeprazole and aspirin. This supports the increasing interest to incorporate newly developed high-throughput assays for drug-target

  18. A review on target drug delivery: magnetic microspheres

    Directory of Open Access Journals (Sweden)

    Amit Chandna

    2013-01-01

    Magnetic microsphere is newer approach in pharmaceutical field. Magnetic microspheres as an alternative to traditional radiation methods which use highly penetrating radiation that is absorbed throughout the body. Its use is limited by toxicity and side effects. The aim of the specific targeting is to enhance the efficiency of drug delivery & at the same time to reduce the toxicity & side effects. This kind of delivery system is very much important which localises the drug to the disease site. In this larger amount of freely circulating drug can be replaced by smaller amount of magnetically targeted drug. Magnetic carriers receive magnetic responses to a magnetic field from incorporated materials that are used for magnetic microspheres are chitosan, dextran etc. magnetic microspheres can be prepared from a variety of carrier material. One of the most utilized is serum albumin from human or other appropriate species. Drug release from albumin microspheres can be sustained or controlled by various stabilization procedures generally involving heat or chemical cross-linking of the protein carrier matrix.

  19. Pericyte-targeting drug delivery and tissue engineering

    Directory of Open Access Journals (Sweden)

    Kang E

    2016-05-01

    Full Text Available Eunah Kang,1 Jong Wook Shin2 1School of Chemical Engineering and Material Science, 2Division of Allergic and Pulmonary Medicine, Department of Internal Medicine, College of Medicine, Chung-Ang University, Dongjak-Gu, Seoul, South Korea Abstract: Pericytes are contractile mural cells that wrap around the endothelial cells of capillaries and venules. Depending on the triggers by cellular signals, pericytes have specific functionality in tumor microenvironments, properties of potent stem cells, and plasticity in cellular pathology. These features of pericytes can be activated for the promotion or reduction of angiogenesis. Frontier studies have exploited pericyte-targeting drug delivery, using pericyte-specific peptides, small molecules, and DNA in tumor therapy. Moreover, the communication between pericytes and endothelial cells has been applied to the induction of vessel neoformation in tissue engineering. Pericytes may prove to be a novel target for tumor therapy and tissue engineering. The present paper specifically reviews pericyte-specific drug delivery and tissue engineering, allowing insight into the emerging research targeting pericytes. Keywords: pericytes, pericyte-targeting drug delivery, tissue engineering, platelet-derived growth factor, angiogenesis, vascular remodeling

  20. Rhamnogalacturonan-I based microcapsules for targeted drug release

    DEFF Research Database (Denmark)

    Svagan, Anna J.; Kusic, Anja; De Gobba, Cristian;

    2016-01-01

    Drug targeting to the colon via the oral administration route for local treatment of e.g. inflammatory bowel disease and colonic cancer has several advantages such as needle-free administration and low infection risk. A new source for delivery is plant-polysaccharide based delivery platforms...... such as Rhamnogalacturonan-I (RG-I). In the gastro-intestinal tract the RG-I is only degraded by the action of the colonic microflora. For assessment of potential drug delivery properties, RG-I based microcapsules (~1 μm in diameter) were prepared by an interfacial poly-addition reaction. The cross-linked capsules were...

  1. NIOSOMES: A ROLE IN TARGETED DRUG DELIVERY SYSTEM

    Directory of Open Access Journals (Sweden)

    Soumya Singh

    2013-02-01

    Full Text Available Niosomes are non-ionic surfactant vesicles inclosing an aqueous phase and a wide range of molecules could be encapsulated within aqueous spaces of lipid membrane vesicles. They are microscopic lamellar structures formed on the admixture of a non-ionic surfactant, cholesterol and phosphate with subsequent hydration in aqueous media. Niosomes belongs to novel drug delivery system which offers a large number of advantages over other conventional and vesicular delivery systems. Namely they are the targeted drug delivery system which showing reduction of dose, stability and compatibility of non-ionic surfactants, easy modification, delayed clearance, suitability for a wide range of Active Pharmaceutical Agents.

  2. Drugs that target pathogen public goods are robust against evolved drug resistance.

    Science.gov (United States)

    Pepper, John W

    2012-11-01

    Pathogen drug resistance is a central problem in medicine and public health. It arises through somatic evolution, by mutation and selection among pathogen cells within a host. Here, we examine the hypothesis that evolution of drug resistance could be reduced by developing drugs that target the secreted metabolites produced by pathogen cells instead of directly targeting the cells themselves. Using an agent-based computational model of an evolving population of pathogen cells, we test this hypothesis and find support for it. We also use our model to explain this effect within the framework of standard evolutionary theory. We find that in our model, the drugs most robust against evolved drug resistance are those that target the most widely shared external products, or 'public goods', of pathogen cells. We also show that these drugs exert a weak selective pressure for resistance because they create only a weak correlation between drug resistance and cell fitness. The same principles apply to design of vaccines that are robust against vaccine escape. Because our theoretical results have crucial practical implications, they should be tested by empirical experiments.

  3. Ultrasound effects on brain-targeting mannosylated liposomes: in vitro and blood–brain barrier transport investigations

    Directory of Open Access Journals (Sweden)

    Zidan AS

    2015-07-01

    Full Text Available Ahmed S Zidan,1,2 Hibah Aldawsari1 1Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia; 2Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt Abstract: Delivering drugs to intracerebral regions can be accomplished by improving the capacity of transport through blood–brain barrier. Using sertraline as model drug for brain targeting, the current study aimed at modifying its liposomal vesicles with mannopyranoside. Box-Behnken design was employed to statistically optimize the ultrasound parameters, namely ultrasound amplitude, time, and temperature, for maximum mannosylation capacity, sertraline entrapment, and surface charge while minimizing vesicular size. Moreover, in vitro blood–brain barrier transport model was established to assess the transendothelial capacity of the optimized mannosylated vesicles. Results showed a dependence of vesicular size, mannosylation capacity, and sertraline entrapment on cavitation and bubble implosion events that were related to ultrasound power amplitude, temperature. However, short ultrasound duration was required to achieve >90% mannosylation with nanosized vesicles (<200 nm of narrow size distribution. Optimized ultrasound parameters of 65°C, 27%, and 59 seconds for ultrasound temperature, amplitude, and time were elucidated to produce 81.1%, 46.6 nm, and 77.6% sertraline entrapment, vesicular size, and mannosylation capacity, respectively. Moreover, the transendothelial ability was significantly increased by 2.5-fold by mannosylation through binding with glucose transporters. Hence, mannosylated liposomes processed by ultrasound could be a promising approach for manufacturing and scale-up of brain-targeting liposomes. Keywords: CNS delivery, sizing, lipid based formulations, quality by design, sertraline hydrochloride

  4. Bacterial Transcription as a Target for Antibacterial Drug Development.

    Science.gov (United States)

    Ma, Cong; Yang, Xiao; Lewis, Peter J

    2016-03-01

    Transcription, the first step of gene expression, is carried out by the enzyme RNA polymerase (RNAP) and is regulated through interaction with a series of protein transcription factors. RNAP and its associated transcription factors are highly conserved across the bacterial domain and represent excellent targets for broad-spectrum antibacterial agent discovery. Despite the numerous antibiotics on the market, there are only two series currently approved that target transcription. The determination of the three-dimensional structures of RNAP and transcription complexes at high resolution over the last 15 years has led to renewed interest in targeting this essential process for antibiotic development by utilizing rational structure-based approaches. In this review, we describe the inhibition of the bacterial transcription process with respect to structural studies of RNAP, highlight recent progress toward the discovery of novel transcription inhibitors, and suggest additional potential antibacterial targets for rational drug design.

  5. New and emerging immune-targeted drugs for the treatment of multiple sclerosis.

    Science.gov (United States)

    Palmer, Alan M

    2014-07-01

    Multiple sclerosis (MS) is a neurodegenerative disease with a major inflammatory component that constitutes the most common progressive and disabling neurological condition in young adults. Injectable immunomodulatory medicines such as interferon drugs and glatiramer acetate have dominated the MS market for over the past two decades but this situation is set to change. This is because of: (i) patent expirations, (ii) the introduction of natalizumab, which targets the interaction between leukocytes and the blood-CNS barrier, (iii) the launch of three oral immunomodulatory drugs (fingolimod, dimethyl fumarate and teriflunomide), with another (laquinimod) under regulatory review and (iv) a number of immunomodulatory monoclonal antibodies (alemtuzumab, daclizumab and ocrelizumab) about to enter the market. Current and emerging medicines are reviewed and their impact on people with MS considered.

  6. Targeted Drug Delivery to the Brain by MRI-guided Focused Ultrasound

    Science.gov (United States)

    Treat, Lisa Hsu; McDannold, Nathan; Vykhodtseva, Natalia; Zhang, Yongzhi; Tam, Karen; Hynynen, Kullervo

    2006-05-01

    The effect of focused ultrasound on the absorption of liposome-encapsulated doxorubicin in the brain was investigated. By applying focused ultrasound in the presence of microbubble ultrasound contrast agent, we achieved targeted drug delivery to the brain in vivo. Tissue drug concentrations in sonicated brain corresponded with cytotoxic levels measured in various human tumors and were significantly different from those measured in unexposed contralateral control samples (p ⩽ 0.02). In addition, increased MR signal enhancement at the focal location on contrast-enhanced T1-weighted fast spin echo images correlated with increased penetration of doxorubicin into brain tissue (r = 0.85), indicating the potential of MRI to be used as an indicator of blood-brain barrier permeability during treatment. Further investigation is required to evaluate the efficacy of this technique and to optimize its parameters for clinical application.

  7. Stroke and Drug Delivery--In Vitro Models of the Ischemic Blood-Brain Barrier

    DEFF Research Database (Denmark)

    Tornabene, Erica; Brodin, Birger

    2016-01-01

    Stroke is a major cause of death and disability worldwide. Both cerebral hypoperfusion and focal cerebral infarcts are caused by a reduction of blood flow to the brain, leading to stroke and subsequent brain damage. At present, only few medical treatments of stroke are available, with the Food...... and Drug Administration-approved tissue plasminogen activator for treatment of acute ischemic stroke being the most prominent example. A large number of potential drug candidates for treatment of ischemic brain tissue have been developed and subsequently failed in clinical trials. A deeper understanding...... of permeation pathways across the barrier in ischemic and postischemic brain endothelium is important for development of new medical treatments. The blood-brain barrier, that is, the endothelial monolayer lining the brain capillaries, changes properties during an ischemic event. In vitro models of the blood-brain...

  8. Approaches of targeting Rho GTPases in cancer drug discovery

    Science.gov (United States)

    Lin, Yuan; Zheng, Yi

    2016-01-01

    Introduction Rho GTPases are master regulators of actomyosin structure and dynamics and play pivotal roles in a variety of cellular processes including cell morphology, gene transcription, cell cycle progression and cell adhesion. Because aberrant Rho GTPase signaling activities are widely associated with human cancer, key components of Rho GTPase signaling pathways have attracted increasing interest as potential therapeutic targets. Similar to Ras, Rho GTPases themselves were, until recently, deemed “undruggable” because of structure-function considerations. Several approaches to interfere with Rho GTPase signaling have been explored and show promise as new ways for tackling cancer cells. Areas covered This review focuses on the recent progress in targeting the signaling activities of three prototypical Rho GTPases, i.e. RhoA, Rac1, and Cdc42. The authors describe the involvement of these Rho GTPases, their key regulators and effectors in cancer. Furthermore, the authors discuss the current approaches for rationally targeting aberrant Rho GTPases along their signaling cascades, upstream and downstream of Rho GTPases and posttranslational modifications at a molecular level. Expert opinion To date, while no clinically effective drugs targeting Rho GTPase signaling for cancer treatment are available, tool compounds and lead drugs that pharmacologically inhibit Rho GTPase pathways have shown promise. Small molecule inhibitors targeting Rho GTPase signaling may add new treatment options for future precision cancer therapy, particularly in combination with other anti-cancer agents. PMID:26087073

  9. Ion channels as drug targets in central nervous system disorders.

    Science.gov (United States)

    Waszkielewicz, A M; Gunia, A; Szkaradek, N; Słoczyńska, K; Krupińska, S; Marona, H

    2013-01-01

    Ion channel targeted drugs have always been related with either the central nervous system (CNS), the peripheral nervous system, or the cardiovascular system. Within the CNS, basic indications of drugs are: sleep disorders, anxiety, epilepsy, pain, etc. However, traditional channel blockers have multiple adverse events, mainly due to low specificity of mechanism of action. Lately, novel ion channel subtypes have been discovered, which gives premises to drug discovery process led towards specific channel subtypes. An example is Na(+) channels, whose subtypes 1.3 and 1.7-1.9 are responsible for pain, and 1.1 and 1.2 - for epilepsy. Moreover, new drug candidates have been recognized. This review is focusing on ion channels subtypes, which play a significant role in current drug discovery and development process. The knowledge on channel subtypes has developed rapidly, giving new nomenclatures of ion channels. For example, Ca(2+)s channels are not any more divided to T, L, N, P/Q, and R, but they are described as Ca(v)1.1-Ca(v)3.3, with even newer nomenclature α1A-α1I and α1S. Moreover, new channels such as P2X1-P2X7, as well as TRPA1-TRPV1 have been discovered, giving premises for new types of analgesic drugs.

  10. Drug delivery application of extracellular vesicles; insight into production, drug loading, targeting, and pharmacokinetics

    Directory of Open Access Journals (Sweden)

    Masaharu Somiya

    2017-01-01

    Full Text Available Extracellular vesicles (EVs are secreted from any types of cells and shuttle between donor cells and recipient cells. Since EVs deliver their cargos such as proteins, nucleic acids, and other molecules for intercellular communication, they are considered as novel mode of drug delivery vesicles. EVs possess advantages such as inherent targeting ability and non-toxicity over conventional nanocarriers. Much efforts have so far been made for the application of EVs as a drug delivery carrier, however, basic techniques, such as mass-scale production, drug loading, and engineering of EVs are still limited. In this review, we summarize following four points. First, recent progress on the production method for EVs is described. Second, current techniques of drug loading methods are summarized. Third, targeting approach to specifically deliver cargo molecules for diseased sites by engineered EVs is discussed. Lastly, strategies to control pharmacokinetics and improve biodistribution are discussed.

  11. Decorating Nanoparticle Surface for Targeted Drug Delivery: Opportunities and Challenges

    Directory of Open Access Journals (Sweden)

    Zhiqiang Shen

    2016-03-01

    Full Text Available The size, shape, stiffness (composition and surface properties of nanoparticles (NPs have been recognized as key design parameters for NP-mediated drug delivery platforms. Among them, the surface functionalization of NPs is of great significance for targeted drug delivery. For instance, targeting moieties are covalently coated on the surface of NPs to improve their selectively and affinity to cancer cells. However, due to a broad range of possible choices of surface decorating molecules, it is difficult to choose the proper one for targeted functions. In this work, we will review several representative experimental and computational studies in selecting the proper surface functional groups. Experimental studies reveal that: (1 the NPs with surface decorated amphiphilic polymers can enter the cell interior through penetrating pathway; (2 the NPs with tunable stiffness and identical surface chemistry can be selectively accepted by the diseased cells according to their stiffness; and (3 the NPs grafted with pH-responsive polymers can be accepted or rejected by the cells due to the local pH environment. In addition, we show that computer simulations could be useful to understand the detailed physical mechanisms behind these phenomena and guide the design of next-generation NP-based drug carriers with high selectivity, affinity, and low toxicity. For example, the detailed free energy analysis and molecular dynamics simulation reveals that amphiphilic polymer-decorated NPs can penetrate into the cell membrane through the “snorkeling” mechanism, by maximizing the interaction energy between the hydrophobic ligands and lipid tails. We anticipate that this work will inspire future studies in the design of environment-responsive NPs for targeted drug delivery.

  12. New alginic acid–atenolol microparticles for inhalatory drug targeting

    Energy Technology Data Exchange (ETDEWEB)

    Ceschan, Nazareth Eliana; Bucalá, Verónica [Planta Piloto de Ingeniería Química (PLAPIQUI), CONICET, Universidad Nacional del Sur (UNS), Camino La Carrindanga Km 7, 8000 Bahía Blanca (Argentina); Departamento de Ingeniería Química, UNS, Avenida Alem 1253, 8000 Bahía Blanca (Argentina); Ramírez-Rigo, María Verónica, E-mail: vrrigo@plapiqui.edu.ar [Planta Piloto de Ingeniería Química (PLAPIQUI), CONICET, Universidad Nacional del Sur (UNS), Camino La Carrindanga Km 7, 8000 Bahía Blanca (Argentina); Departamento de Biología, Bioquímica y Farmacia, UNS, San Juan 670, 8000 Bahía Blanca (Argentina)

    2014-08-01

    The inhalatory route allows drug delivery for local or systemic treatments in a noninvasively way. The current tendency of inhalable systems is oriented to dry powder inhalers due to their advantages in terms of stability and efficiency. In this work, microparticles of atenolol (AT, basic antihypertensive drug) and alginic acid (AA, acid biocompatible polyelectrolyte) were obtained by spray drying. Several formulations, varying the relative composition AT/AA and the total solid content of the atomized dispersions, were tested. The powders were characterized by: Fourier Transform Infrared Spectroscopy, Differential Scanning Calorimetry and Powder X-ray Diffraction, while also the following properties were measured: drug load efficiency, flow properties, particles size and density, moisture content, hygroscopicity and morphology. The ionic interaction between AA and AT was demonstrated, then the new chemical entity could improve the drug targeting to the respiratory membrane and increase its time residence due to the mucoadhesive properties of the AA polymeric chains. Powders exhibited high load efficiencies, low moisture contents, adequate mean aerodynamic diameters and high cumulative fraction of respirable particles (lower than 10 μm). - Highlights: • Novel particulate material to target atenolol to the respiratory membrane was developed. • Crumbled microparticles were obtained by spray drying of alginic–atenolol dispersions. • Ionic interaction between alginic acid and atenolol was demonstrated in the product. • Amorphous solids with low moisture content and high load efficiency were produced. • Relationships between the feed formulation and the product characteristics were found.

  13. Integral membrane pyrophosphatases: a novel drug target for human pathogens?

    Directory of Open Access Journals (Sweden)

    Henri Xhaard

    2016-03-01

    Full Text Available Membrane-integral pyrophosphatases (mPPases are found in several human pathogens, including Plasmodium species, the protozoan parasites that cause malaria. These enzymes hydrolyze pyrophosphate and couple this to the pumping of ions (H+ and/or Na+ across a membrane to generate an electrochemical gradient. mPPases play an important role in stress tolerance in plants, protozoan parasites, and bacteria. The solved structures of mPPases from Vigna radiata and Thermotoga maritima open the possibility of using structure-based drug design to generate novel molecules or repurpose known molecules against this enzyme. Here, we review the current state of knowledge regarding mPPases, focusing on their structure, the proposed mechanism of action, and their role in human pathogens. We also summarize different methodologies in structure-based drug design and propose an example region on the mPPase structure that can be exploited by these structure-based methods for drug targeting. Since mPPases are not found in animals and humans, this enzyme is a promising potential drug target against livestock and human pathogens.

  14. Self-Assembling Peptide Amphiphiles for Targeted Drug Delivery

    Science.gov (United States)

    Moyer, Tyson

    The systemic delivery of therapeutics is currently limited by off-target side effects and poor drug uptake into the cells that need to be treated. One way to circumvent these issues is to target the delivery and release of therapeutics to the desired location while limiting systemic toxicity. Using self-assembling peptide amphiphiles (PAs), this work has investigated supramolecular nanostructures for the development of targeted therapies. Specifically, the research has focused on the interrelationships between presentation of targeting moeities and the control of nanostructure morphology in the context of systemic delivery for targeting cancer and vascular injuries. The self-assembly region of the PA was systematically altered to achieve control of nanostructure widths, from 100 nm to 10 nm, by the addition of valine-glutamic acid dimers into the chemical structure, subsequently increasing the degree of nanostructure twist. For the targeting of tumors, a homing PA was synthesized to include a dimeric, cyclic peptide sequence known to target the cancer-specific, death receptor 5 (DR5) and initiate apoptosis through the oligomerization of DR5. This PA presented a multivalent display of DR5-binding peptides, resulting in improved binding affinity measured by surface plasmon resonance. The DR5-targeting PA also showed enhanced efficacy in both in vitro and in vivo tumor models relative to non-targeted controls. Alternative modifications to the PA-based antitumor therapies included the use of a cytotoxic, membrane-lytic PA coassembled with a pegylated PA, which showed enhanced biodistribution and in vivo activity after coassembly. The functionalization of the hydrophobic core was also accomplished through the encapsulation of the chemotherapy camptothecin, which was shown to be an effective treatment in vivo. Additionally, a targeted PA nanostructure was designed to bind to the site of vascular intervention by targeting collagen IV. Following balloon angioplasty

  15. Nano carriers for drug transport across the blood-brain barrier.

    Science.gov (United States)

    Li, Xinming; Tsibouklis, John; Weng, Tingting; Zhang, Buning; Yin, Guoqiang; Feng, Guangzhu; Cui, Yingde; Savina, Irina N; Mikhalovska, Lyuba I; Sandeman, Susan R; Howel, Carol A; Mikhalovsky, Sergey V

    2017-01-01

    Effective therapy lies in achieving a therapeutic amount of drug to the proper site in the body and then maintaining the desired drug concentration for a sufficient time interval to be clinically effective for treatment. The blood-brain barrier (BBB) hinders most drugs from entering the central nervous system (CNS) from the blood stream, leading to the difficulty of delivering drugs to the brain via the circulatory system for the treatment, diagnosis and prevention of brain diseases. Several brain drug delivery approaches have been developed, such as intracerebral and intracerebroventricular administration, intranasal delivery and blood-to-brain delivery, as a result of transient BBB disruption induced by biological, chemical or physical stimuli such as zonula occludens toxin, mannitol, magnetic heating and ultrasound, but these approaches showed disadvantages of being dangerous, high cost and unsuitability for most brain diseases and drugs. The strategy of vector-mediated blood-to-brain delivery, which involves improving BBB permeability of the drug-carrier conjugate, can minimize side effects, such as being submicrometre objects that behave as a whole unit in terms of their transport and properties, nanomaterials, are promising carrier vehicles for direct drug transport across the intact BBB as a result of their potential to enter the brain capillary endothelial cells by means of normal endocytosis and transcytosis due to their small size, as well as their possibility of being functionalized with multiple copies of the drug molecule of interest. This review provids a concise discussion of nano carriers for drug transport across the intact BBB, various forms of nanomaterials including inorganic/solid lipid/polymeric nanoparticles, nanoemulsions, quantum dots, nanogels, liposomes, micelles, dendrimers, polymersomes and exosomes are critically evaluated, their mechanisms for drug transport across the BBB are reviewed, and the future directions of this area are fully

  16. Reprofiled drug targets ancient protozoans: drug discovery for parasitic diarrheal diseases.

    Science.gov (United States)

    Debnath, Anjan; Ndao, Momar; Reed, Sharon L

    2013-01-01

    Recently, we developed a novel automated, high throughput screening (HTS) methodology for the anaerobic intestinal parasite Entamoeba histolytica. We validated this HTS platform by screening a chemical library containing US Food and Drug Administration (FDA)-approved drugs and bioactive compounds. We identified an FDA-approved drug, auranofin, as most active against E. histolytica both in vitro and in vivo. Our cell culture and animal studies indicated that thioredoxin reductase, an enzyme involved in reactive oxygen species detoxification, was the target for auranofin in E. histolytica. Here, we discuss the rationale for drug development for three parasites which are major causes of diarrhea worldwide, E. histolytica, Giardia lamblia and Cryptosporidium parvum and extend our current finding of antiparasitic activity of auranofin to Entamoeba cysts, G. lamblia and C. parvum. These studies support the use of HTS assays and reprofiling FDA-approved drugs for new therapy for neglected tropical diseases.

  17. Prediction of off-target drug effects through data fusion.

    Science.gov (United States)

    Yera, Emmanuel R; Cleves, Ann E; Jain, Ajay N

    2014-01-01

    We present a probabilistic data fusion framework that combines multiple computational approaches for drawing relationships between drugs and targets. The approach has special relevance to identifying surprising unintended biological targets of drugs. Comparisons between molecules are made based on 2D topological structural considerations, based on 3D surface characteristics, and based on English descriptions of clinical effects. Similarity computations within each modality were transformed into probability scores. Given a new molecule along with a set of molecules sharing some biological effect, a single score based on comparison to the known set is produced, reflecting either 2D similarity, 3D similarity, clinical effects similarity or their combination. The methods were validated within acurated structural pharmacology database (SPDB) and further tested by blind application to data derived from the ChEMBL database. For prediction of off-target effects, 3D-similarity performed best as a single modality, but combining all methods produced performance gains. Striking examples of structurally surprising off-target predictions are presented.

  18. p21-activated kinase family: promising new drug targets

    Directory of Open Access Journals (Sweden)

    Huynh N

    2015-05-01

    Full Text Available Nhi Huynh, Hong He Department of Surgery, University of Melbourne, Austin Health, Melbourne, VIC, Australia Abstract: The p21-activated kinase (PAK family of serine/threonine protein kinases are downstream effectors of the Rho family of GTPases. PAKs are frequently upregulated in human diseases, including various cancers, and their overexpression correlates with disease progression. Current research findings have validated important roles for PAKs in cell proliferation, survival, gene transcription, transformation, and cytoskeletal remodeling. PAKs are shown to act as a converging node for many signaling pathways that regulate these cellular processes. Therefore, PAKs have emerged as attractive targets for treatment of disease. This review discusses the physiological and pathological roles of PAKs, validation of PAKs as new promising drug targets, and current challenges and advances in the development of PAK-targeted anticancer therapy, with a focus on PAKs and human cancers. Keywords: p21-activated kinase, cancer, inhibitor

  19. Salinomycin as a Drug for Targeting Human Cancer Stem Cells

    Directory of Open Access Journals (Sweden)

    Cord Naujokat

    2012-01-01

    Full Text Available Cancer stem cells (CSCs represent a subpopulation of tumor cells that possess self-renewal and tumor initiation capacity and the ability to give rise to the heterogenous lineages of malignant cells that comprise a tumor. CSCs possess multiple intrinsic mechanisms of resistance to chemotherapeutic drugs, novel tumor-targeted drugs, and radiation therapy, allowing them to survive standard cancer therapies and to initiate tumor recurrence and metastasis. Various molecular complexes and pathways that confer resistance and survival of CSCs, including expression of ATP-binding cassette (ABC drug transporters, activation of the Wnt/β-catenin, Hedgehog, Notch and PI3K/Akt/mTOR signaling pathways, and acquisition of epithelial-mesenchymal transition (EMT, have been identified recently. Salinomycin, a polyether ionophore antibiotic isolated from Streptomyces albus, has been shown to kill CSCs in different types of human cancers, most likely by interfering with ABC drug transporters, the Wnt/β-catenin signaling pathway, and other CSC pathways. Promising results from preclinical trials in human xenograft mice and a few clinical pilote studies reveal that salinomycin is able to effectively eliminate CSCs and to induce partial clinical regression of heavily pretreated and therapy-resistant cancers. The ability of salinomycin to kill both CSCs and therapy-resistant cancer cells may define the compound as a novel and an effective anticancer drug.

  20. Development of high drug-loading nanomicelles targeting steroids to the brain.

    Science.gov (United States)

    Zheng, Sijia; Xie, Yanqi; Li, Yuan; Li, Ling; Tian, Ning; Zhu, Wenbo; Yan, Guangmei; Wu, Chuanbin; Hu, Haiyan

    2014-01-01

    The objective of this research was to develop and evaluate high drug-loading ligand-modified nanomicelles to deliver a steroidal compound to the brain. YC1 (5α-cholestane-24-methylene-3β, 5α, 6β, 19-tetraol), with poor solubility and limited access to the brain, for the first time, has been proved to be an effective neuroprotective steroid by our previous studies. Based on the principle of 'like dissolves like', cholesterol, which shares the same steroidal parent nucleus with YC1, was selected to react with sodium alginate, producing amphiphilic sodium alginate- cholesterol derivatives (SACDs). To increase the grafting ratio and drug loading, cholesterol was converted to cholesteryl chloroformate, for the first time, before reacting with sodium alginate. Further, lactoferrin was conjugated on SACDs to provide lactoferrin-SACDs (Lf-SACD), which was established by immune electron microscopy (IEM) and self-assembled into brain-targeting nanomicelles. These nanomicelles were negatively charged and spherical in nature, with an average size of drug loading was increased due to the cholesteryl inner cores of the nanomicelles, and the higher the grafting ratio was, the lower the critical micelle concentration (CMC) value of SACD, and the higher drug loading. The in vitro drug release, studied by bulk-equilibrium dialysis in 20 mL of 6% hydroxypropyl-β-cyclodextrin solution at 37°C, indicated a prolonged release profile. The YC1 concentration in mouse brain delivered by lactoferrin-modified nanomicelles was higher than in those delivered by non-modified nanomicelles and YC1 solution. The unique brain-targeting nanomicelle system may provide a promising carrier to deliver hydrophobic drugs across the blood-brain barrier for the treatment of brain diseases.

  1. Internalized compartments encapsulated nanogels for targeted drug delivery

    Science.gov (United States)

    Yu, Jicheng; Zhang, Yuqi; Sun, Wujin; Wang, Chao; Ranson, Davis; Ye, Yanqi; Weng, Yuyan; Gu, Zhen

    2016-04-01

    Drug delivery systems inspired by natural particulates hold great promise for targeted cancer therapy. An endosome formed by internalization of plasma membrane has a massive amount of membrane proteins and receptors on the surface, which is able to specifically target the homotypic cells. Herein, we describe a simple method to fabricate an internalized compartments encapsulated nanogel with endosome membrane components (EM-NG) from source cancer cells. Following intracellular uptake of methacrylated hyaluronic acid (m-HA) adsorbed SiO2/Fe3O4 nanoparticles encapsulating a crosslinker and a photoinitiator, EM-NG was readily prepared through in situ crosslinking initiated under UV irradiation after internalization. The resulting nanogels loaded with doxorubicin (DOX) displayed enhanced internalization efficiency to the source cells through a specific homotypic affinity in vitro. However, when treated with the non-source cells, the EM-NGs exhibited insignificant difference in therapeutic efficiency compared to a bare HA nanogel with DOX. This study illustrates the potential of utilizing an internalized compartments encapsulated formulation for targeted cancer therapy, and offers guidelines for developing a natural particulate-inspired drug delivery system.Drug delivery systems inspired by natural particulates hold great promise for targeted cancer therapy. An endosome formed by internalization of plasma membrane has a massive amount of membrane proteins and receptors on the surface, which is able to specifically target the homotypic cells. Herein, we describe a simple method to fabricate an internalized compartments encapsulated nanogel with endosome membrane components (EM-NG) from source cancer cells. Following intracellular uptake of methacrylated hyaluronic acid (m-HA) adsorbed SiO2/Fe3O4 nanoparticles encapsulating a crosslinker and a photoinitiator, EM-NG was readily prepared through in situ crosslinking initiated under UV irradiation after internalization. The

  2. Iron Acquisition Pathways as Targets for Antitubercular Drugs.

    Science.gov (United States)

    Meneghetti, Fiorella; Villa, Stefania; Gelain, Arianna; Barlocco, Daniela; Chiarelli, Laurent Roberto; Pasca, Maria Rosalia; Costantino, Luca

    2016-01-01

    Tuberculosis nowadays ranks as the second leading cause of death from an infectious disease worldwide. In the last twenty years, this disease has again started to spread mainly for the appearance of multi-drug resistant forms. Therefore, new targets are needed to address the growing emergence of bacterial resistance and for antitubercular drug development. Efficient iron acquisition is crucial for the pathogenesis of Mycobacterium tuberculosis, because it serves as cofactor in many essential biological processes, including DNA biosynthesis and cellular respiration. Bacteria acquire iron chelating non-heme iron from the host using the siderophore mycobactins and carboxymycobactins and by the uptake of heme iron released by damaged red blood cells, through several acquisition systems. Drug discovery focused its efforts on the inhibition of MbtI and MbtA, which are are two enzymes involved in the mycobactin biosynthetic pathway. In particular, MbtI inhibitors have been studied in vitro, while MbtA inhibitors showed activity also in infected mice. Another class of compounds, MmpL3 inhibitors, showed antitubercular activity in vitro and in vivo, but their mechanism of action seems to be off-target. Some compounds inhibiting 4'-phosphopantetheinyl transferase were discovered but not tested on in vivo assays. The available data reported in this study based on inhibitors and gene deletion studies, suggest that targeting iron acquisition systems could be considered a promising antitubercular strategy. Due to their redundancy, the relative importance of each pathway for Mycobacterium tuberculosis survival has still to be determined. Thus, in vivo studies with new, potent and specific inhibitors are needed to highlight target selection.

  3. Encapsulation of methotrexate loaded magnetic microcapsules for magnetic drug targeting and controlled drug release

    Energy Technology Data Exchange (ETDEWEB)

    Chakkarapani, Prabu [Department of Pharmaceutical Technology & Centre for Excellence in Nanobio Translational Research, Anna University, Bharathidasan Institute of Technology Campus, Tiruchirappalli 620024, Tamil Nadu (India); Subbiah, Latha, E-mail: lathasuba2010@gmail.com [Department of Pharmaceutical Technology & Centre for Excellence in Nanobio Translational Research, Anna University, Bharathidasan Institute of Technology Campus, Tiruchirappalli 620024, Tamil Nadu (India); Palanisamy, Selvamani; Bibiana, Arputha [Department of Pharmaceutical Technology & Centre for Excellence in Nanobio Translational Research, Anna University, Bharathidasan Institute of Technology Campus, Tiruchirappalli 620024, Tamil Nadu (India); Ahrentorp, Fredrik; Jonasson, Christian; Johansson, Christer [Acreo Swedish ICT AB, Arvid Hedvalls backe 4, SE-411 33 Göteborg (Sweden)

    2015-04-15

    We report on the development and evaluation of methotrexate magnetic microcapsules (MMC) for targeted rheumatoid arthritis therapy. Methotrexate was loaded into CaCO{sub 3}-PSS (poly (sodium 4-styrenesulfonate)) doped microparticles that were coated successively with poly (allylamine hydrochloride) and poly (sodium 4-styrenesulfonate) by layer-by-layer technique. Ferrofluid was incorporated between the polyelectrolyte layers. CaCO{sub 3}-PSS core was etched by incubation with EDTA yielding spherical MMC. The MMC were evaluated for various physicochemical, pharmaceutical parameters and magnetic properties. Surface morphology, crystallinity, particle size, zeta potential, encapsulation efficiency, loading capacity, drug release pattern, release kinetics and AC susceptibility studies revealed spherical particles of ~3 µm size were obtained with a net zeta potential of +24.5 mV, 56% encapsulation and 18.6% drug loading capacity, 96% of cumulative drug release obeyed Hixson-Crowell model release kinetics. Drug excipient interaction, surface area, thermal and storage stability studies for the prepared MMC was also evaluated. The developed MMC offer a promising mode of targeted and sustained release drug delivery for rheumatoid arthritis therapy. - Highlights: • Development of methotrexate magnetic microcapsules (MMC) by layer-by-layer method. • Characterization of physicochemical, pharmaceutical and magnetic properties of MMC. • Multiple layers of alternative polyelectrolytes prolongs methotrexate release time. • MMC is capable for targeted and sustained release rheumatoid arthritis therapy.

  4. Nanocomplexes for gene therapy of respiratory diseases: Targeting and overcoming the mucus barrier.

    Science.gov (United States)

    Di Gioia, Sante; Trapani, Adriana; Castellani, Stefano; Carbone, Annalucia; Belgiovine, Giuliana; Craparo, Emanuela Fabiola; Puglisi, Giovanni; Cavallaro, Gennara; Trapani, Giuseppe; Conese, Massimo

    2015-10-01

    Gene therapy, i.e. the delivery and expression of therapeutic genes, holds great promise for congenital and acquired respiratory diseases. Non-viral vectors are less toxic and immunogenic than viral vectors, although they are characterized by lower efficiency. However, they have to overcome many barriers, including inflammatory and immune mediators and cells. The respiratory and airway epithelial cells, the main target of these vectors, are coated with a layer of mucus, which hampers the effective reaching of gene therapy vectors carrying either plasmid DNA or small interfering RNA. This barrier is thicker in many lung diseases, such as cystic fibrosis. This review summarizes the most important advancements in the field of non-viral vectors that have been achieved with the use of nanoparticulate (NP) systems, composed either of polymers or lipids, in the lung gene delivery. In particular, different strategies of targeting of respiratory and airway lung cells will be described. Then, we will focus on the two approaches that attempt to overcome the mucus barrier: coating of the nanoparticulate system with poly(ethylene glycol) and treatment with mucolytics. Our conclusions are: 1) Ligand and physical targeting can direct therapeutic gene expression in specific cell types in the respiratory tract; 2) Mucopenetrating NPs are endowed with promising features to be useful in treating respiratory diseases and should be now advanced in pre-clinical trials. Finally, we discuss the development of such polymer- and lipid-based NPs in the context of in vitro and in vivo disease models, such as lung cancer, as well as in clinical trials.

  5. Application of RNAi to Genomic Drug Target Validation in Schistosomes.

    Directory of Open Access Journals (Sweden)

    Alessandra Guidi

    2015-05-01

    Full Text Available Concerns over the possibility of resistance developing to praziquantel (PZQ, has stimulated efforts to develop new drugs for schistosomiasis. In addition to the development of improved whole organism screens, the success of RNA interference (RNAi in schistosomes offers great promise for the identification of potential drug targets to initiate drug discovery. In this study we set out to contribute to RNAi based validation of putative drug targets. Initially a list of 24 target candidates was compiled based on the identification of putative essential genes in schistosomes orthologous of C. elegans essential genes. Knockdown of Calmodulin (Smp_026560.2 (Sm-Calm, that topped this list, produced a phenotype characterised by waves of contraction in adult worms but no phenotype in schistosomula. Knockdown of the atypical Protein Kinase C (Smp_096310 (Sm-aPKC resulted in loss of viability in both schistosomula and adults and led us to focus our attention on other kinase genes that were identified in the above list and through whole organism screening of known kinase inhibitor sets followed by chemogenomic evaluation. RNAi knockdown of these kinase genes failed to affect adult worm viability but, like Sm-aPKC, knockdown of Polo-like kinase 1, Sm-PLK1 (Smp_009600 and p38-MAPK, Sm-MAPK p38 (Smp_133020 resulted in an increased mortality of schistosomula after 2-3 weeks, an effect more marked in the presence of human red blood cells (hRBC. For Sm-PLK-1 the same effects were seen with the specific inhibitor, BI2536, which also affected viable egg production in adult worms. For Sm-PLK-1 and Sm-aPKC the in vitro effects were reflected in lower recoveries in vivo. We conclude that the use of RNAi combined with culture with hRBC is a reliable method for evaluating genes important for larval development. However, in view of the slow manifestation of the effects of Sm-aPKC knockdown in adults and the lack of effects of Sm-PLK-1 and Sm-MAPK p38 on adult viability

  6. Pleiotropic effects of statins: new therapeutic targets in drug design.

    Science.gov (United States)

    Bedi, Onkar; Dhawan, Veena; Sharma, P L; Kumar, Puneet

    2016-07-01

    The HMG Co-enzyme inhibitors and new lipid-modifying agents expand their new therapeutic target options in the field of medical profession. Statins have been described as the most effective class of drugs to reduce serum cholesterol levels. Since the discovery of the first statin nearly 30 years ago, these drugs have become the main therapeutic approach to lower cholesterol levels. The present scientific research demonstrates numerous non-lipid modifiable effects of statins termed as pleiotropic effects of statins, which could be beneficial for the treatment of various devastating disorders. The most important positive effects of statins are anti-inflammatory, anti-proliferative, antioxidant, immunomodulatory, neuroprotective, anti-diabetes, and antithrombotic, improving endothelial dysfunction and attenuating vascular remodeling besides many others which are discussed under the scope of this review. In particular, inhibition of Rho and its downstream target, Rho-associated coiled-coil-containing protein kinase (ROCK), and their agonistic action on peroxisome proliferator-activated receptors (PPARs) can be viewed as the principle mechanisms underlying the pleiotropic effects of statins. With gradually increasing knowledge of new therapeutic targets of statins, their use has also been advocated in chronic inflammatory disorders for example rheumatoid arthritis (RA) and in systemic lupus erythematosus (SLE). In the scope of review, we highlight statins and their pleiotropic effects with reference to their harmful and beneficial effects as a novel approach for their use in the treatment of devastating disorders. Graphical abstract Pleiotropic effect of statins.

  7. Dual responsive PNIPAM–chitosan targeted magnetic nanopolymers for targeted drug delivery

    Energy Technology Data Exchange (ETDEWEB)

    Yadavalli, Tejabhiram, E-mail: tejabhiram@gmail.com [Nanotechnology Research Centre, SRM University, Chennai 603203 (India); Ramasamy, Shivaraman [Nanotechnology Research Centre, SRM University, Chennai 603203 (India); School of Physics, The University of Western Australia, 35 Stirling Hwy, Crawley, WA 6009 (Australia); Chandrasekaran, Gopalakrishnan; Michael, Isaac; Therese, Helen Annal [Nanotechnology Research Centre, SRM University, Chennai 603203 (India); Chennakesavulu, Ramasamy [Department of Pharmacy practice, SRM College of Pharmacy, Chennai 603203 (India)

    2015-04-15

    A dual stimuli sensitive magnetic hyperthermia based drug delivery system has been developed for targeted cancer treatment. Thermosensitive amine terminated poly-N-isopropylacrylamide complexed with pH sensitive chitosan nanoparticles was prepared as the drug carrier. Folic acid and fluorescein were tagged to the nanopolymer complex via N-hydroxysuccinimide and ethyl-3-(3-dimethylaminopropyl)carbodiimide reaction to form a fluorescent and cancer targeting magnetic carrier system. The formation of the polymer complex was confirmed using infrared spectroscopy. Gadolinium doped nickel ferrite nanoparticles prepared by a hydrothermal method were encapsulated in the polymer complex to form a magnetic drug carrier system. The proton relaxation studies on the magnetic carrier system revealed a 200% increase in the T1 proton relaxation rate. These magnetic carriers were loaded with curcumin using solvent evaporation method with a drug loading efficiency of 86%. Drug loaded nanoparticles were tested for their targeting and anticancer properties on four cancer cell lines with the help of MTT assay. The results indicated apoptosis of cancer cell lines within 3 h of incubation. - Highlights: • The use of gadolinium doped nickel ferrite with the suggested doping level. • The use of PNIPMA–chitosan polymer with folic acid and fluorescein as a drug carrier complex. • Magnetic hyperthermia studies of gadolinium doped nickel ferrites are being reported for the first time. • Proton relaxivity studies which indicate the MRI contrasting properties on the reported system are new. • Use of curcumin, a hydrophobic Indian spice as a cancer killing agent inside the reported magnetic polymer complex.

  8. Transporter protein and drug-conjugated gold nanoparticles capable of bypassing the blood-brain barrier

    Science.gov (United States)

    Zhang, Yanhua; Walker, Janelle Buttry; Minic, Zeljka; Liu, Fangchao; Goshgarian, Harry; Mao, Guangzhao

    2016-05-01

    Drug delivery to the central nervous system (CNS) is challenging due to the inability of many drugs to cross the blood-brain barrier (BBB). Here, we show that wheat germ agglutinin horse radish peroxidase (WGA-HRP) chemically conjugated to gold nanoparticles (AuNPs) can be transported to the spinal cord and brainstem following intramuscular injection into the diaphragm of rats. We synthesized and determined the size and chemical composition of a three-part nanoconjugate consisting of WGA-HRP, AuNPs, and drugs for the treatment of diaphragm paralysis associated with high cervical spinal cord injury (SCI). Upon injection into the diaphragm muscle of rats, we show that the nanoconjugate is capable of delivering the drug at a much lower dose than the unconjugated drug injected systemically to effectively induce respiratory recovery in rats following SCI. This study not only demonstrates a promising strategy to deliver drugs to the CNS bypassing the BBB but also contributes a potential nanotherapy for the treatment of respiratory muscle paralysis resulted from cervical SCI.

  9. Electrospun Nanofibers of Guar Galactomannan for Targeted Drug Delivery

    Science.gov (United States)

    Chu, Hsiao Mei Annie

    2011-12-01

    Guar galactomannan is a biodegradable polysaccharide used widely in the food industry but also in the cosmetics, pharmaceutical, oil drilling, textile and paper industries. Guar consists of a mannose backbone and galactose side groups that are both susceptible to enzyme degradation, a unique property that can be explored for targeted drug delivery especially since those enzymes are naturally secreted by the microflora in human colon. The present study can be divided into three parts. In the first part, we discuss ways to modify guar to produce nanofibers by electrospinning, a process that involves the application of an electric field to a polymer solution or melt to facilitate production of fibers in the sub-micron range. Nanofibers are currently being explored as the next generation of drug carriers due to its many advantages, none more important than the fact that nanofibers are on a size scale that is a fraction of a hair's width and have large surface-to-volume ratio. The incorporation and controlled release of nano-sized drugs is one way in which nanofibers are being utilized in drug delivery. In the second part of the study, we explore various methods to crosslink guar nanofibers as a means to promote water-resistance in a potential drug carrier. The scope and utility of water-resistant guar nanofibers can only be fully appreciated when subsequent drug release studies are carried out. To that end, the third part of our study focuses on understanding the kinetics and diffusion mechanisms of a model drug, Rhodamine B, through moderately-swelling (crosslinked) hydrogel nanofibers in comparison to rapidly-swelling (non-crosslinked) nanofibers. Along the way, our investigations led us to a novel electrospinning set-up that has a unique collector designed to capture aligned nanofibers. These aligned nanofiber bundles can then be twisted to hold them together like yarn. From a practical standpoint, these yarns are advantageous because they come freely suspended and

  10. Blood-brain barrier transport of drugs for the treatment of brain diseases.

    Science.gov (United States)

    Gabathuler, Reinhard

    2009-06-01

    The central nervous system is a sanctuary protected by barriers that regulate brain homeostasis and control the transport of endogenous compounds into the brain. The blood-brain barrier, formed by endothelial cells of the brain capillaries, restricts access to brain cells allowing entry only to amino acids, glucose and hormones needed for normal brain cell function and metabolism. This very tight regulation of brain cell access is essential for the survival of neurons which do not have a significant capacity to regenerate, but also prevents therapeutic compounds, small and large, from reaching the brain. As a result, various strategies are being developed to enhance access of drugs to the brain parenchyma at therapeutically meaningful concentrations to effectively manage disease.

  11. Quantification of biodegradable PLGA nanoparticles for drug targeting

    Directory of Open Access Journals (Sweden)

    Nadira Ibrišimović

    2010-11-01

    Full Text Available Objective. The aim of this work was the development of appropriate analytical methods and assays for determining and monitoring composition and degradation of nanoparticles built from PLGA (poly D, L-lactid-co-glycolid, which can be reloaded with different drugs. A sensitive and precise method for monitoring of nanoparticle degradation in vitro was developed and optimized. Nanoparticles allow a selective enrichment of different drugs and knowledge of the nature and type of their degradation is essential for characterization and control of drug release and dosage. Materials and methods. The first method developed during this work to quantify the PLGA polymer matrix use advantage of the chemical reaction of aliphatic carboxylic acids with ferric chloride (FeCl3 thus quantifying both degradation products of PLGA, lactic and glycol acids, at the same time. A second assay method of choice was to react to the polymer hydrolysate with lactate dehydrogenase, thus assaying selectively the lactic acid part. Results. During development of both of described methods was possible to determine dynamic range for PLGA matrix and nanoparticles, as well as to characterize impact of Pluronic F-68 and glycolic acid on lactate dehydrogenase activity. Conclusion. During our work we were able to develop two sensitive methods for monitoring of biodegradation of polymers which are consecutively used as a nanoparticle matrix in drug targeting.

  12. Drug-target and disease networks: polypharmacology in the post-genomic era

    OpenAIRE

    Masoudi-Nejad, Ali; Mousavian, Zaynab; Bozorgmehr, Joseph H.

    2013-01-01

    With the growing understanding of complex diseases, the focus of drug discovery has shifted away from the well-accepted “one target, one drug” model, to a new “multi-target, multi-drug” model, aimed at systemically modulating multiple targets. Identification of the interaction between drugs and target proteins plays an important role in genomic drug discovery, in order to discover new drugs or novel targets for existing drugs. Due to the laborious and costly experimental process of drug-targe...

  13. Magnetically responsive microparticles for targeted drug and radionuclide delivery.

    Energy Technology Data Exchange (ETDEWEB)

    Kaminski, M. D.; Ghebremeskel, A. N.; Nunez, L.; Kasza, K. E.; Chang, F.; Chien, T.-H.; Fisher, P. F.; Eastman, J. A.; Rosengart, A. J.; McDonald, L.; Xie, Y.; Johns, L.; Pytel, P.; Hafeli, U. O.

    2004-02-16

    We are currently investigating the use of magnetic particles--polymeric-based spheres containing dispersed magnetic nanocrystalline phases--for the precise delivery of drugs via the human vasculature. According to this review, meticulously prepared magnetic drug targeting holds promise as a safe and effective method of delivering drugs to specific organ, tissue or cellular targets. We have critically examined the wide range of approaches in the design and implementation of magnetic-particle-based drug delivery systems to date, including magnetic particle preparation, drug encapsulation, biostability, biocompatibility, toxicity, magnetic field designs, and clinical trials. However, we strongly believe that there are several limitations with past developments that need to be addressed to enable significant strides in the field. First, particle size has to be carefully chosen. Micrometer-sized magnetic particles are better attracted over a distance than nanometer sized magnetic particles by a constant magnetic field gradient, and particle sizes up to 1 {micro}m show a much better accumulation with no apparent side effects in small animal models, since the smallest blood vessels have an inner diameter of 5-7 {micro}m. Nanometer-sized particles <70 nm will accumulate in organ fenestrations despite an effective surface stabilizer. To be suitable for future human applications, our experimental approach synthesizes the magnetic drug carrier according to specific predefined outcome metrics: monodisperse population in a size range of 100 nm to 1.0 {micro}m, non-toxic, with appropriate magnetic properties, and demonstrating successful in vitro and in vivo tests. Another important variable offering possible improvement is surface polarity, which is expected to prolong particle half-life in circulation and modify biodistribution and stability of drugs in the body. The molecules in the blood that are responsible for enhancing the uptake of particles by the reticuloendothelial

  14. Brain-targeting study of stearic acid–grafted chitosan micelle drug-delivery system

    Directory of Open Access Journals (Sweden)

    Xie YT

    2012-06-01

    Full Text Available Yi-Ting Xie, Yong-Zhong Du, Hong Yuan, Fu-Qiang HuCollege of Pharmaceutical Sciences, Zhejiang University, Hangzhou, ChinaPurpose: Therapy for central nervous system disease is mainly restricted by the blood–brain barrier. A drug-delivery system is an effective approach to overcome this barrier. In this research, the potential of polymeric micelles for brain-targeting drug delivery was studied.Methods: Stearic acid–grafted chitosan (CS-SA was synthesized by hydrophobic modification of chitosan with stearic acid. The physicochemical characteristics of CS-SA micelles were investigated. bEnd.3 cells were chosen as model cells to evaluate the internalization ability and cytotoxicity of CS-SA micelles in vitro. Doxorubicin (DOX, as a model drug, was physically encapsulated in CS-SA micelles. The in vivo brain-targeting ability of CS-SA micelles was qualitatively and quantitatively studied by in vivo imaging and high-performance liquid chromatography analysis, respectively. The therapeutic effect of DOX-loaded micelles in vitro was performed on glioma C6 cells.Results: The critical micelle concentration of CS-SA micelles with 26.9% ± 1.08% amino substitute degree was 65 µg/mL. The diameter and surface potential of synthesized CS-SA micelles in aqueous solution was 22 ± 0.98 nm and 36.4 ± 0.71 mV, respectively. CS-SA micelles presented excellent cellular uptake ability on bEnd.3 cells, the IC50 of which was 237.6 ± 6.61 µg/mL. DOX-loaded micelles exhibited slow drug-release behavior, with a cumulative release up to 72% within 48 hours in vitro. The cytotoxicity of DOX-loaded CS-SA micelles against C6 was 2.664 ± 0.036 µg/mL, compared with 0.181 ± 0.066 µg/mL of DOX • HCl. In vivo imaging results indicated that CS-SA was able to transport rapidly across the blood–brain barrier and into the brain. A maximum DOX distribution in brain of 1.01%/g was observed 15 minutes after administration and maintained above 0.45%/g within 1 hour

  15. Brain targeted transcranial route of drug delivery of diazepam

    Directory of Open Access Journals (Sweden)

    Pathirana W

    2006-01-01

    Full Text Available The term transcranial route means the brain targeted transfer of drug molecules across the cranium through the layers of the skin and skin appendages of the head, arteries and veins of the skin of the head, the cranial bones along with the diploe, the cranial bone sutures, the meninges and specifically through the emissary veins. The administration of drugs through the scalp in ayurvedic system for the diseases associated with the brain was evaluated with a view to develop a novel targeted route for central nervous system drugs. It is expected to circumvent the systemic side effects of oral route. Diazepam was dissolved in an oil medium and applied on scalp as practiced in the ayurvedic system. Thirty rats were tested on the rotating rotarod for muscle relaxant effect of diazepam. Five groups of rats tested were the control, diazepam i.v. injected (280 µg/0.1 ml group, two groups treated with transcranial diazepam oil solution (1.5 mg/0.2 ml and the transcranial blank vehicle treated groups. Holding time in triplicate for each rat on the rotating rotarod was measured. The holding times following each treatment was statistically compared (one-way ANOVA. The pooled average times for the control, diazepam i.v. injected, diazepam oil solution transcranial treated two groups and the blank vehicle treated groups were 35.45, 4.73, 16.5, 15.39 and 33.23 seconds respectively. The two groups subjected to the brain targeted transcranial route showed a statistically significant decrease (50% drop in the holding time against the control group indicating the centrally acting muscle relaxant effect due to absorption of diazepam into the brain through the proposed route.

  16. Virtual target screening to rapidly identify potential protein targets of natural products in drug discovery

    Directory of Open Access Journals (Sweden)

    Yuri Pevzner

    2014-05-01

    Full Text Available Inherent biological viability and diversity of natural products make them a potentially rich source for new therapeutics. However, identification of bioactive compounds with desired therapeutic effects and identification of their protein targets is a laborious, expensive process. Extracts from organism samples may show desired activity in phenotypic assays but specific bioactive compounds must be isolated through further separation methods and protein targets must be identified by more specific phenotypic and in vitro experimental assays. Still, questions remain as to whether all relevant protein targets for a compound have been identified. The desire is to understand breadth of purposing for the compound to maximize its use and intellectual property, and to avoid further development of compounds with insurmountable adverse effects. Previously we developed a Virtual Target Screening system that computationally screens one or more compounds against a collection of virtual protein structures. By scoring each compound-protein interaction, we can compare against averaged scores of synthetic drug-like compounds to determine if a particular protein would be a potential target of a compound of interest. Here we provide examples of natural products screened through our system as we assess advantages and shortcomings of our current system in regards to natural product drug discovery.

  17. TRPV1: A Target for Rational Drug Design

    Directory of Open Access Journals (Sweden)

    Vincenzo Carnevale

    2016-08-01

    Full Text Available Transient Receptor Potential Vanilloid 1 (TRPV1 is a non-selective, Ca2+ permeable cation channel activated by noxious heat, and chemical ligands, such as capsaicin and resiniferatoxin (RTX. Many compounds have been developed that either activate or inhibit TRPV1, but none of them are in routine clinical practice. This review will discuss the rationale for antagonists and agonists of TRPV1 for pain relief and other conditions, and strategies to develop new, better drugs to target this ion channel, using the newly available high-resolution structures.

  18. Discovering the first microRNA-targeted drug

    DEFF Research Database (Denmark)

    Lindow, Morten; Kauppinen, Sakari

    2012-01-01

    MicroRNAs (miRNAs) are important post-transcriptional regulators of nearly every biological process in the cell and play key roles in the pathogenesis of human disease. As a result, there are many drug discovery programs that focus on developing miRNA-based therapeutics. The most advanced...... of these programs targets the liver-expressed miRNA-122 using the locked nucleic acid (LNA)–modified antisense oligonucleotide miravirsen. Here, we describe the discovery of miravirsen, which is currently in phase 2 clinical trials for treatment of hepatitis C virus (HCV) infection....

  19. Mining nematode genome data for novel drug targets.

    Science.gov (United States)

    Foster, Jeremy M; Zhang, Yinhua; Kumar, Sanjay; Carlow, Clotilde K S

    2005-03-01

    Expressed sequence tag projects have currently produced over 400 000 partial gene sequences from more than 30 nematode species and the full genomic sequences of selected nematodes are being determined. In addition, functional analyses in the model nematode Caenorhabditis elegans have addressed the role of almost all genes predicted by the genome sequence. This recent explosion in the amount of available nematode DNA sequences, coupled with new gene function data, provides an unprecedented opportunity to identify pre-validated drug targets through efficient mining of nematode genomic databases. This article describes the various information sources available and strategies that can expedite this process.

  20. Nanotech revolution for the anti-cancer drug delivery through blood-brain barrier.

    Science.gov (United States)

    Caraglia, M; De Rosa, G; Salzano, G; Santini, D; Lamberti, M; Sperlongano, P; Lombardi, A; Abbruzzese, A; Addeo, R

    2012-03-01

    Nanotechnology-based drug delivery was born as a chance for pharmaceutical weapons to be delivered in the body sites where drug action is required. Specifically, the incorporation of anti-cancer agents in nanodevices of 100-300 nm allows their delivery in tissues that have a fenestrated vasculature and a reduced lymphatic drainage. These two features are typical of neoplastic tissues and, therefore, allow the accumulation of nanostructured devices in tumours. An important issue of anti-cancer pharmacological strategies is the overcoming of anatomical barriers such as the bloodbrain- barrier (BBB) that protects brain from toxicological injuries but, at the same time, makes impossible for most of the pharmacological agents with anti-cancer activity to reach tumour cells placed in the brain and derived from either primary tumours or metastases. In fact, only highly lipophilic molecules can passively diffuse through BBB to reach central nervous system (CNS). Another possibility is to use nanotechnological approaches as powerful tools to across BBB, by both prolonging the plasma half-life of the drugs and crossing fenestrations of BBB damaged by brain metastases. Moreover, modifications of nanocarrier surface with specific endogenous or exogenous ligands can promote the crossing of intact BBB as in the case of primary brain tumours. This aim can be achieved through the binding of the nanodevices to carriers or receptors expressed by the endothelial cells of BBB and that can favour the internalization of the nanostructured devices delivering anti-cancer drugs. This review summarizes the most meaningful advances in the field of nanotechnologies for brain delivery of drugs.

  1. Development of modified pulsincap drug delivery system of metronidazole for drug targeting

    Directory of Open Access Journals (Sweden)

    Abraham Sindhu

    2007-01-01

    Full Text Available A modified Pulsincap dosage form of metronidazole was developed to target drug release in the colon. Bodies of hard gelatin capsules were treated with formaldehyde keeping the caps as such. Metronidazole pellets prepared by extrusion-spheronization method were incorporated into these specialized capsule shells and plugged with polymers guar gum, hydroxypropylmethylcellulose 10K, carboxymethylcellulose sodium and sodium alginate separately at concentrations 20 mg, 30 mg and 40 mg. The filled capsules were completely coated with 5% cellulose acetate phthalate to prevent variable gastric emptying. All the formulations were assayed to determine drug content and the ability of the modified Pulsincap to provide colon-specific drug delivery was assessed by in vitro drug release studies in buffer pH 1.2 for 2 h, pH 7.4 (simulated intestinal fluid for 3 h and pH 6.8 (stimulated colonic fluid for 7 h. The results indicated that significant drug release occurred only after 5 h from the start of experiment. Thus, metronidazole could be successfully colon targeted by the use of the modified Pulsincap, thereby reducing systemic side effects.

  2. Pharmaceutical technology at the service of targeted drug delivery.

    Science.gov (United States)

    Allémann, Eric; Delie, Florence; Lange, Norbert

    2012-01-01

    Research in pharmaceutical technology has drifted from formulation of systems with improved drug absorption and bioavailability to systems targeting molecular sites of diseases. The research unit of Pharmaceutical Technology from the University of Geneva focuses on the development of systems for both diagnostic and therapeutic purposes. Three types of constructs for targeting are reviewed. With a fine-tuning of size and surface composition, polymeric nanoparticles are developed to improve detection of micrometastasis by fluorescence imaging. Furthermore, surface coating with specific antibodies increase the therapeutic efficiency of the encapsulated chemotherapeutic agent for tumor treatment in animal models. Constructs that are activated by remote sources of energy are investigated in the unit. For instance, microbubbles bearing specific antibody fragments at their surface are useful contrast agents for ultrasound molecular imaging. Microbubbles, if combined with a thrombolytic drug and ultrasound, improve clot lysis, which is promising for stroke treatments. Enzymatically activated prodrug scaffolds are also under development. With this approach, intrinsic enzymatic activity of a diseased tissue activates the formulations. This concept led to the development of theranostic agents that can be used for both diagnostic and therapeutic purposes.

  3. Fighting cancer with nanomedicine---drug-polyester nanoconjugates for targeted cancer therapy

    Science.gov (United States)

    Yin, Qian

    The aim of my Ph. D. research is to develop drug-polyester nanoconjugates (NCs) as a novel translational polymeric drug delivery system that can successfully evade non-specific uptake by reticuloendothelial system (RES) and facilitate targeted cancer diagnosis and therapy. By uniquely integrating well-established chemical reaction-controlled ring opening polymerization (ROP) with nanoprecipitation technique, I successfully developed a polymeric NC system based on poly(lactic acid) and poly(O-carboxyanhydrides) (OCA) that allows for the quantitative loading and controlled release of a variety of anticancer drugs. The developed NC system could be easily modified with parmidronate, one of bisphosphonates commonly used as the treatment for disease characterized by osteolysis, to selectively deliver doxorubicin (Doxo) to the bone tissues and substantially to improve their therapeutic efficiency in inhibiting the growth of osteosarcoma in both murine and canine models. More importantly, the developed NCs could avidly bind to human serum albumin, a ubiquitous protein in the blood, to bypass the endothelium barrier and penetrate into tumor tissues more deeply and efficiently. When compared with PEGylated NCs, these albumin-bound NCs showed significantly reduced accumulation in RES and enhanced tumor accumulation, which consequently contributed to higher their tumor inhibition capabilities. In addition, the developed NC system allows easy incorporation of X-ray computed tomography (CT) contrast agents to largely facilitate personalized therapy by improving diagnosis accuracy and monitoring therapeutic efficacy. Through the synthetic and formulation strategy I developed, a large quantity (grams or larger-scale) of drug-polyester NCs can be easily obtained, which can be used as a model drug delivery system for fundamental studies as well as a real drug delivery system for disease treatment in clinical settings.

  4. Drug-target interaction prediction by random walk on the heterogeneous network.

    Science.gov (United States)

    Chen, Xing; Liu, Ming-Xi; Yan, Gui-Ying

    2012-07-01

    Predicting potential drug-target interactions from heterogeneous biological data is critical not only for better understanding of the various interactions and biological processes, but also for the development of novel drugs and the improvement of human medicines. In this paper, the method of Network-based Random Walk with Restart on the Heterogeneous network (NRWRH) is developed to predict potential drug-target interactions on a large scale under the hypothesis that similar drugs often target similar target proteins and the framework of Random Walk. Compared with traditional supervised or semi-supervised methods, NRWRH makes full use of the tool of the network for data integration to predict drug-target associations. It integrates three different networks (protein-protein similarity network, drug-drug similarity network, and known drug-target interaction networks) into a heterogeneous network by known drug-target interactions and implements the random walk on this heterogeneous network. When applied to four classes of important drug-target interactions including enzymes, ion channels, GPCRs and nuclear receptors, NRWRH significantly improves previous methods in terms of cross-validation and potential drug-target interaction prediction. Excellent performance enables us to suggest a number of new potential drug-target interactions for drug development.

  5. Molecular drug targets and structure based drug design: A holistic approach

    OpenAIRE

    Singh, Shailza; Malik, Balwant Kumar; Sharma, Durlabh Kumar

    2006-01-01

    Access to the complete human genome sequence as well as to the complete sequences of pathogenic organisms provides information that can result in an avalanche of therapeutic targets. Structure-based design is one of the first techniques to be used in drug design. Structure based design refers specifically to finding and complementing the 3D structure (binding and/or active site) of a target molecule such as a receptor protein. The aim of this review is to give an outline of studies in the fie...

  6. Nanomaterials for the Local and Targeted Delivery of Osteoarthritis Drugs

    Directory of Open Access Journals (Sweden)

    Parthiban Chinnagounder Periyasamy

    2012-01-01

    Full Text Available Nanotechnology has found its potential in every possible field of science and engineering. It offers a plethora of options to design tools at the nanometer scale, which can be expected to function more effectively than micro- and macrosystems for specific applications. Although the debate regarding the safety of synthetic nanomaterials for clinical applications endures, it is a promising technology due to its potential to augment current treatments. Various materials such as synthetic polymer, biopolymers, or naturally occurring materials such as proteins and peptides can serve as building blocks for adaptive nanoscale formulations. The choice of materials depends highly on the application. We focus on the use of nanoparticles for the treatment of degenerative cartilage diseases, such as osteoarthritis (OA. Current therapies for OA focus on treating the symptoms rather than modifying the disease. The usefulness of OA disease modifying drugs is hampered by side effects and lack of suitable drug delivery systems that target, deliver, and retain drugs locally. This challenge can be overcome by using nanotechnological formulations. We describe the different nanodrug delivery systems and their potential for cartilage repair. This paper provides the reader basal understanding of nanomaterials and aims at drawing new perspectives on the use of existing nanotechnological formulations for the treatment of osteoarthritis.

  7. Targeting Plasmodium Metabolism to Improve Antimalarial Drug Design.

    Science.gov (United States)

    Avitia-Domínguez, Claudia; Sierra-Campos, Erick; Betancourt-Conde, Irene; Aguirre-Raudry, Miriam; Vázquez-Raygoza, Alejandra; Luevano-De la Cruz, Artemisa; Favela-Candia, Alejandro; Sarabia-Sanchez, Marie; Ríos-Soto, Lluvia; Méndez-Hernández, Edna; Cisneros-Martínez, Jorge; Palacio-Gastélum, Marcelo Gómez; Valdez-Solana, Mónica; Hernández-Rivera, Jessica; De Lira-Sánchez, Jaime; Campos-Almazán, Mara; Téllez-Valencia, Alfredo

    2016-01-01

    Malaria is one of the main infectious diseases in tropical developing countries and represents high morbidity and mortality rates nowadays. The principal etiological agent P. falciparum is transmitted through the bite of the female Anopheles mosquito. The issue has escalated due to the emergence of resistant strains to most of the antimalarials used for the treatment including Chloroquine, Sulfadoxine-Pyrimethamine, and recently Artemisinin derivatives, which has led to diminished effectiveness and by consequence increased the severity of epidemic outbreaks. Due to the lack of effective compounds to treat these drug-resistant strains, the discovery or development of novel anti-malaria drugs is important. In this context, one strategy has been to find inhibitors of enzymes, which play an important role for parasite survival. Today, promising results have been obtained in this regard, involving the entire P. falciparum metabolism. These inhibitors could serve as leads in the search of a new chemotherapy against malaria. This review focuses on the achievements in recent years with regard to inhibition of enzymes used as targets for drug design against malaria.

  8. The Possible Potential Therapeutic Targets for Drug Induced Gingival Overgrowth

    Directory of Open Access Journals (Sweden)

    Tamilselvan Subramani

    2013-01-01

    Full Text Available Gingival overgrowth is a side effect of certain medications. The most fibrotic drug-induced lesions develop in response to therapy with phenytoin, the least fibrotic lesions are caused by cyclosporin A, and the intermediate fibrosis occurs in nifedipine-induced gingival overgrowth. Fibrosis is one of the largest groups of diseases for which there is no therapy but is believed to occur because of a persistent tissue repair program. During connective tissue repair, activated gingival fibroblasts synthesize and remodel newly created extracellular matrix. Proteins such as transforming growth factor (TGF, endothelin-1 (ET-1, angiotensin II (Ang II, connective tissue growth factor (CCN2/CTGF, insulin-like growth factor (IGF, and platelet-derived growth factor (PDGF appear to act in a network that contributes to the development of gingival fibrosis. Since inflammation is the prerequisite for gingival overgrowth, mast cells and its protease enzymes also play a vital role in the pathogenesis of gingival fibrosis. Drugs targeting these proteins are currently under consideration as antifibrotic treatments. This review summarizes recent observations concerning the contribution of TGF-β, CTGF, IGF, PDGF, ET-1, Ang II, and mast cell chymase and tryptase enzymes to fibroblast activation in gingival fibrosis and the potential utility of agents blocking these proteins in affecting the outcome of drug-induced gingival overgrowth.

  9. Enhanced molecular dynamics sampling of drug target conformations.

    Science.gov (United States)

    Rodriguez-Bussey, Isela G; Doshi, Urmi; Hamelberg, Donald

    2016-01-01

    Computational docking and virtual screening are two main important methods employed in structure-based drug design. Unlike the traditional approach that allows docking of a flexible ligand against a handful of receptor structures, receptor flexibility has now been appreciated and increasingly incorporated in computer-aided docking. Using a diverse set of receptor conformations increases the chances of finding potential drugs and inhibitors. Molecular dynamics (MD) is greatly useful to generate various receptor conformations. However, the diversity of the structures of the receptor, which is usually much larger than the ligand, depends on the sampling efficiency of MD. Enhanced sampling methods based on accelerated molecular dynamics (aMD) can alleviate the sampling limitation of conventional MD and aid in representation of the phase space to a much greater extent. RaMD-db, a variant of aMD that applies boost potential to the rotatable dihedrals and non-bonded diffusive degrees of freedom has been proven to reproduce the equilibrium properties more accurately and efficiently than aMD. Here, we discuss recent advances in the aMD methodology and review the applicability of RaMD-db as an enhanced sampling method. RaMD-db is shown to be able to generate a broad distribution of structures of a drug target, Cyclophilin A. These structures that have never been observed previously in very long conventional MD can be further used for structure-based computer-aided drug discovery, and docking, and thus, in the identification and design of potential novel inhibitors.

  10. Micro RNA, A Review: Pharmacogenomic drug targets for complex diseases

    Directory of Open Access Journals (Sweden)

    Ritesh Bajaj

    2010-01-01

    Full Text Available Micro RNAs (miRNAs are non-coding RNAs that can regulate gene expression to target several mRNAs in a gene regulatory network. MiRNA related Single Nucleotide Polymorphisms (S.N.P.s represent a newly identified type of genetic variability that can be of influence to the risk of certain human diseases and also affect how drugs can be activated and metabolized by patients. This will help in personalized medicines which are used for adminis-trating the correct dosage of drug and drug efficacy. miRNA deregulated expression has been extensively de-scribed in a variety of diseases such as Cancer, Obesity , Diabetes, Schizophrenia and control and self renewal of stem cells. MiRNA can function as oncogenes and/or tumor suppressors. MiRNAs may act as key regulators of processes as diverse as early development, cell proliferation and cell death, apoptosis and fat metabolism and cell differentiation .miRNA expression have shown their role in brain development chronic lymphocytic leukemia, colonic adeno carcinoma, Burkiff′s lymphoma and viral infection. These show their links with viral disease, neu-rodevelopment and cancer. It has been shown that they play a key role in melanoma metastasis. These may be differentially expressed in malignant cells compared to normal cells altering the regulation of expression of many important genes. MiRNA expression has been used for prognosis and early diagnosis of these complex diseases. The present paper focuses on the role of miRNAs in various complex diseases, which will help in improving the drug discovery process and personalized medicines.

  11. AVN-101: A Multi-Target Drug Candidate for the Treatment of CNS Disorders

    Science.gov (United States)

    Ivachtchenko, Alexandre V.; Lavrovsky, Yan; Okun, Ilya

    2016-01-01

    Lack of efficacy of many new highly selective and specific drug candidates in treating diseases with poorly understood or complex etiology, as are many of central nervous system (CNS) diseases, encouraged an idea of developing multi-modal (multi-targeted) drugs. In this manuscript, we describe molecular pharmacology, in vitro ADME, pharmacokinetics in animals and humans (part of the Phase I clinical studies), bio-distribution, bioavailability, in vivo efficacy, and safety profile of the multimodal drug candidate, AVN-101. We have carried out development of a next generation drug candidate with a multi-targeted mechanism of action, to treat CNS disorders. AVN-101 is a very potent 5-HT7 receptor antagonist (Ki = 153 pM), with slightly lesser potency toward 5-HT6, 5-HT2A, and 5HT-2C receptors (Ki = 1.2–2.0 nM). AVN-101 also exhibits a rather high affinity toward histamine H1 (Ki = 0.58 nM) and adrenergic α2A, α2B, and α2C (Ki = 0.41–3.6 nM) receptors. AVN-101 shows a good oral bioavailability and facilitated brain-blood barrier permeability, low toxicity, and reasonable efficacy in animal models of CNS diseases. The Phase I clinical study indicates the AVN-101 to be well tolerated when taken orally at doses of up to 20 mg daily. It does not dramatically influence plasma and urine biochemistry, nor does it prolong QT ECG interval, thus indicating low safety concerns. The primary therapeutic area for AVN-101 to be tested in clinical trials would be Alzheimer’s disease. However, due to its anxiolytic and anti-depressive activities, there is a strong rational for it to also be studied in such diseases as general anxiety disorders, depression, schizophrenia, and multiple sclerosis. PMID:27232215

  12. Transport of carbamazepine and drug interactions at blood-brain barrier

    Institute of Scientific and Technical Information of China (English)

    Jing-jing SUN; Lin XIE; Xiao-dong LIU

    2006-01-01

    Aim: To investigate the characteristics of carbamazepine (CBZ) transport and drug interactions at the blood-brain barrier. Methods: Cultured rat brain microvascular endothelial cells (rBMEC) were used as an in vitro model of the blood-brain barrier (BBB). When cells became confluent, CBZ uptake over time was recorded by incubation of the cells in a medium containing 10 mg/L CBZ at 37 ℃. The steady-state uptake of CBZ by rBMEC was tested for different CBZ concentrations at 37 ℃. The effects of various agents on the steady-state uptake of CBZ and efflux of CBZ from rBMEC were also studied. Results: The uptake of CBZ by rBMEC was time- and concentration-dependent. The steady-state uptake occurred at 30 min for incubation. The steady-state uptake was significantly increased (P<0.01) by treatment with dinitrophenol. The co-administration of cyclosporine A significantly increased the steady-state uptake of CBZ by the rBMEC, whereas co-administration of olanzapine significantly decreased the uptake in a concentration- and temperature-dependent manner. The efflux of CBZ from rBMEC was inhibited by CsA. Conclusion: The transport of CBZ at the BBB is mediated by many transporters. Some specific ABC (ATP-binding cassette,ABC ) efflux transporters may be involved in the transport of CBZ. Drugs influence the transport of CBZ at the BBB in different ways.

  13. Schizophrenia drug discovery and development in an evolving era: are new drug targets fulfilling expectations?

    Science.gov (United States)

    Dunlop, John; Brandon, Nicholas J

    2015-02-01

    Current therapeutics for schizophrenia, the typical and atypical antipsychotic class of drugs, derive their therapeutic benefit predominantly by antagonism of the dopamine D2 receptor subtype and have robust clinical benefit on positive symptoms of the disease with limited to no impact on negative symptoms and cognitive impairment. Driven by these therapeutic limitations of current treatments and the recognition that transmitter systems beyond the dopaminergic system in particular glutamatergic transmission contribute to the etiology of schizophrenia significant recent efforts have focused on the discovery and development of novel treatments for schizophrenia with mechanisms of action that are distinct from current drugs. Specifically, compounds selectively targeting the metabotropic glutamate receptor 2/3 subtype, phosphodiesterase subtype 10, glycine transporter subtype 1 and the alpha7 nicotinic acetylcholine receptor have been the subject of intense drug discovery and development efforts. Here we review recent clinical experience with the most advanced drug candidates targeting each of these novel mechanisms and discuss whether these new agents are living up to expectations.

  14. Pharmacoinformatics elucidation of potential drug targets against migraine to target ion channel protein KCNK18

    Directory of Open Access Journals (Sweden)

    Sehgal SA

    2014-05-01

    Full Text Available Sheikh Arslan Sehgal, Mubashir Hassan, Sajid Rashid National Center for Bioinformatics, Quaid-i-Azam University, Islamabad, Pakistan Abstract: Migraine, a complex debilitating neurological disorder is strongly associated with potassium channel subfamily K member 18 (KCNK18. Research has emphasized that high levels of KCNK18 may be responsible for improper functioning of neurotransmitters, resulting in neurological disorders like migraine. In the present study, a hybrid approach of molecular docking and virtual screening were followed by pharmacophore identification and structure modeling. Screening was performed using a two-dimensional similarity search against recommended migraine drugs, keeping in view the physicochemical properties of drugs. LigandScout tool was used for exploring pharmacophore properties and designing novel molecules. Here, we report the screening of four novel compounds that have showed maximum binding affinity against KCNK18, obtained through the ZINC database, and Drug and Drug-Like libraries. Docking studies revealed that Asp-46, Ile-324, Ile-44, Gly-118, Leu-338, Val-113, and Phe-41 are critical residues for receptor–ligand interaction. A virtual screening approach coupled with docking energies and druglikeness rules illustrated that ergotamine and PB-414901692 are potential inhibitor compounds for targeting KCNK18. We propose that selected compounds may be more potent than the previously listed drug analogs based on the binding energy values. Further analysis of these inhibitors through site-directed mutagenesis could be helpful for exploring the details of ligand-binding pockets. Overall, the findings of this study may be helpful for designing novel therapeutic targets to cure migraine. Keywords: migraine, bioinformatics, modeling and docking, KCNK18, TRESK, virtual screening, pharmacoinformatics

  15. New approaches for the identification of drug targets in protozoan parasites.

    Science.gov (United States)

    Müller, Joachim; Hemphill, Andrew

    2013-01-01

    Antiparasitic chemotherapy is an important issue for drug development. Traditionally, novel compounds with antiprotozoan activities have been identified by screening of compound libraries in high-throughput systems. More recently developed approaches employ target-based drug design supported by genomics and proteomics of protozoan parasites. In this chapter, the drug targets in protozoan parasites are reviewed. The gene-expression machinery has been among the first targets for antiparasitic drugs and is still under investigation as a target for novel compounds. Other targets include cytoskeletal proteins, proteins involved in intracellular signaling, membranes, and enzymes participating in intermediary metabolism. In apicomplexan parasites, the apicoplast is a suitable target for established and novel drugs. Some drugs act on multiple subcellular targets. Drugs with nitro groups generate free radicals under anaerobic growth conditions, and drugs with peroxide groups generate radicals under aerobic growth conditions, both affecting multiple cellular pathways. Mefloquine and thiazolides are presented as examples for antiprotozoan compounds with multiple (side) effects. The classic approach of drug discovery employing high-throughput physiological screenings followed by identification of drug targets has yielded the mainstream of current antiprotozoal drugs. Target-based drug design supported by genomics and proteomics of protozoan parasites has not produced any antiparasitic drug so far. The reason for this is discussed and a synthesis of both methods is proposed.

  16. Delivery of antihuman African trypanosomiasis drugs across the blood-brain and blood-CSF barriers.

    Science.gov (United States)

    Sekhar, Gayathri N; Watson, Christopher P; Fidanboylu, Mehmet; Sanderson, Lisa; Thomas, Sarah A

    2014-01-01

    Human African trypanosomiasis (HAT or sleeping sickness) is a potentially fatal disease caused by the parasite, Trypanosoma brucei sp. The parasites are transmitted by the bite of insect vectors belonging to the genus Glossina (tsetse flies) and display a life cycle strategy that is equally spread between human and insect hosts. T.b. gambiense is found in western and central Africa whereas, T.b. rhodesiense is found in eastern and southern Africa. The disease has two clinical stages: a blood stage after the bite of an infected tsetse fly, followed by a central nervous system (CNS) stage where the parasite penetrates the brain; causing death if left untreated. The blood-brain barrier (BBB) makes the CNS stage difficult to treat because it prevents 98% of all known compounds from entering the brain, including some anti-HAT drugs. Those that do enter the brain are toxic compounds in their own right and have serious side effects. There are only a few drugs available to treat HAT and those that do are stage specific. This review summarizes the incidence, diagnosis, and treatment of HAT and provides a close examination of the BBB transport of anti-HAT drugs and an overview of the latest drugs in development.

  17. Improved drug targeting of cancer cells by utilizing actively targetable folic acid-conjugated albumin nanospheres.

    Science.gov (United States)

    Shen, Zheyu; Li, Yan; Kohama, Kazuhiro; Oneill, Brian; Bi, Jingxiu

    2011-01-01

    Folic acid-conjugated albumin nanospheres (FA-AN) have been developed to provide an actively targetable drug delivery system for improved drug targeting of cancer cells with reduced side effects. The nanospheres were prepared by conjugating folic acid onto the surface of albumin nanospheres using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDAC) as a catalyst. To test the efficacy of these nanospheres as a potential delivery platform, doxorubicin-loaded albumin nanospheres (DOX-AN) and doxorubicin-loaded FA-AN (FA-DOX-AN) were prepared by entrapping DOX (an anthracycline, antibiotic drug widely used in cancer chemotherapy that works by intercalating DNA) into AN and FA-AN nanoparticles. Cell uptake of the DOX was then measured. The results show that FA-AN was incorporated into HeLa cells (tumor cells) only after 2.0h incubation, whereas HeLa cells failed to incorporate albumin nanospheres without conjugated folic acid after 4.0h incubation. When HeLa cells were treated with the DOX-AN, FA-DOX-AN nanoparticles or free DOX, cell viability decreased with increasing culture time (i.e. cell death increases with time) over a 70h period. Cell viability was always the lowest for free DOX followed by FA-DOX-AN4 and then DOX-AN. In a second set of experiments, HeLa cells washed to remove excess DOX after an initial incubation for 2h were incubated for 70h. The corresponding cell viability was slightly higher when the cells were treated with FA-DOX-AN or free DOX whilst cells treated with DOX-AN nanoparticles remained viable. The above experiments were repeated for non-cancerous, aortic smooth muscle cells (AoSMC). As expected, cell viability of the HeLa cells (with FA receptor alpha, FRα) and AoSMC cells (without FRα) decreased rapidly with time in the presence of free DOX, but treatment with FA-DOX-AN resulted in selective killing of the tumor cells. These results indicated that FA-AN may be used as a promising actively targetable drug delivery system to improve drug

  18. Advanced drug delivery and targeting technologies for the ocular diseases

    Science.gov (United States)

    Barar, Jaleh; Aghanejad, Ayuob; Fathi, Marziyeh; Omidi, Yadollah

    2016-01-01

    Introduction: Ocular targeted therapy has enormously been advanced by implementation of new methods of drug delivery and targeting using implantable drug delivery systems (DDSs) or devices (DDDs), stimuli-responsive advanced biomaterials, multimodal nanomedicines, cell therapy modalities and medical bioMEMs. These technologies tackle several ocular diseases such as inflammation-based diseases (e.g., scleritis, keratitis, uveitis, iritis, conjunctivitis, chorioretinitis, choroiditis, retinitis, retinochoroiditis), ocular hypertension and neuropathy, age-related macular degeneration and mucopolysaccharidosis (MPS) due to accumulation of glycosaminoglycans (GAGs). Such therapies appear to provide ultimate treatments, even though much more effective, yet biocompatible, noninvasive therapies are needed to control some disabling ocular diseases/disorders. Methods: In the current study, we have reviewed and discussed recent advancements on ocular targeted therapies. Results: On the ground that the pharmacokinetic and pharmacodynamic analyses of ophthalmic drugs need special techniques, most of ocular DDSs/devices developments have been designed to localized therapy within the eye. Application of advanced DDSs such as Subconjunctival insert/implants (e.g., latanoprost implant, Gamunex-C), episcleral implant (e.g., LX201), cationic emulsions (e.g., Cationorm™, Vekacia™, Cyclokat™), intac/punctal plug DDSs (latanoprost punctal plug delivery system, L-PPDS), and intravitreal implants (I-vitaion™, NT-501, NT- 503, MicroPump, Thethadur, IB-20089 Verisome™, Cortiject, DE-102, Retisert™, Iluvein™ and Ozurdex™) have significantly improved the treatment of ocular diseases. However, most of these DDSs/devices are applied invasively and even need surgical procedures. Of these, use of de novo technologies such as advanced stimuli-responsive nanomaterials, multimodal nanosystems (NSs)/nanoconjugates (NCs), biomacromolecualr scaffolds, and bioengineered cell therapies

  19. Candidiasis drug discovery and development: new approaches targeting virulence for discovering and identifying new drugs

    Science.gov (United States)

    Pierce, Christopher G.; Lopez-Ribot, Jose L.

    2014-01-01

    Introduction Targeting pathogenetic mechanisms rather than essential processes represents a very attractive alternative for the development of new antibiotics. This may be particularly important in the case of antimycotics, due to the urgent need for novel antifungal drugs and the paucity of selective fungal targets. The opportunistic pathogenic fungus Candida albicans is the main etiological agent of candidiasis, the most common human fungal infection. These infections carry unacceptably high mortality rates, a clear reflection of the many shortcomings of current antifungal therapy, including the limited armamentarium of antifungal agents, their toxicity, and the emergence of resistance. Moreover the antifungal pipeline is mostly dry. Areas covered This review covers some of the most recent progress towards understanding C. albicans pathogenetic processes and how to harness this information for the development of anti-virulence agents. The two principal areas covered are filamentation and biofilm formation, as C. albicans pathogenicity is intimately linked to its ability to undergo morphogenetic conversions between yeast and filamentous morphologies and to its ability to form biofilms. Expert opinion We argue that filamentation and biofilm formation represent high value targets, yet clinically unexploited, for the development of novel anti-virulence approaches against candidiasis. Although this has proved a difficult task despite increasing understanding at the molecular level of C. albicans virulence, we highlight new opportunities and prospects for antifungal drug development targeting these two important biological processes. PMID:23738751

  20. Nanoscale Quantifying the Effects of Targeted Drug on Chemotherapy in Lymphoma Treatment Using Atomic Force Microscopy.

    Science.gov (United States)

    Li, Mi; Xiao, Xiubin; Liu, Lianqing; Xi, Ning; Wang, Yuechao

    2016-10-01

    The applications of targeted drugs in treating cancers have significantly improved the survival rates of patients. However, in the clinical practice, targeted drugs are commonly combined with chemotherapy drugs, causing that the exact contribution of targeted drugs to the clinical outcome is difficult to evaluate. Quantitatively investigating the effects of targeted drugs on chemotherapy drugs on cancer cells is useful for us to understand drug actions and design better drugs. The advent of atomic force microscopy (AFM) provides a powerful tool for probing the nanoscale physiological activities of single live cells. In this paper, the detailed changes in cell morphology and mechanical properties were quantified on single lymphoma cells during the actions of rituximab (a monoclonal antibody targeted drug) and two chemotherapy drugs (cisplatin and cytarabine) by AFM. AFM imaging revealed the distinct changes of cellular ultramicrostructures induced by the drugs. The changes of cellular mechanical properties after the drug stimulations were measured by AFM indenting. The statistical histograms of cellular surface roughness and mechanical properties quantitatively showed that rituximab could remarkably strengthen the killing effects of chemotherapy drugs. The study offers a new way to quantify the synergistic interactions between targeted drugs and chemotherapy drugs at the nanoscale, which will have potential impacts on predicting the efficacies of drug combinations before clinical treatments.

  1. Hierarchical targeted hepatocyte mitochondrial multifunctional chitosan nanoparticles for anticancer drug delivery.

    Science.gov (United States)

    Chen, Zhipeng; Zhang, Liujie; Song, Yang; He, Jiayu; Wu, Li; Zhao, Can; Xiao, Yanyu; Li, Wei; Cai, Baochang; Cheng, Haibo; Li, Weidong

    2015-06-01

    The overwhelming majority of drugs exert their pharmacological effects after reaching their target sites of action, however, these target sites are mainly located in the cytosol or intracellular organelles. Consequently, delivering drugs to the specific organelle is the key to achieve maximum therapeutic effects and minimum side-effects. In the work reported here, we designed, synthesized, and evaluated a novel mitochondrial-targeted multifunctional nanoparticles (MNPs) based on chitosan derivatives according to the physiological environment of the tumor and the requirement of mitochondrial targeting drug delivery. The intelligent chitosan nanoparticles possess various functions such as stealth, hepatocyte targeting, multistage pH-response, lysosomal escape and mitochondrial targeting, which lead to targeted drug release after the progressively shedding of functional groups, thus realize the efficient intracellular delivery and mitochondrial localization, inhibit the growth of tumor, elevate the antitumor efficacy, and reduce the toxicity of anticancer drugs. It provides a safe and efficient nanocarrier platform for mitochondria targeting anticancer drug delivery.

  2. Autophagy modulation as a target for anticancer drug discovery

    Institute of Scientific and Technical Information of China (English)

    Xin LI; Huai-long XU; Yong-xi LIU; Na AN; Si ZHAO; Jin-ku BAO

    2013-01-01

    Autophagy,an evolutionarily conserved catabolic process involving the engulfment and degradation of non-essential or abnormal cellular organelles and proteins,is crucial for homeostatic maintenance in living cells.This highly regulated,multi-step process has been implicated in diverse diseases including cancer.Autophagy can function as either a promoter or a suppressor of cancer,which makes it a promising and challenging therapeutic target.Herein,we overview the regulatory mechanisms and dual roles of autophagy in cancer.We also describe some of the representative agents that exert their anticancer effects by regulating autophagy.Additionally,some emerging strategies aimed at modulating autophagy are discussed as having the potential for future anticancer drug discovery.In summary,these findings will provide valuable information to better utilize autophagy in the future development of anticancer therapeutics that meet clinical requirements.

  3. Current drug treatments targeting dopamine D3 receptor.

    Science.gov (United States)

    Leggio, Gian Marco; Bucolo, Claudio; Platania, Chiara Bianca Maria; Salomone, Salvatore; Drago, Filippo

    2016-09-01

    Dopamine receptors (DR) have been extensively studied, but only in recent years they became object of investigation to elucidate the specific role of different subtypes (D1R, D2R, D3R, D4R, D5R) in neural transmission and circuitry. D1-like receptors (D1R and D5R) and D2-like receptors (D2R, D2R and D4R) differ in signal transduction, binding profile, localization in the central nervous system and physiological effects. D3R is involved in a number of pathological conditions, including schizophrenia, Parkinson's disease, addiction, anxiety, depression and glaucoma. Development of selective D3R ligands has been so far challenging, due to the high sequence identity and homology shared by D2R and D3R. As a consequence, despite a rational design of selective DR ligands has been carried out, none of currently available medicines selectively target a given D2-like receptor subtype. The availability of the D3R ligand [(11)C]-(+)-PHNO for positron emission tomography studies in animal models as well as in humans, allows researchers to estimate the expression of D3R in vivo; displacement of [(11)C]-(+)-PHNO binding by concurrent drug treatments is used to estimate the in vivo occupancy of D3R. Here we provide an overview of studies indicating D3R as a target for pharmacological therapy, and a review of market approved drugs endowed with significant affinity at D3R that are used to treat disorders where D3R plays a relevant role.

  4. Discovery of the target for immunomodulatory drugs (IMiDs).

    Science.gov (United States)

    Ito, Takumi; Ando, Hideki; Handa, Hiroshi

    2016-05-01

    Half a century ago, the sedative thalidomide caused a serious drug disaster because of its teratogenicity and was withdrawn from the market. However, thalidomide, which has returned to the market, is now used for the treatment of leprosy and multiple myeloma (MM) under strict control. The mechanism of thalidomide action had been a long-standing question. We developed a new affinity bead technology and identified cereblon (CRBN) as a thalidomide-binding protein. We found that CRBN functions as a substrate receptor of an E3 cullin-Ring ligase complex 4 (CRL4) and is a primary target of thalidomide teratogenicity. Recently, new thalidomide derivatives, called immunomodulatory drugs (IMiDs), have been developed by Celgene. Among them, lenalidomide (Len) and pomalidomide (Pom) were shown to exert strong therapeutic effects against MM. It was found that Len and Pom both bind CRBN-CRL4 and recruit neomorphic substrates (Ikaros and Aiolos). More recently it was reported that casein kinase 1a (Ck1a) was identified as a substrate for CRBN-CRL4 in the presence of Len, but not Pom. Ck1a breakdown explains why Len is specifically effective for myelodysplastic syndrome with 5q deletion. It is now proposed that binding of IMiDs to CRBN appears to alter the substrate specificity of CRBN-CRL4. In this review, we introduce recent findings on IMiDs.

  5. Adipokines as drug targets in diabetes and underlying disturbances.

    Science.gov (United States)

    Andrade-Oliveira, Vinícius; Câmara, Niels O S; Moraes-Vieira, Pedro M

    2015-01-01

    Diabetes and obesity are worldwide health problems. White fat dynamically participates in hormonal and inflammatory regulation. White adipose tissue is recognized as a multifactorial organ that secretes several adipose-derived factors that have been collectively termed "adipokines." Adipokines are pleiotropic molecules that gather factors such as leptin, adiponectin, visfatin, apelin, vaspin, hepcidin, RBP4, and inflammatory cytokines, including TNF and IL-1β, among others. Multiple roles in metabolic and inflammatory responses have been assigned to these molecules. Several adipokines contribute to the self-styled "low-grade inflammatory state" of obese and insulin-resistant subjects, inducing the accumulation of metabolic anomalies within these individuals, including autoimmune and inflammatory diseases. Thus, adipokines are an interesting drug target to treat autoimmune diseases, obesity, insulin resistance, and adipose tissue inflammation. The aim of this review is to present an overview of the roles of adipokines in different immune and nonimmune cells, which will contribute to diabetes as well as to adipose tissue inflammation and insulin resistance development. We describe how adipokines regulate inflammation in these diseases and their therapeutic implications. We also survey current attempts to exploit adipokines for clinical applications, which hold potential as novel approaches to drug development in several immune-mediated diseases.

  6. TRPV1: A Potential Drug Target for Treating Various Diseases

    Directory of Open Access Journals (Sweden)

    Rafael Brito

    2014-05-01

    Full Text Available Transient receptor potential vanilloid 1 (TRPV1 is an ion channel present on sensory neurons which is activated by heat, protons, capsaicin and a variety of endogenous lipids termed endovanilloids. As such, TRPV1 serves as a multimodal sensor of noxious stimuli which could trigger counteractive measures to avoid pain and injury. Activation of TRPV1 has been linked to chronic inflammatory pain conditions and peripheral neuropathy, as observed in diabetes. Expression of TRPV1 is also observed in non-neuronal sites such as the epithelium of bladder and lungs and in hair cells of the cochlea. At these sites, activation of TRPV1 has been implicated in the pathophysiology of diseases such as cystitis, asthma and hearing loss. Therefore, drugs which could modulate TRPV1 channel activity could be useful for the treatment of conditions ranging from chronic pain to hearing loss. This review describes the roles of TRPV1 in the normal physiology and pathophysiology of selected organs of the body and highlights how drugs targeting this channel could be important clinically.

  7. Tyrosine aminotransferase from Leishmania infantum: A new drug target candidate

    Directory of Open Access Journals (Sweden)

    Miguel Angel Moreno

    2014-12-01

    Full Text Available Leishmania infantum is the etiological agent of zoonotic visceral leishmaniasis in the Mediterranean basin. The disease is fatal without treatment, which has been based on antimonial pentavalents for more than 60 years. Due to resistances, relapses and toxicity to current treatment, the development of new drugs is required. The structure of the L. infantum tyrosine aminotransferase (LiTAT has been recently solved showing important differences with the mammalian orthologue. The characterization of LiTAT is reported herein. This enzyme is cytoplasmic and is over-expressed in the more infective stages and nitric oxide resistant parasites. Unlike the mammalian TAT, LiTAT is able to use ketomethiobutyrate as co-substrate. The pharmacophore model of LiTAT with this specific co-substrate is described herein. This may allow the identification of new inhibitors present in the databases. All the data obtained support that LiTAT is a good target candidate for the development of new anti-leishmanial drugs.

  8. Metabotropic glutamate receptors and interacting proteins: evolving drug targets.

    Science.gov (United States)

    Enz, Ralf

    2012-01-01

    The correct targeting, localization, regulation and signaling of metabotropic glutamate receptors (mGluRs) represent major mechanisms underlying the complex function of neuronal networks. These tasks are accomplished by the formation of synaptic signal complexes that integrate functionally related proteins such as neurotransmitter receptors, enzymes and scaffold proteins. By these means, proteins interacting with mGluRs are important regulators of glutamatergic neurotransmission. Most described mGluR interaction partners bind to the intracellular C-termini of the receptors. These domains are extensively spliced and phosphorylated, resulting in a high variability of binding surfaces offered to interacting proteins. Malfunction of mGluRs and associated proteins are linked to neurodegenerative and neuropsychiatric disorders including addiction, depression, epilepsy, schizophrenia, Alzheimer's, Huntington's and Parkinson's disease. MGluR associated signal complexes are dynamic structures that assemble and disassemble in response to the neuronal fate. This, in principle, allows therapeutic intervention, defining mGluRs and interacting proteins as promising drug targets. In the last years, several studies elucidated the geometry of mGluRs in contact with regulatory proteins, providing a solid fundament for the development of new therapeutic strategies. Here, I will give an overview of human disorders directly associated with mGluR malfunction, provide an up-to-date summary of mGluR interacting proteins and highlight recently described structures of mGluR domains in contact with binding partners.

  9. Optimized shapes of magnetic arrays for drug targeting applications

    Science.gov (United States)

    Barnsley, Lester C.; Carugo, Dario; Stride, Eleanor

    2016-06-01

    Arrays of permanent magnet elements have been utilized as light-weight, inexpensive sources for applying external magnetic fields in magnetic drug targeting applications, but they are extremely limited in the range of depths over which they can apply useful magnetic forces. In this paper, designs for optimized magnet arrays are presented, which were generated using an optimization routine to maximize the magnetic force available from an arbitrary arrangement of magnetized elements, depending on a set of design parameters including the depth of targeting (up to 50 mm from the magnet) and direction of force required. A method for assembling arrays in practice is considered, quantifying the difficulty of assembly and suggesting a means for easing this difficulty without a significant compromise to the applied field or force. Finite element simulations of in vitro magnetic retention experiments were run to demonstrate the capability of a subset of arrays to retain magnetic microparticles against flow. The results suggest that, depending on the choice of array, a useful proportion of particles (more than 10% ) could be retained at flow velocities up to 100 mm s-1 or to depths as far as 50 mm from the magnet. Finally, the optimization routine was used to generate a design for a Halbach array optimized to deliver magnetic force to a depth of 50 mm inside the brain.

  10. Cellular uptake and transcytosis of lipid-based nanoparticles across the intestinal barrier: Relevance for oral drug delivery.

    Science.gov (United States)

    Neves, Ana Rute; Queiroz, Joana Fontes; Costa Lima, Sofia A; Figueiredo, Francisco; Fernandes, Rui; Reis, Salette

    2016-02-01

    Oral administration is the preferred route for drug delivery and nanosystems represent a promising tool for protection and transport of hardly soluble, chemically unstable and poorly permeable drugs through the intestinal barrier. In the present work, we have studied lipid nanoparticles cellular uptake, internalization pathways and transcytosis routes through Caco-2 cell monolayers. Both lipid nanosystems presented similar size (∼180nm) and surface charge (-30mV). Nanostructured lipid carriers showed a higher cellular uptake and permeability across the barrier, but solid lipid nanoparticles could enter cells faster than the former. The internalization of lipid nanoparticles occurs mainly through a clathrin-mediated endocytosis mechanism, although caveolae-mediated endocytosis is also involved in the uptake. Both lipid nanoparticles were able to cross the intestinal barrier by a preferential transcellular route. This work contributed to a better knowledge of the developed nanosystems for the oral delivery of a wide spectrum of drugs.

  11. Testing paradigm for prediction of development-limiting barriers and human drug toxicity.

    Science.gov (United States)

    Sasseville, V G; Lane, J H; Kadambi, V J; Bouchard, P; Lee, F W; Balani, S K; Miwa, G T; Smith, P F; Alden, C L

    2004-11-01

    The financial investment grows exponentially as a new chemical entity advances through each stage of discovery and development. The opportunity exists for the modern toxicologist to significantly impact expenditures by the early prediction of potential toxicity/side effect barriers to development by aggressive evaluation of development-limiting liabilities early in drug discovery. Improved efficiency in pharmaceutical research and development lies both in leveraging "best in class" technology and integration with pharmacologic activities during hit-to-lead and early lead optimization stages. To meet this challenge, a discovery assay by stage (DABS) paradigm should be adopted. The DABS clearly delineates to discovery project teams the timing and type of assay required for advancement of compounds to each subsequent level of discovery and development. An integrative core pathology function unifying Drug Safety Evaluation, Molecular Technologies and Clinical Research groups that effectively spans all phases of drug discovery and development is encouraged to drive the DABS. The ultimate goal of such improved efficiency being the accurate prediction of toxicity and side effects that would occur in development before commitment of the large prerequisite resource. Good justification of this approach is that every reduction of development attrition by 10% results in an estimated increase in net present value by $100 million.

  12. Leptin signaling molecular actions and drug target in hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Jiang N

    2014-11-01

    leptin and Ob-R in cancer cells compared to normal cells, makes leptin an ideal drug target for the prevention and treatment of HCC, especially in obese patients. Keywords: hepatocellular carcinoma, leptin, leptin antagonist, leptin signaling, tumor angiogenesis, drug target

  13. PBIT: pipeline builder for identification of drug targets for infectious diseases.

    Science.gov (United States)

    Shende, Gauri; Haldankar, Harshala; Barai, Ram Shankar; Bharmal, Mohammed Husain; Shetty, Vinit; Idicula-Thomas, Susan

    2016-12-30

    PBIT (Pipeline Builder for Identification of drug Targets) is an online webserver that has been developed for screening of microbial proteomes for critical features of human drug targets such as being non-homologous to human proteome as well as the human gut microbiota, essential for the pathogen's survival, participation in pathogen-specific pathways etc. The tool has been validated by analyzing 57 putative targets of Candida albicans documented in literature. PBIT integrates various in silico approaches known for drug target identification and will facilitate high-throughput prediction of drug targets for infectious diseases, including multi-pathogenic infections.

  14. A platinum-based hybrid drug design approach to circumvent acquired resistance to molecular targeted tyrosine kinase inhibitors

    Science.gov (United States)

    Wei, Yuming; Poon, Daniel C.; Fei, Rong; Lam, Amy S. M.; Au-Yeung, Steve C. F.; To, Kenneth K. W.

    2016-05-01

    Three molecular targeted tyrosine kinase inhibitors (TKI) were conjugated to classical platinum-based drugs with an aim to circumvent TKI resistance, predominately mediated by the emergence of secondary mutations on oncogenic kinases. The hybrids were found to maintain specificity towards the same oncogenic kinases as the original TKI. Importantly, they are remarkably less affected by TKI resistance, presumably due to their unique structure and the observed dual mechanism of anticancer activity (kinase inhibition and DNA damage). The study is also the first to report the application of a hybrid drug approach to switch TKIs from being efflux transporter substrates into non-substrates. TKIs cannot penetrate into the brain for treating metastases because of efflux transporters at the blood brain barrier. The hybrids were found to escape drug efflux and they accumulate more than the original TKI in the brain in BALB/c mice. Further development of the hybrid compounds is warranted.

  15. A platinum-based hybrid drug design approach to circumvent acquired resistance to molecular targeted tyrosine kinase inhibitors.

    Science.gov (United States)

    Wei, Yuming; Poon, Daniel C; Fei, Rong; Lam, Amy S M; Au-Yeung, Steve C F; To, Kenneth K W

    2016-05-06

    Three molecular targeted tyrosine kinase inhibitors (TKI) were conjugated to classical platinum-based drugs with an aim to circumvent TKI resistance, predominately mediated by the emergence of secondary mutations on oncogenic kinases. The hybrids were found to maintain specificity towards the same oncogenic kinases as the original TKI. Importantly, they are remarkably less affected by TKI resistance, presumably due to their unique structure and the observed dual mechanism of anticancer activity (kinase inhibition and DNA damage). The study is also the first to report the application of a hybrid drug approach to switch TKIs from being efflux transporter substrates into non-substrates. TKIs cannot penetrate into the brain for treating metastases because of efflux transporters at the blood brain barrier. The hybrids were found to escape drug efflux and they accumulate more than the original TKI in the brain in BALB/c mice. Further development of the hybrid compounds is warranted.

  16. Dendrimers in drug delivery and targeting: Drug-dendrimer interactions and toxicity issues

    Directory of Open Access Journals (Sweden)

    Kanika Madaan

    2014-01-01

    Full Text Available Dendrimers are the emerging polymeric architectures that are known for their defined structures, versatility in drug delivery and high functionality whose properties resemble with biomolecules. These nanostructured macromolecules have shown their potential abilities in entrapping and/or conjugating the high molecular weight hydrophilic/hydrophobic entities by host-guest interactions and covalent bonding (prodrug approach respectively. Moreover, high ratio of surface groups to molecular volume has made them a promising synthetic vector for gene delivery. Owing to these properties dendrimers have fascinated the researchers in the development of new drug carriers and they have been implicated in many therapeutic and biomedical applications. Despite of their extensive applications, their use in biological systems is limited due to toxicity issues associated with them. Considering this, the present review has focused on the different strategies of their synthesis, drug delivery and targeting, gene delivery and other biomedical applications, interactions involved in formation of drug-dendrimer complex along with characterization techniques employed for their evaluation, toxicity problems and associated approaches to alleviate their inherent toxicity.

  17. From laptop to benchtop to bedside: Structure-based Drug Design on Protein Targets

    OpenAIRE

    Chen, Lu; Morrow, John K.; Tran, Hoang T.; Phatak, Sharangdhar S.; Du-Cuny, Lei; Zhang, Shuxing

    2012-01-01

    As an important aspect of computer-aided drug design, structure-based drug design brought a new horizon to pharmaceutical development. This in silico method permeates all aspects of drug discovery today, including lead identification, lead optimization, ADMET prediction and drug repurposing. Structure-based drug design has resulted in fruitful successes drug discovery targeting protein-ligand and protein-protein interactions. Meanwhile, challenges, noted by low accuracy and combinatoric issue...

  18. Blood-brain barrier pathology in Alzheimer's and Parkinson's disease: implications for drug therapy.

    Science.gov (United States)

    Desai, Brinda S; Monahan, Angela J; Carvey, Paul M; Hendey, Bill

    2007-01-01

    The blood-brain barrier (BBB) is a tightly regulated barrier in the central nervous system. Though the BBB is thought to be intact during neurodegenerative diseases such as Alzheimer's (AD) and Parkinson's disease (PD), recent evidence argues otherwise. Dysfunction of the BBB may be involved in disease progression, eliciting of peripheral immune response, and, most importantly, altered drug efficacy. In this review, we will give a brief overview of the BBB, its components, and their functions. We will critically evaluate the current literature in AD and PD BBB pathology resulting from insult, neuroinflammation, and neurodegeneration. Specifically, we will discuss alterations in tight junction, transport and endothelial cell surface proteins, and vascular density changes, all of which result in altered permeability. Finally, we will discuss the implications of BBB dysfunction in current and future therapeutics. Developing a better appreciation of BBB dysfunction in AD and PD may not only provide novel strategies in treatment, but will prove an interesting milestone in understanding neurodegenerative disease etiology and progression.

  19. Social and structural barriers to housing among street-involved youth who use illicit drugs.

    Science.gov (United States)

    Krüsi, Andrea; Fast, Danya; Small, Will; Wood, Evan; Kerr, Thomas

    2010-05-01

    In Canada, approximately 150,000 youth live on the street. Street-involvement and homelessness have been associated with various health risks, including increased substance use, blood-borne infections and sexually transmitted diseases. We undertook a qualitative study to better understand the social and structural barriers street-involved youth who use illicit drugs encounter when seeking housing. We conducted 38 semi-structured interviews with street-involved youth in Vancouver, Canada from May to October 2008. Interviewees were recruited from the At-risk Youth Study (ARYS) cohort, which follows youth aged 14 to 26 who have experience with illicit drug use. All interviews were thematically analyzed, with particular emphasis on participants' perspectives regarding their housing situation and their experiences seeking housing. Many street-involved youth reported feeling unsupported in their efforts to find housing. For the majority of youth, existing abstinence-focused shelters did not constitute a viable option and, as a result, many felt excluded from these facilities. Many youth identified inflexible shelter rules and a lack of privacy as outweighing the benefits of sleeping indoors. Single-room occupancy hotels (SROs) were reported to be the only affordable housing options, as many landlords would not rent to youth on welfare. Many youth reported resisting moving to SROs as they viewed them as unsafe and as giving up hope for a return to mainstream society. The findings of the present study shed light on the social and structural barriers street-involved youth face in attaining housing and challenge the popular view of youth homelessness constituting a lifestyle choice. Our findings point to the need for housing strategies that include safe, low threshold, harm reduction focused housing options for youth who engage in illicit substance use.

  20. Blood-brain barrier models and their relevance for a successful development of CNS drug delivery systems: a review.

    Science.gov (United States)

    Bicker, Joana; Alves, Gilberto; Fortuna, Ana; Falcão, Amílcar

    2014-08-01

    During the research and development of new drugs directed at the central nervous system, there is a considerable attrition rate caused by their hampered access to the brain by the blood-brain barrier. Throughout the years, several in vitro models have been developed in an attempt to mimic critical functionalities of the blood-brain barrier and reliably predict the permeability of drug candidates. However, the current challenge lies in developing a model that retains fundamental blood-brain barrier characteristics and simultaneously remains compatible with the high throughput demands of pharmaceutical industries. This review firstly describes the roles of all elements of the neurovascular unit and their influence on drug brain penetration. In vitro models, including non-cell based and cell-based models, and in vivo models are herein presented, with a particular emphasis on their methodological aspects. Lastly, their contribution to the improvement of brain drug delivery strategies and drug transport across the blood-brain barrier is also discussed.

  1. Identification of multi-drug resistant Pseudomonas aeruginosa clinical isolates that are highly disruptive to the intestinal epithelial barrier

    Directory of Open Access Journals (Sweden)

    Shevchenko Olga

    2006-06-01

    Full Text Available Abstract Background Multi-drug resistant Pseudomonas aeruginosa nosocomial infections are increasingly recognized worldwide. In this study, we focused on the virulence of multi-drug resistant clinical strains P. aeruginosa against the intestinal epithelial barrier, since P. aeruginosa can cause lethal sepsis from within the intestinal tract of critically ill and immuno-compromised patients via mechanisms involving disruption of epithelial barrier function. Methods We screened consecutively isolated multi-drug resistant P. aeruginosa clinical strains for their ability to disrupt the integrity of human cultured intestinal epithelial cells (Caco-2 and correlated these finding to related virulence phenotypes such as adhesiveness, motility, biofilm formation, and cytotoxicity. Results Results demonstrated that the majority of the multi-drug resistant P. aeruginosa clinical strains were attenuated in their ability to disrupt the barrier function of cultured intestinal epithelial cells. Three distinct genotypes were found that displayed an extreme epithelial barrier-disrupting phenotype. These strains were characterized and found to harbor the exoU gene and to display high swimming motility and adhesiveness. Conclusion These data suggest that detailed phenotypic analysis of the behavior of multi-drug resistant P. aeruginosa against the intestinal epithelium has the potential to identify strains most likely to place patients at risk for lethal gut-derived sepsis. Surveillance of colonizing strains of P. aeruginosa in critically ill patients beyond antibiotic sensitivity is warranted.

  2. Permeability analysis of neuroactive drugs through a dynamic microfluidic in vitro blood-brain barrier model.

    Science.gov (United States)

    Booth, R; Kim, H

    2014-12-01

    This paper presents the permeability analysis of neuroactive drugs and correlation with in vivo brain/plasma ratios in a dynamic microfluidic blood-brain barrier (BBB) model. Permeability of seven neuroactive drugs (Ethosuximide, Gabapentin, Sertraline, Sunitinib, Traxoprodil, Varenicline, PF-304014) and trans-endothelial electrical resistance (TEER) were quantified in both dynamic (microfluidic) and static (transwell) BBB models, either with brain endothelial cells (bEnd.3) in monoculture, or in co-culture with glial cells (C6). Dynamic cultures were exposed to 15 dyn/cm(2) shear stress to mimic the in vivo environment. Dynamic models resulted in significantly higher average TEER (respective 5.9-fold and 8.9-fold increase for co-culture and monoculture models) and lower drug permeabilities (average respective decrease of 0.050 and 0.052 log(cm/s) for co-culture and monoculture) than static models; and co-culture models demonstrated higher average TEER (respective 90 and 25% increase for static and dynamic models) and lower drug permeability (average respective decrease of 0.063 and 0.061 log(cm/s) for static and dynamic models) than monoculture models. Correlation of the resultant logP e values [ranging from -4.06 to -3.63 log(cm/s)] with in vivo brain/plasma ratios (ranging from 0.42 to 26.8) showed highly linear correlation (R (2) > 0.85) for all model conditions, indicating the feasibility of the dynamic microfluidic BBB model for prediction of BBB clearance of pharmaceuticals.

  3. Identification and Characterization of Genes Involved in Leishmania Pathogenesis: The Potential for Drug Target Selection

    Directory of Open Access Journals (Sweden)

    Robert Duncan

    2011-01-01

    Full Text Available Identifying and characterizing Leishmania donovani genes and the proteins they encode for their role in pathogenesis can reveal the value of this approach for finding new drug targets. Effective drug targets are likely to be proteins differentially expressed or required in the amastigote life cycle stage found in the patient. Several examples and their potential for chemotherapeutic disruption are presented. A pathway nearly ubiquitous in living cells targeted by anticancer drugs, the ubiquitin system, is examined. New findings in ubiquitin and ubiquitin-like modifiers in Leishmania show how disruption of those pathways could point to additional drug targets. The programmed cell death pathway, now recognized among protozoan parasites, is reviewed for some of its components and evidence that suggests they could be targeted for antiparasitic drug therapy. Finally, the endoplasmic reticulum quality control system is involved in secretion of many virulence factors. How disruptions in this pathway reduce virulence as evidence for potential drug targets is presented.

  4. A series of case studies: practical methodology for identifying antinociceptive multi-target drugs.

    Science.gov (United States)

    Pang, Min-Hee; Kim, Yuntae; Jung, Kyung Woon; Cho, Sunyoung; Lee, Doo H

    2012-05-01

    Since the introduction of drug discovery based on single targets, the number of newly developed drugs has steadily declined, and the reliablility of the current drug-discovery paradigm has been unceasingly questioned. As an alternative, an emerging approach pursuing multi-targeting drugs has arisen to reflect multifactorial diseases caused by the complex networks of various mechanisms. The purpose of this paper is to review multi-target drugs and introduce our progress in establishing a practical methodology for identifying antinociceptive multi-target drugs. We have adopted a system of ex vivo efficacy screening using long-term potentiation in rat spinal cord as a surrogate biomarker for neuropathic pain. A bait-target approach is also adopted to lure an unknown target combination that induces synergistic mechanisms.

  5. Identifying the Right Disease Targets to Develop Better Drugs, Faster | NIH MedlinePlus the Magazine

    Science.gov (United States)

    ... JavaScript on. Identifying the Right Disease Targets to Develop Better Drugs, Faster Past Issues / Spring 2014 Table ... a-dozen pharmaceutical companies are now racing to develop drugs that lower cholesterol by blocking PCSK9. Are ...

  6. Drugging the Undruggable: Therapeutic Potential of Targeting Protein Tyrosine Phosphatases.

    Science.gov (United States)

    Zhang, Zhong-Yin

    2017-01-17

    Protein tyrosine phosphatases (PTPs) are essential signaling enzymes that, together with protein tyrosine kinases, regulate tyrosine phosphorylation inside the cell. Proper level of tyrosine phosphorylation is important for a diverse array of cellular processes, such as proliferation, metabolism, motility, and survival. Aberrant tyrosine phosphorylation, resulting from alteration of PTP expression, misregulation, and mutation, has been linked to the etiology of many human ailments including cancer, diabetes/obesity, autoimmune disorders, and infectious diseases. However, despite the fact that PTPs have been garnering attention as compelling drug targets, they remain a largely underexploited resource for therapeutic intervention. Indeed, PTPs have been widely dismissed as "undruggable", due to concerns that (1) the highly conserved active site (i.e., pTyr-binding pocket) makes it difficult to achieve inhibitor selectivity among closely related family members, and (2) the positive-charged active site prefers negatively charged molecules, which usually lack cell permeability. To address the issue of selectivity, we advanced a novel paradigm for the acquisition of highly potent and selective PTP inhibitors through generation of bivalent ligands that interact with both PTP active site and adjacent unique peripheral pockets. To overcome the bioavailability issue, we have identified nonhydrolyzable pTyr mimetics that are sufficiently polar to bind the PTP active site, yet still capable of efficiently penetrating cell membranes. We show that these pTyr mimetics interact in the desired inhibitory fashion with the PTP active site and tethering them to appropriate molecular fragments to engage less conserved interactions outside of PTP active site can increase PTP inhibitor potency and selectivity. We demonstrate through three pTyr mimetics fragment-based approaches that it is completely feasible to obtain highly potent and selective PTP inhibitors with robust in vivo

  7. RFDT: A Rotation Forest-based Predictor for Predicting Drug-Target Interactions using Drug Structure and Protein Sequence Information.

    Science.gov (United States)

    Wang, Lei; You, Zhu-Hong; Chen, Xing; Yan, Xin; Liu, Gang; Zhang, Wei

    2016-11-14

    Identification of interaction between drugs and target proteins plays an important role in discovering new drug candidates. However, through the experimental method to identify the drug-target interactions remain to be extremely time-consuming, expensive and challenging even nowadays. Therefore, it is urgent to develop new computational methods to predict potential drug-target interactions (DTI). In this article, a novel computational model is developed for predicting potential drug-target interactions under the theory that each drug-target interaction pair can be represented by the structural properties from drugs and evolutionary information derived from proteins. Specifically, the protein sequences are encoded as Position-Specific Scoring Matrix (PSSM) descriptor which contains information of biological evolutionary and the drug molecules are encoded as fingerprint feature vector which represents the existence of certain functional groups or fragments. Four benchmark datasets involving enzymes, ion channels, GPCRs and nuclear receptors, are independently used for establishing predictive models with Rotation Forest (RF) model. The proposed method achieved the prediction accuracy of 91.3%, 89.1%, 84.1% and 71.1% for four datasets respectively. In order to make our method more persuasive, we compared our classifier with the state-of-the-art Support Vector Machine (SVM) classifier. We also compared the proposed method with other excellent methods. Experimental results demonstrate that the proposed method is effective in the prediction of DTI, and can provide assistance for new drug research and development.

  8. Legionella pneumophila Carbonic Anhydrases: Underexplored Antibacterial Drug Targets

    Directory of Open Access Journals (Sweden)

    Claudiu T. Supuran

    2016-06-01

    Full Text Available Carbonic anhydrases (CAs, EC 4.2.1.1 are metalloenzymes which catalyze the hydration of carbon dioxide to bicarbonate and protons. Many pathogenic bacteria encode such enzymes belonging to the α-, β-, and/or γ-CA families. In the last decade, enzymes from some of these pathogens, including Legionella pneumophila, have been cloned and characterized in detail. These enzymes were shown to be efficient catalysts for CO2 hydration, with kcat values in the range of (3.4–8.3 × 105 s−1 and kcat/KM values of (4.7–8.5 × 107 M−1·s−1. In vitro inhibition studies with various classes of inhibitors, such as anions, sulfonamides and sulfamates, were also reported for the two β-CAs from this pathogen, LpCA1 and LpCA2. Inorganic anions were millimolar inhibitors, whereas diethyldithiocarbamate, sulfamate, sulfamide, phenylboronic acid, and phenylarsonic acid were micromolar ones. The best LpCA1 inhibitors were aminobenzolamide and structurally similar sulfonylated aromatic sulfonamides, as well as acetazolamide and ethoxzolamide (KIs in the range of 40.3–90.5 nM. The best LpCA2 inhibitors belonged to the same class of sulfonylated sulfonamides, together with acetazolamide, methazolamide, and dichlorophenamide (KIs in the range of 25.2–88.5 nM. Considering such preliminary results, the two bacterial CAs from this pathogen represent promising yet underexplored targets for obtaining antibacterials devoid of the resistance problems common to most of the clinically used antibiotics, but further studies are needed to validate them in vivo as drug targets.

  9. Platelets as Contractile Nanomachines for Targeting Drug Delivery in Hemostasis and Thrombosis

    Science.gov (United States)

    2015-12-01

    AWARD NUMBER: W81XWH-13-1-0495 TITLE: Platelets as Contractile Nanomachines for Targeting Drug Delivery in Hemostasis and Thrombosis PRINCIPAL...TITLE AND SUBTITLE 5a. CONTRACT NUMBER Platelets as Contractile Nanomachines for Targeting Drug Delivery in Hemostasis and Thrombosis 5b. GRANT...controlled nanocarriers as a novel and potentially paradigm-shifting strategy for targeted drug delivery to achieve hemostasis during bleeding. We have

  10. Off-Target Effects of Psychoactive Drugs Revealed by Genome-Wide Assays in Yeast

    OpenAIRE

    2008-01-01

    To better understand off-target effects of widely prescribed psychoactive drugs, we performed a comprehensive series of chemogenomic screens using the budding yeast Saccharomyces cerevisiae as a model system. Because the known human targets of these drugs do not exist in yeast, we could employ the yeast gene deletion collections and parallel fitness profiling to explore potential off-target effects in a genome-wide manner. Among 214 tested, documented psychoactive drugs, we identified 81 comp...

  11. Combating Drug Abuse by Targeting Toll-Like Receptor 4 (TLR)

    Science.gov (United States)

    2015-12-01

    AWARD NUMBER: W81XWH-12-1-0345 PROJECT TITLE: Combating drug abuse by targeting toll-like receptor 4 (TLR) PRINCIPAL INVESTIGATOR: Dr. Linda...5a. CONTRACT NUMBER not applicable Combating drug abuse by targeting toll-like receptor 4 (TLR) 5b. GRANT NUMBER W81XWH-12-1-0345 5c. PROGRAM...naltrexone; drug abuse ; glial activation; therapeutic approach to treating drug abuse ; opioids; cocaine 16. SECURITY CLASSIFICATION OF: 17. LIMITATION

  12. Serine Proteases of Malaria Parasite Plasmodium falciparum: Potential as Antimalarial Drug Targets

    OpenAIRE

    Asrar Alam

    2014-01-01

    Malaria is a major global parasitic disease and a cause of enormous mortality and morbidity. Widespread drug resistance against currently available antimalarials warrants the identification of novel drug targets and development of new drugs. Malarial proteases are a group of molecules that serve as potential drug targets because of their essentiality for parasite life cycle stages and feasibility of designing specific inhibitors against them. Proteases belonging to various mechanistic classes...

  13. Drug-target interaction prediction: databases, web servers and computational models.

    Science.gov (United States)

    Chen, Xing; Yan, Chenggang Clarence; Zhang, Xiaotian; Zhang, Xu; Dai, Feng; Yin, Jian; Zhang, Yongdong

    2016-07-01

    Identification of drug-target interactions is an important process in drug discovery. Although high-throughput screening and other biological assays are becoming available, experimental methods for drug-target interaction identification remain to be extremely costly, time-consuming and challenging even nowadays. Therefore, various computational models have been developed to predict potential drug-target associations on a large scale. In this review, databases and web servers involved in drug-target identification and drug discovery are summarized. In addition, we mainly introduced some state-of-the-art computational models for drug-target interactions prediction, including network-based method, machine learning-based method and so on. Specially, for the machine learning-based method, much attention was paid to supervised and semi-supervised models, which have essential difference in the adoption of negative samples. Although significant improvements for drug-target interaction prediction have been obtained by many effective computational models, both network-based and machine learning-based methods have their disadvantages, respectively. Furthermore, we discuss the future directions of the network-based drug discovery and network approach for personalized drug discovery based on personalized medicine, genome sequencing, tumor clone-based network and cancer hallmark-based network. Finally, we discussed the new evaluation validation framework and the formulation of drug-target interactions prediction problem by more realistic regression formulation based on quantitative bioactivity data.

  14. Targeted lipid based drug conjugates: a novel strategy for drug delivery.

    Science.gov (United States)

    Vadlapudi, Aswani Dutt; Vadlapatla, Ramya Krishna; Kwatra, Deep; Earla, Ravinder; Samanta, Swapan K; Pal, Dhananjay; Mitra, Ashim K

    2012-09-15

    A majority of studies involving prodrugs are directed to overcome low bioavailability of the parent drug. The aim of this study is to increase the bioavailability of acyclovir (ACV) by designing a novel prodrug delivery system which is more lipophilic, and at the same time site specific. In this study, a lipid raft has been conjugated to the parent drug molecule to impart lipophilicity. Simultaneously a targeting moiety that can be recognized by a specific transporter/receptor in the cell membrane has also been tethered to the other terminal of lipid raft. Targeted lipid prodrugs i.e., biotin-ricinoleicacid-acyclovir (B-R-ACV) and biotin-12hydroxystearicacid-acyclovir (B-12HS-ACV) were synthesized with ricinoleicacid and 12hydroxystearicacid as the lipophilic rafts and biotin as the targeting moiety. Biotin-ACV (B-ACV), ricinoleicacid-ACV (R-ACV) and 12hydroxystearicacid-ACV (12HS-ACV) were also synthesized to delineate the individual effects of the targeting and the lipid moieties. Cellular accumulation studies were performed in confluent MDCK-MDR1 and Caco-2 cells. The targeted lipid prodrugs B-R-ACV and B-12HS-ACV exhibited much higher cellular accumulation than B-ACV, R-ACV and 12HS-ACV in both cell lines. This result indicates that both the targeting and the lipid moiety act synergistically toward cellular uptake. The biotin conjugated prodrugs caused a decrease in the uptake of [(3)H] biotin suggesting the role of sodium dependent multivitamin transporter (SMVT) in uptake. The affinity of these targeted lipid prodrugs toward SMVT was studied in MDCK-MDR1 cells. Both the targeted lipid prodrugs B-R-ACV (20.25 ± 1.74 μM) and B-12HS-ACV (23.99 ± 3.20 μM) demonstrated higher affinity towards SMVT than B-ACV (30.90 ± 4.19 μM). Further, dose dependent studies revealed a concentration dependent inhibitory effect on [(3)H] biotin uptake in the presence of biotinylated prodrugs. Transepithelial transport studies showed lowering of [(3)H] biotin permeability in

  15. The drug-target residence time model: a 10-year retrospective.

    Science.gov (United States)

    Copeland, Robert A

    2016-02-01

    The drug-target residence time model was first introduced in 2006 and has been broadly adopted across the chemical biology, biotechnology and pharmaceutical communities. While traditional in vitro methods view drug-target interactions exclusively in terms of equilibrium affinity, the residence time model takes into account the conformational dynamics of target macromolecules that affect drug binding and dissociation. The key tenet of this model is that the lifetime (or residence time) of the binary drug-target complex, and not the binding affinity per se, dictates much of the in vivo pharmacological activity. Here, this model is revisited and key applications of it over the past 10 years are highlighted.

  16. Drug delivery in overcoming the blood–brain barrier: role of nasal mucosal grafting

    Science.gov (United States)

    Marianecci, Carlotta; Rinaldi, Federica; Hanieh, Patrizia Nadia; Di Marzio, Luisa; Paolino, Donatella; Carafa, Maria

    2017-01-01

    The blood–brain barrier (BBB) plays a fundamental role in protecting and maintaining the homeostasis of the brain. For this reason, drug delivery to the brain is much more difficult than that to other compartments of the body. In order to bypass or cross the BBB, many strategies have been developed: invasive techniques, such as temporary disruption of the BBB or direct intraventricular and intracerebral administration of the drug, as well as noninvasive techniques. Preliminary results, reported in the large number of studies on the potential strategies for brain delivery, are encouraging, but it is far too early to draw any conclusion about the actual use of these therapeutic approaches. Among the most recent, but still pioneering, approaches related to the nasal mucosa properties, the permeabilization of the BBB via nasal mucosal engrafting can offer new potential opportunities. It should be emphasized that this surgical procedure is quite invasive, but the implication for patient outcome needs to be compared to the gold standard of direct intracranial injection, and evaluated whilst keeping in mind that central nervous system diseases and lysosomal storage diseases are chronic and severely debilitating and that up to now no therapy seems to be completely successful. PMID:28184152

  17. Neuropeptides as targets for the development of anticonvulsant drugs.

    Science.gov (United States)

    Clynen, Elke; Swijsen, Ann; Raijmakers, Marjolein; Hoogland, Govert; Rigo, Jean-Michel

    2014-10-01

    Epilepsy is a common neurological disorder characterized by recurrent seizures. These seizures are due to abnormal excessive and synchronous neuronal activity in the brain caused by a disruption of the delicate balance between excitation and inhibition. Neuropeptides can contribute to such misbalance by modulating the effect of classical excitatory and inhibitory neurotransmitters. In this review, we discuss 21 different neuropeptides that have been linked to seizure disorders. These neuropeptides show an aberrant expression and/or release in animal seizure models and/or epilepsy patients. Many of these endogenous peptides, like adrenocorticotropic hormone, angiotensin, cholecystokinin, cortistatin, dynorphin, galanin, ghrelin, neuropeptide Y, neurotensin, somatostatin, and thyrotropin-releasing hormone, are able to suppress seizures in the brain. Other neuropeptides, such as arginine-vasopressine peptide, corticotropin-releasing hormone, enkephalin, β-endorphin, pituitary adenylate cyclase-activating polypeptide, and tachykinins have proconvulsive properties. For oxytocin and melanin-concentrating hormone both pro- and anticonvulsive effects have been reported, and this seems to be dose or time dependent. All these neuropeptides and their receptors are interesting targets for the development of new antiepileptic drugs. Other neuropeptides such as nesfatin-1 and vasoactive intestinal peptide have been less studied in this field; however, as nesfatin-1 levels change over the course of epilepsy, this can be considered as an interesting marker to diagnose patients who have suffered a recent epileptic seizure.

  18. Solid lipid nanoparticles carrying chemotherapeutic drug across the blood-brain barrier through insulin receptor-mediated pathway.

    Science.gov (United States)

    Kuo, Yung-Chih; Shih-Huang, Chun-Yuan

    2013-09-01

    Carmustine (BCNU)-loaded solid lipid nanoparticles (SLNs) were grafted with 83-14 monoclonal antibody (MAb) (83-14 MAb/BCNU-SLNs) and applied to the brain-targeting delivery. Human brain-microvascular endothelial cells (HBMECs) incubated with 83-14 MAb/BCNU-SLNs were stained to demonstrate the interaction between the nanocarriers and expressed insulin receptors (IRs). The results revealed that the particle size of 83-14 MAb/BCNU-SLNs decreased with an increasing weight percentage of Dynasan 114 (DYN). Storage at 4 °C for 6 weeks slightly deformed the colloidal morphology. In addition, poloxamer 407 on 83-14 MAb/BCNU-SLNs induced cytotoxicity to RAW264.7 cells and inhibited phagocytosis by RAW264.7 cells. An increase in the weight percentage of DYN from 0% to 67% slightly reduced the viability of RAW264.7 cells and promoted phagocytosis. Moreover, the transport ability of 83-14 MAb/BCNU-SLNs across the blood-brain barrier (BBB) in vitro enhanced with an increasing weight percentage of Tween 80. 83-14 MAb on MAb/BCNU-SLNs stimulated endocytosis by HBMECs via IRs and enhanced the permeability of BCNU across the BBB. 83-14 MAb/BCNU-SLNs can be a promising antitumor drug delivery system for transporting BCNU to the brain.

  19. Micro RNA, A Review: Pharmacogenomic drug targets for complex diseases

    Directory of Open Access Journals (Sweden)

    Sandhya Bawa

    2010-01-01

    Full Text Available

    Micro RNAs (miRNAs are non-coding RNAs that can regulate gene expression to target several mRNAs in a gene regulatory network. MiRNA related Single Nucleotide Polymorphisms (S.N.P.s represent a newly identified type of genetic variability that can be of influence to the risk of certain human diseases and also affect how drugs can be activated and metabolized by patients. This will help in personalized medicines which are used for administrating the correct dosage of drug and drug efficacy. miRNA deregulated expression has been extensively described in a variety of diseases such as Cancer, Obesity , Diabetes, Schizophrenia and control and self renewal of stem cells. MiRNA can function as oncogenes and/or tumor suppressors. MiRNAs may act as key regulators of processes as diverse as early development, cell proliferation and cell death, apoptosis and fat metabolism and cell differentiation .miRNA expression have shown their role in brain development chronic lymphocytic leukemia, colonic adeno carcinoma, Burkiff’s lymphoma and viral infection. These show their links with viral disease, neurodevelopment and cancer. It has been shown that they play a key role in melanoma metastasis. These may be

  20. Drug delivery in overcoming the blood–brain barrier: role of nasal mucosal grafting

    Directory of Open Access Journals (Sweden)

    Marianecci C

    2017-01-01

    Full Text Available Carlotta Marianecci,1 Federica Rinaldi,2 Patrizia Nadia Hanieh,1 Luisa Di Marzio,3 Donatella Paolino,4,5 Maria Carafa1 1Department of Drug Chemistry and Technology, University of Rome “Sapienza”, Rome, Italy; 2Center for Life Nano Science@Sapienza, Fondazione Istituto Italiano di Tecnologia, Rome, Italy; 3Department of Pharmacy, University “G. d’Annunzio”, Chieti, Italy; 4IRC FSH-Interregional Research Center for Food Safety & Health, Campus Universitario “S. Venuta”, University of Catanzaro “Magna Græcia”, Catanzaro, Italy; 5Department of Health Sciences, Campus Universitario “S. Venuta”, University of Catanzaro “Magna Græcia”, Catanzaro, Italy Abstract: The blood–brain barrier (BBB plays a fundamental role in protecting and maintaining the homeostasis of the brain. For this reason, drug delivery to the brain is much more difficult than that to other compartments of the body. In order to bypass or cross the BBB, many strategies have been developed: invasive techniques, such as temporary disruption of the BBB or direct intraventricular and intracerebral administration of the drug, as well as noninvasive techniques. Preliminary results, reported in the large number of studies on the potential strategies for brain delivery, are encouraging, but it is far too early to draw any conclusion about the actual use of these therapeutic approaches. Among the most recent, but still pioneering, approaches related to the nasal mucosa properties, the permeabilization of the BBB via nasal mucosal engrafting can offer new potential opportunities. It should be emphasized that this surgical procedure is quite invasive, but the implication for patient outcome needs to be compared to the gold standard of direct intracranial injection, and evaluated whilst keeping in mind that central nervous system diseases and lysosomal storage diseases are chronic and severely debilitating and that up to now no therapy seems to be completely

    1. Thiamin (Vitamin B1 Biosynthesis and Regulation: A Rich Source of Antimicrobial Drug Targets?

      Directory of Open Access Journals (Sweden)

      Qinglin Du, Honghai Wang, Jianping Xie

      2011-01-01

      Full Text Available Drug resistance of pathogens has necessitated the identification of novel targets for antibiotics. Thiamin (vitamin B1 is an essential cofactor for all organisms in its active form thiamin diphosphate (ThDP. Therefore, its metabolic pathways might be one largely untapped source of antibiotics targets. This review describes bacterial thiamin biosynthetic, salvage, and transport pathways. Essential thiamin synthetic enzymes such as Dxs and ThiE are proposed as promising drug targets. The regulation mechanism of thiamin biosynthesis by ThDP riboswitch is also discussed. As drug targets of existing antimicrobial compound pyrithiamin, the ThDP riboswitch might serves as alternative targets for more antibiotics.

    2. For Some Skin Cancers, Targeted Drug Hits the Mark

      Science.gov (United States)

      ... Food and Drug Administration approved a drug called vismodegib (Erivedge™) for treating advanced cases of basal cell ... the trial that led to the approval of vismodegib appeared in the New England Journal of Medicine ...

    3. iDrug-Target: predicting the interactions between drug compounds and target proteins in cellular networking via benchmark dataset optimization approach.

      Science.gov (United States)

      Xiao, Xuan; Min, Jian-Liang; Lin, Wei-Zhong; Liu, Zi; Cheng, Xiang; Chou, Kuo-Chen

      2015-01-01

      Information about the interactions of drug compounds with proteins in cellular networking is very important for drug development. Unfortunately, all the existing predictors for identifying drug-protein interactions were trained by a skewed benchmark data-set where the number of non-interactive drug-protein pairs is overwhelmingly larger than that of the interactive ones. Using this kind of highly unbalanced benchmark data-set to train predictors would lead to the outcome that many interactive drug-protein pairs might be mispredicted as non-interactive. Since the minority interactive pairs often contain the most important information for drug design, it is necessary to minimize this kind of misprediction. In this study, we adopted the neighborhood cleaning rule and synthetic minority over-sampling technique to treat the skewed benchmark datasets and balance the positive and negative subsets. The new benchmark datasets thus obtained are called the optimized benchmark datasets, based on which a new predictor called iDrug-Target was developed that contains four sub-predictors: iDrug-GPCR, iDrug-Chl, iDrug-Ezy, and iDrug-NR, specialized for identifying the interactions of drug compounds with GPCRs (G-protein-coupled receptors), ion channels, enzymes, and NR (nuclear receptors), respectively. Rigorous cross-validations on a set of experiment-confirmed datasets have indicated that these new predictors remarkably outperformed the existing ones for the same purpose. To maximize users' convenience, a public accessible Web server for iDrug-Target has been established at http://www.jci-bioinfo.cn/iDrug-Target/ , by which users can easily get their desired results. It has not escaped our notice that the aforementioned strategy can be widely used in many other areas as well.

    4. The biological significance of brain barrier mechanisms: help or hindrance in drug delivery to the central nervous system? [version 1; referees: 2 approved

      Directory of Open Access Journals (Sweden)

      Norman R. Saunders

      2016-03-01

      transporters, that provide an important component of the barrier functions by either preventing entry of or expelling numerous molecules including toxins, drugs, and other xenobiotics. In this review, we summarize these influx and efflux mechanisms in normal developing and adult brain, as well as indicating their likely involvement in a wide range of neuropathologies. There have been extensive attempts to overcome the barrier mechanisms that prevent the entry of many drugs of therapeutic potential into the brain. We outline those that have been tried and discuss why they may so far have been largely unsuccessful. Currently, a promising approach appears to be focal, reversible disruption of the blood-brain barrier using focused ultrasound, but more work is required to evaluate the method before it can be tried in patients. Overall, our view is that much more fundamental knowledge of barrier mechanisms and development of new experimental methods will be required before drug targeting to the brain is likely to be a successful endeavor. In addition, such studies, if applied to brain pathologies such as stroke, trauma, or multiple sclerosis, will aid in defining the contribution of brain barrier pathology to these conditions, either causative or secondary.

    5. Sterol Biosynthesis Pathway as Target for Anti-trypanosomatid Drugs

      Directory of Open Access Journals (Sweden)

      Wanderley de Souza

      2009-01-01

      Full Text Available Sterols are constituents of the cellular membranes that are essential for their normal structure and function. In mammalian cells, cholesterol is the main sterol found in the various membranes. However, other sterols predominate in eukaryotic microorganisms such as fungi and protozoa. It is now well established that an important metabolic pathway in fungi and in members of the Trypanosomatidae family is one that produces a special class of sterols, including ergosterol, and other 24-methyl sterols, which are required for parasitic growth and viability, but are absent from mammalian host cells. Currently, there are several drugs that interfere with sterol biosynthesis (SB that are in use to treat diseases such as high cholesterol in humans and fungal infections. In this review, we analyze the effects of drugs such as (a statins, which act on the mevalonate pathway by inhibiting HMG-CoA reductase, (b bisphosphonates, which interfere with the isoprenoid pathway in the step catalyzed by farnesyl diphosphate synthase, (c zaragozic acids and quinuclidines, inhibitors of squalene synthase (SQS, which catalyzes the first committed step in sterol biosynthesis, (d allylamines, inhibitors of squalene epoxidase, (e azoles, which inhibit C14α-demethylase, and (f azasterols, which inhibit Δ24(25-sterol methyltransferase (SMT. Inhibition of this last step appears to have high selectivity for fungi and trypanosomatids, since this enzyme is not found in mammalian cells. We review here the IC50 values of these various inhibitors, their effects on the growth of trypanosomatids (both in axenic cultures and in cell cultures, and their effects on protozoan structural organization (as evaluted by light and electron microscopy and lipid composition. The results show that the mitochondrial membrane as well as the membrane lining the protozoan cell body and flagellum are the main targets. Probably as a consequence of these primary effects, other important changes take

    6. Perception of the usefulness of drug/gene pairs and barriers for pharmacogenomics in Latin America.

      Science.gov (United States)

      Quinones, Luis Abel; Lavanderos, Maria Alejandra; Cayun, Juan Pablo; Garcia-Martin, Elena; Agundez, Jose Augusto; Caceres, Dante Daniel; Roco, Angela Margarita; Morales, Jorge E; Herrera, Luisa; Encina, Gonzalo; Isaza, Carlos Alberto; Redal, Maria Ana; Larovere, Laura; Soria, Nestor Walter; Eslava-Schmalbach, Javier; Castaneda-Hernandez, Gilberto; Lopez-Cortes, Andres; Magno, Luiz Alexandre; Lopez, Marisol; Chiurillo, Miguel Angel; Rodeiro, Idania; Castro de Guerra, Dinorah; Teran, Enrique; Estevez-Carrizo, Francisco; Lares-Assef, Ismael

      2014-02-01

      Pharmacogenetics and Pharmacogenomics areas are currently emerging fields focused to manage pharmacotherapy that may prevent undertreatment while avoiding associated drug toxicity in patients. Large international differences in the awareness and in the use of pharmacogenomic testing are presumed, but not well assessed to date. In the present study we review the awareness of Latin American scientific community about pharmacogenomic testing and the perceived barriers for their clinical application. In order to that, we have compiled information from 9 countries of the region using a structured survey which is compared with surveys previously performed in USA and Spain. The most relevant group of barriers was related to the need for clear guidelines for the use of pharmacogenomics in clinical practice, followed by insufficient awareness about pharmacogenomics among clinicians and the absence of regulatory institutions that facilitate the use of pharmacogenetic tests. The higher ranked pairs were TPMT/thioguanine, TPMT/azathioprine, CYP2C9/warfarin, UGT1A1/irinotecan, CYP2D6/amitriptiline, CYP2C19/citalopram and CYP2D6/clozapine. The lower ranked pairs were SLCO1B1/simvastatin, CYP2D6/metoprolol and GP6D/chloroquine. Compared with USA and Spanish surveys, 25 pairs were of lower importance for Latin American respondents. Only CYP2C19/esomeprazole, CYP2C19/omeprazole, CYP2C19/celecoxib and G6PD/dapsone were ranked higher or similarly to the USA and Spanish surveys. Integration of pharmacogenomics in clinical practice needs training of healthcare professionals and citizens, but in addition legal and regulatory guidelines and safeguards will be needed. We propose that the approach offered by pharmacogenomics should be incorporated into the decision-making plans in Latin America.

    7. Are Pharmaceuticals with Evolutionary Conserved Molecular Drug Targets More Potent to Cause Toxic Effects in Non-Target Organisms?

      Science.gov (United States)

      Furuhagen, Sara; Fuchs, Anne; Lundström Belleza, Elin; Breitholtz, Magnus; Gorokhova, Elena

      2014-01-01

      The ubiquitous use of pharmaceuticals has resulted in a continuous discharge into wastewater and pharmaceuticals and their metabolites are found in the environment. Due to their design towards specific drug targets, pharmaceuticals may be therapeutically active already at low environmental concentrations. Several human drug targets are evolutionary conserved in aquatic organisms, raising concerns about effects of these pharmaceuticals in non-target organisms. In this study, we hypothesized that the toxicity of a pharmaceutical towards a non-target invertebrate depends on the presence of the human drug target orthologs in this species. This was tested by assessing toxicity of pharmaceuticals with (miconazole and promethazine) and without (levonorgestrel) identified drug target orthologs in the cladoceran Daphnia magna. The toxicity was evaluated using general toxicity endpoints at individual (immobility, reproduction and development), biochemical (RNA and DNA content) and molecular (gene expression) levels. The results provide evidence for higher toxicity of miconazole and promethazine, i.e. the drugs with identified drug target orthologs. At the individual level, miconazole had the lowest effect concentrations for immobility and reproduction (0.3 and 0.022 mg L−1, respectively) followed by promethazine (1.6 and 0.18 mg L−1, respectively). At the biochemical level, individual RNA content was affected by miconazole and promethazine already at 0.0023 and 0.059 mg L−1, respectively. At the molecular level, gene expression for cuticle protein was significantly suppressed by exposure to both miconazole and promethazine; moreover, daphnids exposed to miconazole had significantly lower vitellogenin expression. Levonorgestrel did not have any effects on any endpoints in the concentrations tested. These results highlight the importance of considering drug target conservation in environmental risk assessments of pharmaceuticals. PMID:25140792

    8. Are pharmaceuticals with evolutionary conserved molecular drug targets more potent to cause toxic effects in non-target organisms?

      Science.gov (United States)

      Furuhagen, Sara; Fuchs, Anne; Lundström Belleza, Elin; Breitholtz, Magnus; Gorokhova, Elena

      2014-01-01

      The ubiquitous use of pharmaceuticals has resulted in a continuous discharge into wastewater and pharmaceuticals and their metabolites are found in the environment. Due to their design towards specific drug targets, pharmaceuticals may be therapeutically active already at low environmental concentrations. Several human drug targets are evolutionary conserved in aquatic organisms, raising concerns about effects of these pharmaceuticals in non-target organisms. In this study, we hypothesized that the toxicity of a pharmaceutical towards a non-target invertebrate depends on the presence of the human drug target orthologs in this species. This was tested by assessing toxicity of pharmaceuticals with (miconazole and promethazine) and without (levonorgestrel) identified drug target orthologs in the cladoceran Daphnia magna. The toxicity was evaluated using general toxicity endpoints at individual (immobility, reproduction and development), biochemical (RNA and DNA content) and molecular (gene expression) levels. The results provide evidence for higher toxicity of miconazole and promethazine, i.e. the drugs with identified drug target orthologs. At the individual level, miconazole had the lowest effect concentrations for immobility and reproduction (0.3 and 0.022 mg L-1, respectively) followed by promethazine (1.6 and 0.18 mg L-1, respectively). At the biochemical level, individual RNA content was affected by miconazole and promethazine already at 0.0023 and 0.059 mg L-1, respectively. At the molecular level, gene expression for cuticle protein was significantly suppressed by exposure to both miconazole and promethazine; moreover, daphnids exposed to miconazole had significantly lower vitellogenin expression. Levonorgestrel did not have any effects on any endpoints in the concentrations tested. These results highlight the importance of considering drug target conservation in environmental risk assessments of pharmaceuticals.

    9. Are pharmaceuticals with evolutionary conserved molecular drug targets more potent to cause toxic effects in non-target organisms?

      Directory of Open Access Journals (Sweden)

      Sara Furuhagen

      Full Text Available The ubiquitous use of pharmaceuticals has resulted in a continuous discharge into wastewater and pharmaceuticals and their metabolites are found in the environment. Due to their design towards specific drug targets, pharmaceuticals may be therapeutically active already at low environmental concentrations. Several human drug targets are evolutionary conserved in aquatic organisms, raising concerns about effects of these pharmaceuticals in non-target organisms. In this study, we hypothesized that the toxicity of a pharmaceutical towards a non-target invertebrate depends on the presence of the human drug target orthologs in this species. This was tested by assessing toxicity of pharmaceuticals with (miconazole and promethazine and without (levonorgestrel identified drug target orthologs in the cladoceran Daphnia magna. The toxicity was evaluated using general toxicity endpoints at individual (immobility, reproduction and development, biochemical (RNA and DNA content and molecular (gene expression levels. The results provide evidence for higher toxicity of miconazole and promethazine, i.e. the drugs with identified drug target orthologs. At the individual level, miconazole had the lowest effect concentrations for immobility and reproduction (0.3 and 0.022 mg L-1, respectively followed by promethazine (1.6 and 0.18 mg L-1, respectively. At the biochemical level, individual RNA content was affected by miconazole and promethazine already at 0.0023 and 0.059 mg L-1, respectively. At the molecular level, gene expression for cuticle protein was significantly suppressed by exposure to both miconazole and promethazine; moreover, daphnids exposed to miconazole had significantly lower vitellogenin expression. Levonorgestrel did not have any effects on any endpoints in the concentrations tested. These results highlight the importance of considering drug target conservation in environmental risk assessments of pharmaceuticals.

    10. ORAL COLON TARGETED DRUG DELIVERY SYSTEM: A REVIEW ON CURRENT AND NOVEL PERSPECTIVES

      Directory of Open Access Journals (Sweden)

      Asija Rajesh

      2012-10-01

      Full Text Available Small intestine is mostly the site for drug absorption but in some cases the drug needs to be targeted to colon due to some factors like local colonic disease, degradation related conditions, delayed release of drugs, systemic delivery of protein and peptide drugs etc. Colon targeted drug delivery is important and relatively new concept for the absorption of drugs because it offers almost neutral pH and long residence time, thereby increasing the drug absorption. Colon has proved to be a site for the absorption of poorly soluble drugs. For the successful targeting of drugs to colon the dosage form should be designed such that it prevents the drug release in upper GIT and releasing it in the colonic region. This review article discusses in brief about introduction of colon along with the novel and emerging technologies for colon targeting of drug molecule. Treatment of these diseases with colon-specific drug delivery system provides an interesting alternative over systemic drug administration because of lower dosing and fewer systemic side effects.

    11. Computer Aided Drug Design for Multi-Target Drug Design: SAR /QSAR, Molecular Docking and Pharmacophore Methods.

      Science.gov (United States)

      Abdolmaleki, Azizeh; Ghasemi, Jahan B; Ghasemi, Fatemeh

      2017-01-01

      Multi-target drugs against particular multiple targets get better protection, resistance profiles and curative influence by cooperative rules of a key beneficial target with resistance behavior and compensatory elements. Computational techniques can assist us in the efforts to design novel drugs (ligands) with a preferred bioactivity outline and alternative bioactive molecules at an early stage. A number of in silico methods have been explored extensively in order to facilitate the investigation of individual target agents and to propose a selective drug. A different, progressively more significant field which is used to predict the bioactivity of chemical compounds is the data mining method. Some of the previously mentioned methods have been investigated for multi-target drug design (MTDD) to find drug leads interact simultaneously with multiple targets. Several cheminformatics methods and structure-based approaches try to extract information from units working cooperatively in a biomolecular system to fulfill their task. To dominate the difficulties of the experimental specification of ligand-target structures, rational methods, namely molecular docking, SAR and QSAR are vital substitutes to obtain knowledge for each structure in atomic insight. These procedures are logically successful for the prediction of binding affinity and have shown promising potential in facilitating MTDD. Here, we review some of the important features of the multi-target therapeutics discoveries using the computational approach, highlighting the SAR, QSAR, docking and pharmacophore methods to discover interactions between drug-target that could be leveraged for curative benefits. A summary of each, followed by examples of its applications in drug design has been provided. Computational efficiency of each method has been represented according to its main strengths and limitations.

    12. Targeted and non-targeted drug screening in whole blood by UHPLC-TOF-MS with data-independent acquisition

      DEFF Research Database (Denmark)

      Mollerup, Christian Brinch; Dalsgaard, Petur Weihe; Mardal, Marie;

      2016-01-01

      High-resolution mass spectrometry (HRMS) is widely used for the drug screening of biological samples in clinical and forensic laboratories. With the continuous addition of new psychoactive substances (NPS), keeping such methods updated is challenging. HRMS allows for combined targeted and non-targeted...... screening. The aims of the study were to apply a combined targeted and non-targeted screening approach to authentic driving-under-the-influence-of-drugs (DUID) samples (n = 44) and further validate the approach using whole-blood samples spiked with eleven low-dose synthetic benzodiazepine analogues (SBA......). Analytical data were acquired using ultra-high-performance liquid chromatography coupled with a time-of-flight mass spectrometer (UHPLC-TOF-MS) with data-independent acquisition (DIA). We present a combined targeted and non-targeted screening, where peak deconvolution and filtering reduced the number...

    13. Drugs developed to treat diabetes, liraglutide and lixisenatide, cross the blood brain barrier and enhance neurogenesis

      Directory of Open Access Journals (Sweden)

      Hunter Kerry

      2012-03-01

      Full Text Available Abstract Background Type 2 diabetes is a risk factor for Alzheimer's disease (AD, most likely linked to an impairment of insulin signalling in the brain. Therefore, drugs that enhance insulin signalling may have therapeutic potential for AD. Liraglutide (Victoza and exenatide (Byetta are novel long-lasting analogues of the GLP-1 incretin hormone and are currently available to treat diabetes. They facilitate insulin signalling via the GLP-1 receptor (GLP-1R. Numerous in vitro and in vivo studies have shown that GLP-1 analogues have a range of neuroprotective properties. GLP-1Rs are expressed in the hippocampal area of the brain an important site of adult neurogenesis and maintenance of cognition and memory formation. Therefore, if GLP-1 analogues can cross the blood brain barrier, diffuse through the brain to reach the receptors and most importantly activate them, their neuroprotective effects may be realized. Results In the present study we profiled the GLP-1 receptor agonists liraglutide (Victoza and lixisenatide (Lyxumia. We measured the kinetics of crossing the blood brain barrier (BBB, activation of the GLP-1R by measuring cAMP levels, and physiological effects in the brain on neuronal stem cell proliferation and neurogenesis. Both drugs were able to cross the BBB. Lixisenatide crossed the BBB at all doses tested (2.5, 25, or 250 nmol/kg bw ip. when measured 30 min post-injection and at 2.5-25 nmol/kg bw ip. 3 h post-injection. Lixisenatide also enhanced neurogenesis in the brain. Liraglutide crossed the BBB at 25 and 250 nmol/kg ip. but no increase was detectable at 2.5 nmol/kg ip. 30 min post-injection, and at 250 nmol/kg ip. at 3 h post-injection. Liraglutide and lixisenatide enhanced cAMP levels in the brain, with lixisenatide being more effective. Conclusions Our results suggest that these novel incretin analogues cross the BBB and show physiological activity and neurogenesis in the brain, which may be of use as a treatment of

    14. Associating Drugs, Targets and Clinical Outcomes into an Integrated Network Affords a New Platform for Computer-Aided Drug Repurposing

      DEFF Research Database (Denmark)

      Oprea, Tudor; Nielsen, Sonny Kim; Ursu, Oleg

      2011-01-01

      benefit from an integrated, semantic-web compliant computer-aided drug repurposing (CADR) effort, one that would enable deep data mining of associations between approved drugs (D), targets (T), clinical outcomes (CO) and SE. We report preliminary results from text mining and multivariate statistics, based...

    15. On the possibility of the unification of drug targeting systems. Studies with liposome transport to the mixtures of target antigens.

      Science.gov (United States)

      Trubetskoy, V S; Berdichevsky, V R; Efremov, E E; Torchilin, V P

      1987-03-15

      In order to make the drug targeting system more effective, simple and technological, we suggest creation of drug-bearing conjugates capable of simultaneous binding with different antigenic components of the target via specific antibodies. It is supposed that the targeted therapy should include sequential administration of the mixture of modified antibodies (or other specific vectors) against different components of affected tissue and, upon antibody accumulation in the desired region, administration of modified drugs or drug carrying systems which can recognize and bind with the target via accumulated antibodies due to the interaction between vector modifier and carrier modifier. Using as a model system monolayers consisting of the mixture of extracellular antigens and appropriated antibodies, it was shown that the treatment of the target with the mixture of biotinylated antibodies against all target components and subsequent binding with the target of biotinylated liposomes via avidin permits high liposome accumulation on the monolayer. The binding achieved is always higher than in the case of the utilization of single antibody-bearing liposomes. Besides, the system suggested is very simple and its components can be easily obtained on technological scale in standardized conditions.

    16. Current Status of Targets and Assays for Anti-HIV Drug Screening

      Institute of Scientific and Technical Information of China (English)

      2007-01-01

      HIV/AIDS is one of the most serious public health challenges globally. Despite the great efforts that are being devoted to prevent, treat and to better understand the disease, it is one of the main causes of morbidity and mortality worldwide. Currently, there are 30 drugs or combinations of drugs approved by FDA. Because of the side-effects, price and drug resistance, it is essential to discover new targets, to develop new technology and to find new anti-HIV drugs. This review summarizes the major targets and assays currently used in anti-HIV drug screening.

    17. The application of antitumor drug-targeting models on liver cancer.

      Science.gov (United States)

      Yan, Yan; Chen, Ningbo; Wang, Yunbing; Wang, Ke

      2016-06-01

      Hepatocarcinoma animal models, such as the induced tumor model, transplanted tumor model, gene animal model, are significant experimental tools for the evaluation of targeting drug delivery system as well as the pre-clinical studies of liver cancer. The application of antitumor drug-targeting models not only furnishes similar biological characteristics to human liver cancer but also offers guarantee of pharmacokinetic indicators of the liver-targeting preparations. In this article, we have reviewed some kinds of antitumor drug-targeting models of hepatoma and speculated that the research on this field would be capable of attaining a deeper level and expecting a superior achievement in the future.

    18. THERMO-TARGETED DRUG DELIVERY OF GELDANAMYCIN TO HYPERTHERMIC TUMOR MARGINS WITH DIBLOCK ELASTIN-BASED BIOPOLYMERS

      Science.gov (United States)

      Chen, Y; Youn, P; Furgeson, DY

      2011-01-01

      The tumor margins are the barrier to hepatocellular carcinoma (HCC) eradication for tumors > 3 cm. Indeed, inadequately treated tumor margins commonly result in local and regional HCC recurrence with increased size and mass. Tumor recurrence is a common problem with chemotherapy, radiotherapy, thermal ablation, and/or surgical resection, by the inability to properly treat the tumor core and the tumor margins. Here we present novel thermosensitive biopolymer-drug conjugates for thermo-targeted chemotherapy at hyperthermic isotherms produced by focal, locoregional thermal ablation. The chemotherapeutic target is heat shock protein 90 (HSP90), a key molecular chaperone of several, and potent pro-oncogenic pathways including Akt, Raf-1, and mutated p53 that is upregulated in HCC. To inhibit HSP90, we have chosen geldanamycin (GA), a potent HSP90 inhibitor. GA has gained significant attention for its low IC50 ~ 1nM and inhibition of Akt and Raf-1, amongst other critical pro-oncogenic pathways. Despite such evidence, clinical trials of GA have not shown promise due to off-target toxicity and poor formulation design. Here, we propose using diblock elastin-based biopolymers as a Ringsdorf macromolecular GA solubilizer - a new generation containing functional poly(Asp)/(Glu) blocks for facile drug conjugation and an ELP block for thermo-targeting of hyperthermic ablative margins. GA release is controlled by pH-sensitive, covalent hydrazone bonds with the biopolymer backbone to avoid systemic toxicity and off-target effects. The resultant biopolymer-conjugates form stable nanoconstructs and display tunable, acute phase transitions at high temperatures. Drug release kinetics are favorable with or without the presence of serum. Thermo-targeted chemotherapy and synchronous thermal ablation provide a unique opportunity for simultaneous destruction of the HCC ablative margins and tumor core for focal, locoregional control of HCC. PMID:21846483

    19. 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.

    20. Raltegravir permeability across blood-tissue barriers and the potential role of drug efflux transporters.

      Science.gov (United States)

      Hoque, M Tozammel; Kis, Olena; De Rosa, María F; Bendayan, Reina

      2015-05-01

      The objectives of this study were to investigate raltegravir transport across several blood-tissue barrier models and the potential interactions with drug efflux transporters. Raltegravir uptake, accumulation, and permeability were evaluated in vitro in (i) P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), multidrug resistance-associated protein 1 (MRP1), or MRP4-overexpressing MDA-MDR1 (P-gp), HEK-ABCG2, HeLa-MRP1, or HEK-MRP4 cells, respectively; (ii) cell culture systems of the human blood-brain (hCMEC/D3), mouse blood-testicular (TM4), and human blood-intestinal (Caco-2) barriers; and (iii) rat jejunum and ileum segments using an in situ single-pass intestinal perfusion model. [(3)H]Raltegravir accumulation by MDA-MDR1 (P-gp) and HEK-ABCG2-overexpressing cells was significantly enhanced in the presence of PSC833 {6-[(2S,4R,6E)-4-methyl-2-(methylamino)-3-oxo-6-octenoic acid]-7-L-valine-cyclosporine}, a P-gp inhibitor, or Ko143 [(3S,6S,12aS)-1,2,3,4,6,7,12,12a-octahydro-9-methoxy-6-(2-methylpropyl)-1,4-dioxopyrazino[1',2':1,6]pyrido[3,4-b]indole-3-propanoic acid 1,1-dimethylethyl ester], a BCRP inhibitor, suggesting the inhibition of a P-gp- or BCRP-mediated efflux process, respectively. Furthermore, [(3)H]raltegravir accumulation by human cerebral microvessel endothelial hCMEC/D3 and mouse Sertoli TM4 cells was significantly increased by PSC833 and Ko143. In human intestinal Caco-2 cells grown on Transwell filters, PSC833, but not Ko143, significantly decreased the [(3)H]raltegravir efflux ratios. In rat intestinal segments, [(3)H]raltegravir in situ permeability was significantly enhanced by the concurrent administration of PSC833 and Ko143. In contrast, in the transporter inhibition assays, raltegravir (10 to 500 μM) did not increase the accumulation of substrate for P-gp (rhodamine-6G), BCRP ([(3)H]mitoxantrone), or MRP1 [2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein (BCECF)] by MDA-MDR1 (P-gp)-, HEK-ABCG2-, or HeLa-MRP1-overexpressing

    1. Finding potential drug targets against Shigella flexneri through druggable proteome exploration.

      Directory of Open Access Journals (Sweden)

      Mohammad Uzzal Hossain

      2016-11-01

      Full Text Available Abstract:Background: Shigella flexneri is a gram negative bacteria that causes the infectious disease ‘shigellosis’. Shigella flexneri (S. flexneri is responsible for developing diarrhea, fever and stomach cramps in human. Antibiotics are mostly given to patients infected with shigella. Resistance to antibiotics can hinder its treatment significantly. Upon identification of essential therapeutic targets, vaccine and drug could be effective therapy for the treatment of shigellosis. Methods: The study was designed for the identification and qualitative characterization for potential drug targets from S. flexneri by using the subtractive genome analysis. A set of computational tools were used to identify essential proteins those are required for the survival of S. flexneri. Total proteome (13503 proteins of S. flexneri was retrieved from NCBI and further analyzed by subtractive channel analysis. After identification of the metabolic proteins we have also performed its qualitative characterization to pave the way for the identification of promising drug targets. Results: Subtractive analysis revealed that a list of 53 targets of S. flexneri were human non-homologous essential metabolic proteins that might be used for potential drug targets. We have also found that 11 drug targets are involved in unique pathway. Most of these proteins are cytoplasmic, can be used as broad spectrum drug targets, can interact with other proteins and show the druggable properties. The functionality and drug binding site analysis suggest a promising effective way to design the new drugs against S. flexneri. Conclusion: We have identified 13 potential novel drug and one vaccine target(s against S. flexneri. The outcome might also be used as module as well as circuit design in systems biology. Keywords: S. flexneri, drug target, therapeutics, metabolic proteins, proteome

    2. Towards a clinical practice guide in pharmacogenomics testing for functional polymorphisms of drug-metabolising enzymes. Gene/drug pairs and barriers perceived in Spain.

      Directory of Open Access Journals (Sweden)

      José A G Agúndez

      2012-11-01

      Full Text Available The development of clinical practice recommendations or guidelines for the clinical use of biomarkers is an issue of great importance with regard to adverse drug reactions. The potential of pharmacogenomic biomarkers has been extensively investigated in recent years. However, several barriers to implementing the use of pharmacogenomics testing exist. We conducted a survey among members of the Spanish Societies of Pharmacology and Clinical Pharmacology to obtain information about the perception of such barriers and to compare the perceptions of participants about the relative importance of major gene/drug pairs.Of 11 potential barriers, the highest importance was attributed to lack of institutional support for pharmacogenomics testing, and to the issues related to the lack of guidelines. Of the proposed gene/drug pairs the highest importance was assigned to HLA-B/abacavir, UGT1A1/irinotecan and CYP2D6/tamoxifen. In this perspective article we compare the relative importance of 29 gene/drug pairs in the Spanish study with that of the same pairs in the American Society for Clinical Pharmacology & Therapeutics study, and we provide suggestions and areas of focus to develop a guide for clinical practice in pharmacogenomics testing.

    3. Associating Drugs, Targets and Clinical Outcomes into an Integrated Network Affords a New Platform for Computer-Aided Drug Repurposing.

      Science.gov (United States)

      Oprea, Tudor I; Nielsen, Sonny Kim; Ursu, Oleg; Yang, Jeremy J; Taboureau, Olivier; Mathias, Stephen L; Kouskoumvekaki, Lrene; Sklar, Larry A; Bologa, Cristian G

      2011-03-14

      Finding new uses for old drugs is a strategy embraced by the pharmaceutical industry, with increasing participation from the academic sector. Drug repurposing efforts focus on identifying novel modes of action, but not in a systematic manner. With intensive data mining and curation, we aim to apply bio- and cheminformatics tools using the DRUGS database, containing 3,837 unique small molecules annotated on 1,750 proteins. These are likely to serve as drug targets and antitargets (i.e., associated with side effects, SE). The academic community, the pharmaceutical sector and clinicians alike could benefit from an integrated, semantic-web compliant computer-aided drug repurposing (CADR) effort, one that would enable deep data mining of associations between approved drugs (D), targets (T), clinical outcomes (CO) and SE. We report preliminary results from text mining and multivariate statistics, based on 7,684 approved drug labels, ADL (Dailymed) via text mining. From the ADL corresponding to 988 unique drugs, the "adverse reactions" section was mapped onto 174 SE, then clustered via principal component analysis into a 5x5 self-organizing map that was integrated into a Cytoscape network of SE-D-T-CO. This type of data can be used to streamline drug repurposing and may result in novel insights that can lead to the identification of novel drug actions.

    4. [Metabotropic glutamate receptors as targets for new drug development].

      Science.gov (United States)

      Arkhipov, V I; Kapralova, M V

      2011-01-01

      The review is devoted to experimental investigations of metabotropic glutamate receptors and the properties of drugs (ligands) belonging to agonists, antagonists, and modulators of the activity of these receptors. Possibilities of the treatment of neurodegenerative disorders, cognitive disturbances in schizophrenia patients, and narcotic dependency by using drugs of this class are considered.

    5. Preparation and Optimization of Nanoemulsions for targeting Drug Delivery

      Directory of Open Access Journals (Sweden)

      Navneet Sharma

      2013-12-01

      Full Text Available Nanoemulsions have appeared as a novel drug delivery system which allows sustained or controlled release of drug, biological active ingredient and genetic material. Nanoemulsion is a dispersion consisting of oil, surfactant and an aqueous phase, which is a isotropically clear and thermo-dynamically or kinetically stable liquid solution, usually with droplet diameter within the range of 10-500nm. Although interest in nano-emulsions was developed for more than two decades now, mainly for nanoparticle preparation, it is in the last few years that direct applications of nano-emulsions in consumer products are being developed, mainly in pharmacy and cosmetics. These recent applications have made that studies on optimization methods for nano-emulsion preparation be a requirement. The design of effective formulations for drugs has long been a major task, because drug efficacy can severely limited by instability or poor solubility in the vehicle. Nanoemulsion is being applied to enhance the solubility and bioavailability of water insoluble drugs. The nanosized droplets leading to an enormous increase in interfacial areas associated with nanoemulsion would influence the transport properties of the drug [1, 2]. Recently, there has been a considerable attraction for this formulation, for the delivery of hydrophilic as well as hydrophobic drug as drug carriers because of its improved drug solubilization capacity, long shelf life, ease of preparation and improvement of bioavailability of drugs. This review is focused on the most recent literature on developments of nano-emulsions as final application products and on the optimization of their preparation.

    6. AS1411 aptamer tagged PLGA-lecithin-PEG nanoparticles for tumor cell targeting and drug delivery.

      Science.gov (United States)

      Aravind, Athulya; Jeyamohan, Prashanti; Nair, Remya; Veeranarayanan, Srivani; Nagaoka, Yutaka; Yoshida, Yasuhiko; Maekawa, Toru; Kumar, D Sakthi

      2012-11-01

      Liposomes and polymers are widely used drug carriers for controlled release since they offer many advantages like increased treatment effectiveness, reduced toxicity and are of biodegradable nature. In this work, anticancer drug-loaded PLGA-lecithin-PEG nanoparticles (NPs) were synthesized and were functionalized with AS1411 anti-nucleolin aptamers for site-specific targeting against tumor cells which over expresses nucleolin receptors. The particles were characterized by transmission electron microscope (TEM) and X-ray photoelectron spectroscopy (XPS). The drug-loading efficiency, encapsulation efficiency and in vitro drug release studies were conducted using UV spectroscopy. Cytotoxicity studies were carried out in two different cancer cell lines, MCF-7 and GI-1 cells and two different normal cells, L929 cells and HMEC cells. Confocal microscopy and flowcytometry confirmed the cellular uptake of particles and targeted drug delivery. The morphology analysis of the NPs proved that the particles were smooth and spherical in shape with a size ranging from 60 to 110 nm. Drug-loading studies indicated that under the same drug loading, the aptamer-targeted NPs show enhanced cancer killing effect compared to the corresponding non-targeted NPs. In addition, the PLGA-lecithin-PEG NPs exhibited high encapsulation efficiency and superior sustained drug release than the drug loaded in plain PLGA NPs. The results confirmed that AS1411 aptamer-PLGA-lecithin-PEG NPs are potential carrier candidates for differential targeted drug delivery.

    7. A Modular Probe Strategy for Drug Localization, Target Identification and Target Occupancy Measurement on Single Cell Level.

      Science.gov (United States)

      Rutkowska, Anna; Thomson, Douglas W; Vappiani, Johanna; Werner, Thilo; Mueller, Katrin M; Dittus, Lars; Krause, Jana; Muelbaier, Marcel; Bergamini, Giovanna; Bantscheff, Marcus

      2016-09-16

      Late stage failures of candidate drug molecules are frequently caused by off-target effects or inefficient target engagement in vivo. In order to address these fundamental challenges in drug discovery, we developed a modular probe strategy based on bioorthogonal chemistry that enables the attachment of multiple reporters to the same probe in cell extracts and live cells. In a systematic evaluation, we identified the inverse electron demand Diels-Alder reaction between trans-cyclooctene labeled probe molecules and tetrazine-tagged reporters to be the most efficient bioorthogonal reaction for this strategy. Bioorthogonal biotinylation of the probe allows the identification of drug targets in a chemoproteomics competition binding assay using quantitative mass spectrometry. Attachment of a fluorescent reporter enables monitoring of spatial localization of probes as well as drug-target colocalization studies. Finally, direct target occupancy of unlabeled drugs can be determined at single cell resolution by competitive binding with fluorescently labeled probe molecules. The feasibility of the modular probe strategy is demonstrated with noncovalent PARP inhibitors.

    8. SimBoost: A Read-Across Approach for Drug-Target Interaction Prediction Using Gradient Boosting Machines

      OpenAIRE

      He, Tong

      2016-01-01

      Computational prediction of the interaction between drugs and targets is a standing challenge in drug discovery. High performance on binary drug-target benchmark datasets was reported for a number of methods. A possible drawback of binary data is that missing values and non-interacting drug-target pairs are not differentiated. In this paper, we present a method called SimBoost that predicts the continuous binding affinities of drugs and targets and thus incorporates the whole interaction spec...

    9. [Multimorbidity and multi-target-therapy with herbal drugs].

      Science.gov (United States)

      Saller, R; Rostock, M

      2012-12-12

      The active components of herbal drugs and substances are pleiotropic multi-ingredient compounds with multitarget properties including antiinflammatory effects. A pleiotropic inhibition of inflammation could play an important role in mutlimorbide patients as an attempt of prevention or retardation of metastasis. A large number of experimental data for European and non-European herbal drugs as well as various herbal drug combinations suggest such a possibility. Despite the so far small number of clinical studies, such an experimental herbal treatment could appear to be reasonable and acceptable, provided that there are data available on quality and safety of these herbal drugs by treatments of patients with various diseases. Besides, herbal drugs and substances play a growing role the treatment of patients with multimorbidity. Many of these herbal drugs have antiinflammatory effects beside their proved symptomatic efficacy in a lot of other diseases. The specific selection of herbal drugs that are efficacious in specific indications and additionally showed antiinflammatory effects offers the possibility of simultaneous antiinflammatory and specific efficacy. St. John's Wort and milk thistle belong to the oldest and to the best experimentally and clinically examined herbal remedies. The spectrum of internal and external uses of Hypercum perforatum as a multicompound herbal drug includes functional gastro-intestinal complaint and illness, skin disease, mucosal lesion, superficial injury, depressive upset and depression, somatoform disorders, restlessness, nervosity, convalescence, exhaustion and sleep disturbances respectively. The plurivalent character of the multicompound even enables a broad spectrum of activity. This might justify to prefer St. John's Wort to other drugs in a wide range of treatments: In multimorbide patients with depression or in depressive patients with coronary heart disease the anti-inflammatory effects could mean an additional advantage

    10. Scattering of light halo nuclei on heavy target at energies around the Coulomb barrier

      OpenAIRE

      Tengblad O.; Borge M.J.G.; Cubero M.; Nacher E.; Pesudo V.; Perea A.; Gomez-Camacho J.; Moro A. M.; Fernandez-Garcia J.P.; Alvarez M.A.G.; Rodriguez-Gallardo M.; Lay J. A.; Martel I.; Acosta L.; Sanchez-Benitez A.M.

      2014-01-01

      INPC 2013 – International Nuclear Physics Conference We report here on experiments performed at TRIUMF to study the scattering of the light halo nuclei 11Li on lead at energies below and around the Coulomb barrier. The the elastic and break-up differential cross section are interpreted in the framework of Continuum-Discretized Coupled-Channel calculations. The departure from Rutherford scattering at energies below the barrier is well beyond the behavior of normal nuclei Consejo Interins...

    11. Scattering of light halo nuclei on heavy target at energies around the Coulomb barrier

      Directory of Open Access Journals (Sweden)

      Tengblad O.

      2014-03-01

      Full Text Available We report here on experiments performed at TRIUMF to study the scattering of the light halo nuclei 11Li on lead at energies below and around the Coulomb barrier. The the elastic and break-up differential cross section are interpreted in the framework of Continuum-Discretized Coupled-Channel calculations. The departure from Rutherford scattering at energies below the barrier is well beyond the behavior of normal nuclei.

    12. The use of microbubbles to target drug delivery

      Directory of Open Access Journals (Sweden)

      Porter Richard

      2004-11-01

      Full Text Available Abstract Ultrasound-mediated microbubbles destruction has been proposed as an innovative method for noninvasive delivering of drugs and genes to different tissues. Microbubbles are used to carry a drug or gene until a specific area of interest is reached, and then ultrasound is used to burst the microbubbles, causing site-specific delivery of the bioactive materials. Furthermore, the ability of albumin-coated microbubbles to adhere to vascular regions with glycocalix damage or endothelial dysfunction is another possible mechanism to deliver drugs even in the absence of ultrasound. This review focuses on the characteristics of microbubbles that give them therapeutic properties and some important aspects of ultrasound parameters that are known to influence microbubble-mediated drug delivery. In addition, current studies involving this novel therapeutical application of microbubbles will be discussed.

    13. Identification of drug targets by chemogenomic and metabolomic profiling in yeast

      KAUST Repository

      Wu, Manhong

      2012-12-01

      OBJECTIVE: To advance our understanding of disease biology, the characterization of the molecular target for clinically proven or new drugs is very important. Because of its simplicity and the availability of strains with individual deletions in all of its genes, chemogenomic profiling in yeast has been used to identify drug targets. As measurement of drug-induced changes in cellular metabolites can yield considerable information about the effects of a drug, we investigated whether combining chemogenomic and metabolomic profiling in yeast could improve the characterization of drug targets. BASIC METHODS: We used chemogenomic and metabolomic profiling in yeast to characterize the target for five drugs acting on two biologically important pathways. A novel computational method that uses a curated metabolic network was also developed, and it was used to identify the genes that are likely to be responsible for the metabolomic differences found. RESULTS AND CONCLUSION: The combination of metabolomic and chemogenomic profiling, along with data analyses carried out using a novel computational method, could robustly identify the enzymes targeted by five drugs. Moreover, this novel computational method has the potential to identify genes that are causative of metabolomic differences or drug targets. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.

    14. Targeting DDX3 in cancer: personalized drug development and delivery

      NARCIS (Netherlands)

      Bol, G.M.

      2013-01-01

      Cancer begins when a cell in an organ of our body starts to grow uncontrollably. Only recently has it become clear that targeting the cancer cells’ dependency on specific proteins, rather than their origin, has greater therapeutic potential. The vast majority of potential targets for cancer therapy

    15. Systems biology-embedded target validation: improving efficacy in drug discovery.

      Science.gov (United States)

      Vandamme, Drieke; Minke, Benedikt A; Fitzmaurice, William; Kholodenko, Boris N; Kolch, Walter

      2014-01-01

      The pharmaceutical industry is faced with a range of challenges with the ever-escalating costs of drug development and a drying out of drug pipelines. By harnessing advances in -omics technologies and moving away from the standard, reductionist model of drug discovery, there is significant potential to reduce costs and improve efficacy. Embedding systems biology approaches in drug discovery, which seek to investigate underlying molecular mechanisms of potential drug targets in a network context, will reduce attrition rates by earlier target validation and the introduction of novel targets into the currently stagnant market. Systems biology approaches also have the potential to assist in the design of multidrug treatments and repositioning of existing drugs, while stratifying patients to give a greater personalization of medical treatment.

    16. Structure-based DNA-targeting strategies with small molecule ligands for drug discovery.

      Science.gov (United States)

      Sheng, Jia; Gan, Jianhua; Huang, Zhen

      2013-09-01

      Nucleic acids are the molecular targets of many clinical anticancer drugs. However, compared with proteins, nucleic acids have traditionally attracted much less attention as drug targets in structure-based drug design, partially because limited structural information of nucleic acids complexed with potential drugs is available. Over the past several years, enormous progresses in nucleic acid crystallization, heavy-atom derivatization, phasing, and structural biology have been made. Many complicated nucleic acid structures have been determined, providing new insights into the molecular functions and interactions of nucleic acids, especially DNAs complexed with small molecule ligands. Thus, opportunities have been created to further discover nucleic acid-targeting drugs for disease treatments. This review focuses on the structure studies of DNAs complexed with small molecule ligands for discovering lead compounds, drug candidates, and/or therapeutics.

    17. Predicted essential proteins ofPlasmodium falciparum for potential drug targets

      Institute of Scientific and Technical Information of China (English)

      Qing-Feng He; Li Deng; Qin-Ying Xu; Zheng Shao

      2012-01-01

      ABSTRACT Objective:To identify novel drug targets for treatment ofPlasmodium falciparum.Methods:LocalBLASTP were used to find the proteins non-homologous to human essential proteins as novel drug targets. Functional domains of novel drug targets were identified by InterPro and Pfam,3D structures of potential drug targets were predicated by theSWISS-MODELworkspace. Ligands and ligand-binding sites of the proteins were searched byEf-seek.Results:Three essential proteins were identified that might be considered as potential drug targets.AAN37254.1 belonged to1-deoxy-D-xylulose5-phosphate reductoisomerase,CAD50499.1 belonged to chorismate synthase,CAD51220.1 belonged toFAD binging3 family, but the function of CAD51220.1 was unknown. The3D structures, ligands and ligand-binding sites ofAAN37254.1 andCAD50499.1 were successfully predicated.Conclusions:Two of these potential drug targets are key enzymes in2-C-methyl-d-erythritol4-phosphate pathway and shikimate pathway, which are absent in humans, so these two essential proteins are good potential drug targets. The function and3D structures ofCAD50499.1 is still unknown, it still need further study.

    18. Delineation on Therapeutic Significance of Transporters as Molecular Targets of Drugs

      Institute of Scientific and Technical Information of China (English)

      KANAI Yoshikat; HE Xin; LIU Chang-xiao

      2011-01-01

      Transporters are membrane proteins mediating permeation of organic and inorganic solutes through the plasma membrane and membranes of intracellular organella.They play essential roles in the epithelial absorption and cellular uptake of nutrients as well as absorption,distribution,metabolism,and excretion of drugs.Because transporters contribute to determining the distribution of compounds in the body in concert with metabolic/synthetic enzymes,the drugs that affect the functions of transporters are expected to alter the distribution of compounds in the body and to ameliorate disrupted homeostasis.In this context,drugs targeting transporters have been used clinically.Such drugs include antidepressants targeting monoamine transporters,diuretics targeting inorganic ion transporters of renal tubules,and uricosuric agents targeting renal urate transporters.Now new transporter-targeting drugs designed based on post-genome drug development strategy have been in the process of clinical trials or basic/clinical researches.For example,the inhibitors of renal Na/glucose cotransporter SGLT2 have been proved for their efficacy in the treatment of diabetes mellitus.The cancer L-type amino acid transporter 1(LAT1)has been considered as a target of cancer diagnosis and therapeutics.The transporter-targeting drugs are expected to provide new rationale in the therapeutics of various diseases.

    19. Using compound similarity and functional domain composition for prediction of drug-target interaction networks.

      Science.gov (United States)

      Chen, Lei; He, Zhi-Song; Huang, Tao; Cai, Yu-Dong

      2010-11-01

      Study of interactions between drugs and target proteins is an essential step in genomic drug discovery. It is very hard to determine the compound-protein interactions or drug-target interactions by experiment alone. As supplementary, effective prediction model using machine learning or data mining methods can provide much help. In this study, a prediction method based on Nearest Neighbor Algorithm and a novel metric, which was obtained by combining compound similarity and functional domain composition, was proposed. The target proteins were divided into the following groups: enzymes, ion channels, G protein-coupled receptors, and nuclear receptors. As a result, four predictors with the optimal parameters were established. The overall prediction accuracies, evaluated by jackknife cross-validation test, for four groups of target proteins are 90.23%, 94.74%, 97.80%, and 97.51%, respectively, indicating that compound similarity and functional domain composition are very effective to predict drug-target interaction networks.

    20. PCR-based ordered genomic libraries: a new approach to drug target identification for Streptococcus pneumoniae.

      Science.gov (United States)

      Belanger, Aimee E; Lai, Angel; Brackman, Marcia A; LeBlanc, Donald J

      2002-08-01

      Described here are the development and validation of a novel approach to identify genes encoding drug targets in Streptococcus pneumoniae. The method relies on the use of an ordered genomic library composed of PCR amplicons that were generated under error-prone conditions so as to introduce random mutations into the DNA. Since some of the mutations occur in drug target-encoding genes and subsequently affect the binding of the drug to its respective cellular target, amplicons containing drug targets can be identified as those producing drug-resistant colonies when transformed into S. pneumoniae. Examination of the genetic content of the amplicon giving resistance coupled with bioinformatics and additional genetic approaches could be used to rapidly identify candidate drug target genes. The utility of this approach was verified by using a number of known antibiotics. For drugs with single protein targets, amplicons were identified that rendered S. pneumoniae drug resistant. Assessment of amplicon composition revealed that each of the relevant amplicons contained the gene encoding the known target for the particular drug tested. Fusidic acid-resistant mutants that resulted from the transformation of S. pneumoniae with amplicons containing fusA were further characterized by sequence analysis. A single mutation was found to occur in a region of the S. pneumoniae elongation factor G protein that is analogous to that already implicated in other bacteria as being associated with fusidic acid resistance. Thus, in addition to facilitating the identification of genes encoding drug targets, this method could provide strains that aid future mechanistic studies.

    1. Delivery of drugs to intracellular organelles using drug delivery systems: Analysis of research trends and targeting efficiencies.

      Science.gov (United States)

      Maity, Amit Ranjan; Stepensky, David

      2015-12-30

      Targeting of drug delivery systems (DDSs) to specific intracellular organelles (i.e., subcellular targeting) has been investigated in numerous publications, but targeting efficiency of these systems is seldom reported. We searched scientific publications in the subcellular DDS targeting field and analyzed targeting efficiency and major formulation parameters that affect it. We identified 77 scientific publications that matched the search criteria. In the majority of these studies nanoparticle-based DDSs were applied, while liposomes, quantum dots and conjugates were used less frequently. The nucleus was the most common intracellular target, followed by mitochondrion, endoplasmic reticulum and Golgi apparatus. In 65% of the publications, DDSs surface was decorated with specific targeting residues, but the efficiency of this surface decoration was not analyzed in predominant majority of the studies. Moreover, only 23% of the analyzed publications contained quantitative data on DDSs subcellular targeting efficiency, while the majority of publications reported qualitative results only. From the analysis of publications in the subcellular targeting field, it appears that insufficient efforts are devoted to quantitative analysis of the major formulation parameters and of the DDSs' intracellular fate. Based on these findings, we provide recommendations for future studies in the field of organelle-specific drug delivery and targeting.

    2. A systematic prediction of multiple drug-target interactions from chemical, genomic, and pharmacological data.

      Directory of Open Access Journals (Sweden)

      Hua Yu

      Full Text Available In silico prediction of drug-target interactions from heterogeneous biological data can advance our system-level search for drug molecules and therapeutic targets, which efforts have not yet reached full fruition. In this work, we report a systematic approach that efficiently integrates the chemical, genomic, and pharmacological information for drug targeting and discovery on a large scale, based on two powerful methods of Random Forest (RF and Support Vector Machine (SVM. The performance of the derived models was evaluated and verified with internally five-fold cross-validation and four external independent validations. The optimal models show impressive performance of prediction for drug-target interactions, with a concordance of 82.83%, a sensitivity of 81.33%, and a specificity of 93.62%, respectively. The consistence of the performances of the RF and SVM models demonstrates the reliability and robustness of the obtained models. In addition, the validated models were employed to systematically predict known/unknown drugs and targets involving the enzymes, ion channels, GPCRs, and nuclear receptors, which can be further mapped to functional ontologies such as target-disease associations and target-target interaction networks. This approach is expected to help fill the existing gap between chemical genomics and network pharmacology and thus accelerate the drug discovery processes.

    3. The Research Progress of Nano Drug Carrier Transporting Drugs through the Blood-Brain Barrier%纳米药物载体转运药物通过血脑屏障的研究进展

      Institute of Scientific and Technical Information of China (English)

      阙中有

      2011-01-01

      Blood-brain barrier is an important structure which maintains the homeostasis within the brain and ensuring effective metabolites transportation and preventing harmful substance from the brain.However,it also becomes the main obstacle of the entrance of the therapeutic drugs for central nerval system into the brain.With the great development of nanotechnology, various novel nano drug carriers such as polymer nanoparticles, ligand-mediated nano drugs and the nano drugs used in gene therapy have greatly increased the treating effect of central nerval system diseases due to more effective trasportation of the drug through the bloodbrain barrier thanks to the features of targetting, controllable releasing and biocompatibility etc.%血脑屏障是维持大脑生理稳态的重要结构,可以有效地转运脑内的代谢产物,并且阻止有害物质进入脑内.然而,血脑屏障也成为阻碍中枢神经系统治疗药物进入脑的主要障碍.随着纳米技术的蓬勃发展,聚合物纳米颗粒、配体介导的纳米药物、用于基因治疗的纳米药物等多种新型纳米药物载体,由于具有靶向性、可控释放性、生物相容性等特点,能够比传统方法更有效地转运药物通过血脑屏障,提高其对中枢神经系统疾病的治疗效果.

    4. Nanoparticle-Enabled Transdermal Drug Delivery Systems for Enhanced Dose Control and Tissue Targeting

      Directory of Open Access Journals (Sweden)

      Brian C. Palmer

      2016-12-01

      Full Text Available Transdermal drug delivery systems have been around for decades, and current technologies (e.g., patches, ointments, and creams enhance the skin permeation of low molecular weight, lipophilic drugs that are efficacious at low doses. The objective of current transdermal drug delivery research is to discover ways to enhance skin penetration of larger, hydrophilic drugs and macromolecules for disease treatment and vaccination. Nanocarriers made of lipids, metals, or polymers have been successfully used to increase penetration of drugs or vaccines, control drug release, and target drugs to specific areas of skin in vivo. While more research is needed to identify the safety of nanocarriers, this technology has the potential to expand the use of transdermal routes of administration to a wide array of therapeutics. Here, we review the current state of nanoparticle skin delivery systems with special emphasis on targeting skin diseases.

    5. Smart linkers in polymer-drug conjugates for tumor-targeted delivery.

      Science.gov (United States)

      Chang, Minglu; Zhang, Fang; Wei, Ting; Zuo, Tiantian; Guan, Yuanyuan; Lin, Guimei; Shao, Wei

      2016-01-01

      To achieve effective chemotherapy, many types of drug delivery systems have been developed for the specific environments in tumor tissues. Polymer-drug conjugates are increasingly used in tumor therapy due to several significant advantages over traditional delivery systems. In the fabrication of polymer-drug conjugates, a smart linker is an important component that joins two fragments or molecules together and can be cleared by a specific stimulus, which results in targeted drug delivery and controlled release. By regulating the conjugation between the drug and the nanocarriers, stimulus-sensitive systems based on smart linkers can offer high payloads, certified stability, controlled release and targeted delivery. In this review, we summarize the current state of smart linkers (e.g. disulfide, hydrazone, peptide, azo) used recently in various polymer-drug conjugate-based delivery systems with a primary focus on their sophisticated design principles and drug delivery mechanisms as well as in vivo processes.

    6. Orexin Receptor Targets for Anti-Relapse Medication Development in Drug Addiction

      Directory of Open Access Journals (Sweden)

      Ronald E. See

      2011-06-01

      Full Text Available Drug addiction is a chronic illness characterized by high rates of relapse. Relapse to drug use can be triggered by re-exposure to drug-associated cues, stressful events, or the drug itself after a period of abstinence. Pharmacological intervention to reduce the impact of relapse-instigating factors offers a promising target for addiction treatment. Growing evidence has implicated an important role of the orexin/hypocretin system in drug reward and drug-seeking, including animal models of relapse. Here, we review the evidence for the role of orexins in modulating reward and drug-seeking in animal models of addiction and the potential for orexin receptors as specific targets for anti-relapse medication approaches.

    7. Advances in Bone-targeted Drug Delivery Systems for Neoadjuvant Chemotherapy for Osteosarcoma.

      Science.gov (United States)

      Li, Cheng-Jun; Liu, Xiao-Zhou; Zhang, Lei; Chen, Long-Bang; Shi, Xin; Wu, Su-Jia; Zhao, Jian-Ning

      2016-05-01

      Targeted therapy for osteosarcoma includes organ, cell and molecular biological targeting; of these, organ targeting is the most mature. Bone-targeted drug delivery systems are used to concentrate chemotherapeutic drugs in bone tissues, thus potentially resolving the problem of reaching the desired foci and minimizing the toxicity and adverse effects of neoadjuvant chemotherapy. Some progress has been made in bone-targeted drug delivery systems for treatment of osteosarcoma; however, most are still at an experimental stage and there is a long transitional period to clinical application. Therefore, determining how to combine new, polymolecular and multi-pathway targets is an important research aspect of designing new bone-targeted drug delivery systems in future studies. The purpose of this article was to review the status of research on targeted therapy for osteosarcoma and to summarize the progress made thus far in developing bone-targeted drug delivery systems for neoadjuvant chemotherapy for osteosarcoma with the aim of providing new ideas for highly effective therapeutic protocols with low toxicity for patients with osteosarcoma.

    8. Comparative genomics study for identification of putative drug targets in Salmonella typhi Ty2.

      Science.gov (United States)

      Batool, Nisha; Waqar, Maleeha; Batool, Sidra

      2016-01-15

      Typhoid presents a major health concern in developing countries with an estimated annual infection rate of 21 million. The disease is caused by Salmonella typhi, a pathogenic bacterium acquiring multiple drug resistance. We aim to identify proteins that could prove to be putative drug targets in the genome of S. typhi str. Ty2. We employed comparative and subtractive genomics to identify targets that are absent in humans and are essential to S. typhi Ty2. We concluded that 46 proteins essential to pathogen are absent in the host genome. Filtration on the basis of drug target prioritization singled out 20 potentially therapeutic targets. Their absence in the host and specificity to S. typhi Ty2 makes them ideal targets for treating typhoid in Homo sapiens. 3D structures of two of the final target enzymes, MurA and MurB have been predicted via homology modeling which are then used for a docking study.

    9. Bacterial Histidine Kinases as Novel Antibacterial Drug Targets

      NARCIS (Netherlands)

      Bem, A.E.; Velikova, N.R.; Pellicer, M.T.; Baarlen, van P.; Marina, A.; Wells, J.M.

      2015-01-01

      Bacterial histidine kinases (HKs) are promising targets for novel antibacterials. Bacterial HKs are part of bacterial two-component systems (TCSs), the main signal transduction pathways in bacteria, regulating various processes including virulence, secretion systems and antibiotic resistance. In thi

    10. Tailored polymer-lipid hybrid nanoparticles for the delivery of drug conjugate: dual strategy for brain targeting.

      Science.gov (United States)

      Agrawal, Udita; Chashoo, Gousia; Sharma, Parduman Raj; Kumar, Ashok; Saxena, Ajit Kumar; Vyas, S P

      2015-02-01

      The object of the present study was to investigate the glioma targeting propensity of folic acid (F) decorated polymer-lipid hybrid nanoparticles (PLNs) encapsulating cyclo-[Arg-Gly-Asp-D-Phe-Lys] (cRGDfK) modified paclitaxel (PtxR-FPLNs). The prepared PLNs were supposed to bypass the blood-brain barrier (BBB) efficiently and subsequently target integrin rich glioma cells. The developed formulations were characterized for size, shape, drug entrapment efficiency, and in vitro release profile. PtxR-FPLNs demonstrated highest in vitro inhibitory effect, cell apoptosis and cell uptake. Pharmacokinetics and biodistribution studies showed efficacy of PtxR-FPLNs in vivo. In vivo anti-tumor studies clearly revealed that the median survival time for Balb/C mice treated with PtxR-FPLNs (42 days) was extended significantly as compared to PtxR-PLNs (35 days), free PtxR (18 days), Ptx-FPLNs (38 days), Ptx-PLNs (30 days), free Ptx (14 days) and control group (12 days). From the results it can be concluded that the developed dual targeted nanoformulation was able to efficiently cross the BBB and significantly deliver higher amounts of drug to brain tumor for better therapeutic outcome.

    11. The application of carbon nanotubes in target drug delivery systems for cancer therapies

      Directory of Open Access Journals (Sweden)

      Zhang Zhenzhong

      2011-01-01

      Full Text Available Abstract Among all cancer treatment options, chemotherapy continues to play a major role in killing free cancer cells and removing undetectable tumor micro-focuses. Although chemotherapies are successful in some cases, systemic toxicity may develop at the same time due to lack of selectivity of the drugs for cancer tissues and cells, which often leads to the failure of chemotherapies. Obviously, the therapeutic effects will be revolutionarily improved if human can deliver the anticancer drugs with high selectivity to cancer cells or cancer tissues. This selective delivery of the drugs has been called target treatment. To realize target treatment, the first step of the strategies is to build up effective target drug delivery systems. Generally speaking, such a system is often made up of the carriers and drugs, of which the carriers play the roles of target delivery. An ideal carrier for target drug delivery systems should have three pre-requisites for their functions: (1 they themselves have target effects; (2 they have sufficiently strong adsorptive effects for anticancer drugs to ensure they can transport the drugs to the effect-relevant sites; and (3 they can release the drugs from them in the effect-relevant sites, and only in this way can the treatment effects develop. The transporting capabilities of carbon nanotubes combined with appropriate surface modifications and their unique physicochemical properties show great promise to meet the three pre-requisites. Here, we review the progress in the study on the application of carbon nanotubes as target carriers in drug delivery systems for cancer therapies.

    12. One for All? Hitting Multiple Alzheimer's Disease Targets with One Drug.

      Science.gov (United States)

      Hughes, Rebecca E; Nikolic, Katarina; Ramsay, Rona R

      2016-01-01

      HIGHLIGHTS Many AD target combinations are being explored for multi-target drug design.New databases and models increase the potential of computational drug designLiraglutide and other antidiabetics are strong candidates for repurposing to AD.Donecopride a dual 5-HT/AChE inhibitor shows promise in pre-clinical studies Alzheimer's Disease is a complex and multifactorial disease for which the mechanism is still not fully understood. As new insights into disease progression are discovered, new drugs must be designed to target those aspects of the disease that cause neuronal damage rather than just the symptoms currently addressed by single target drugs. It is becoming possible to target several aspects of the disease pathology at once using multi-target drugs (MTDs). Intended as an introduction for non-experts, this review describes the key MTD design approaches, namely structure-based, in silico, and data-mining, to evaluate what is preventing compounds progressing through the clinic to the market. Repurposing current drugs using their off-target effects reduces the cost of development, time to launch, and the uncertainty associated with safety and pharmacokinetics. The most promising drugs currently being investigated for repurposing to Alzheimer's Disease are rasagiline, originally developed for the treatment of Parkinson's Disease, and liraglutide, an antidiabetic. Rational drug design can combine pharmacophores of multiple drugs, systematically change functional groups, and rank them by virtual screening. Hits confirmed experimentally are rationally modified to generate an effective multi-potent lead compound. Examples from this approach are ASS234 with properties similar to rasagiline, and donecopride, a hybrid of an acetylcholinesterase inhibitor and a 5-HT4 receptor agonist with pro-cognitive effects. Exploiting these interdisciplinary approaches, public-private collaborative lead factories promise faster delivery of new drugs to the clinic.

    13. PDTD: a web-accessible protein database for drug target identification

      Directory of Open Access Journals (Sweden)

      Gao Zhenting

      2008-02-01

      Full Text Available Abstract Background Target identification is important for modern drug discovery. With the advances in the development of molecular docking, potential binding proteins may be discovered by docking a small molecule to a repository of proteins with three-dimensional (3D structures. To complete this task, a reverse docking program and a drug target database with 3D structures are necessary. To this end, we have developed a web server tool, TarFisDock (Target Fishing Docking http://www.dddc.ac.cn/tarfisdock, which has been used widely by others. Recently, we have constructed a protein target database, Potential Drug Target Database (PDTD, and have integrated PDTD with TarFisDock. This combination aims to assist target identification and validation. Description PDTD is a web-accessible protein database for in silico target identification. It currently contains >1100 protein entries with 3D structures presented in the Protein Data Bank. The data are extracted from the literatures and several online databases such as TTD, DrugBank and Thomson Pharma. The database covers diverse information of >830 known or potential drug targets, including protein and active sites structures in both PDB and mol2 formats, related diseases, biological functions as well as associated regulating (signaling pathways. Each target is categorized by both nosology and biochemical function. PDTD supports keyword search function, such as PDB ID, target name, and disease name. Data set generated by PDTD can be viewed with the plug-in of molecular visualization tools and also can be downloaded freely. Remarkably, PDTD is specially designed for target identification. In conjunction with TarFisDock, PDTD can be used to identify binding proteins for small molecules. The results can be downloaded in the form of mol2 file with the binding pose of the probe compound and a list of potential binding targets according to their ranking scores. Conclusion PDTD serves as a comprehensive and

    14. In vivo characteristics of targeted drug-carrying filamentous bacteriophage nanomedicines

      Directory of Open Access Journals (Sweden)

      Vaks Lilach

      2011-12-01

      Full Text Available Abstract Background Targeted drug-carrying phage nanomedicines are a new class of nanomedicines that combines biological and chemical components into a modular nanometric drug delivery system. The core of the system is a filamentous phage particle that is produced in the bacterial host Escherichia coli. Target specificity is provided by a targeting moiety, usually an antibody that is displayed on the tip of the phage particle. A large drug payload is chemically conjugated to the protein coat of the phage via a chemically or genetically engineered linker that provides for controlled release of the drug after the particle homed to the target cell. Recently we have shown that targeted drug-carrying phage nanomedicines can be used to eradicate pathogenic bacteria and cultured tumor cells with great potentiation over the activity of the free untargeted drug. We have also shown that poorly water soluble drugs can be efficiently conjugated to the phage coat by applying hydrophilic aminoglycosides as branched solubility-enhancing linkers. Results With an intention to move to animal experimentation of efficacy, we tested anti-bacterial drug-carrying phage nanomedicines for toxicity and immunogenicity and blood pharmacokinetics upon injection into mice. Here we show that anti-bacterial drug-carrying phage nanomedicines that carry the antibiotic chloramphenicol conjugated via an aminoglycoside linker are non-toxic to mice and are greatly reduced in immunogenicity in comparison to native phage particles or particles to which the drug is conjugated directly and are cleared from the blood more slowly in comparison to native phage particles. Conclusion Our results suggest that aminoglycosides may serve as branched solubility enhancing linkers for drug conjugation that also provide for a better safety profile of the targeted nanomedicine.

    15. Optimal drug cocktail design: methods for targeting molecular ensembles and insights from theoretical model systems.

      Science.gov (United States)

      Radhakrishnan, Mala L; Tidor, Bruce

      2008-05-01

      Drug resistance is a significant obstacle in the effective treatment of diseases with rapidly mutating targets, such as AIDS, malaria, and certain forms of cancer. Such targets are remarkably efficient at exploring the space of functional mutants and at evolving to evade drug binding while still maintaining their biological role. To overcome this challenge, drug regimens must be active against potential target variants. Such a goal may be accomplished by one drug molecule that recognizes multiple variants or by a drug "cocktail"--a small collection of drug molecules that collectively binds all desired variants. Ideally, one wants the smallest cocktail possible due to the potential for increased toxicity with each additional drug. Therefore, the task of designing a regimen for multiple target variants can be framed as an optimization problem--find the smallest collection of molecules that together "covers" the relevant target variants. In this work, we formulate and apply this optimization framework to theoretical model target ensembles. These results are analyzed to develop an understanding of how the physical properties of a target ensemble relate to the properties of the optimal cocktail. We focus on electrostatic variation within target ensembles, as it is one important mechanism by which drug resistance is achieved. Using integer programming, we systematically designed optimal cocktails to cover model target ensembles. We found that certain drug molecules covered much larger regions of target space than others, a phenomenon explained by theory grounded in continuum electrostatics. Molecules within optimal cocktails were often dissimilar, such that each drug was responsible for binding variants with a certain electrostatic property in common. On average, the number of molecules in the optimal cocktails correlated with the number of variants, the differences in the variants' electrostatic properties at the binding interface, and the level of binding affinity

    16. Polymeric micelles with stimuli-triggering systems for advanced cancer drug targeting.

      Science.gov (United States)

      Nakayama, Masamichi; Akimoto, Jun; Okano, Teruo

      2014-08-01

      Since the 1990s, nanoscale drug carriers have played a pivotal role in cancer chemotherapy, acting through passive drug delivery mechanisms and subsequent pharmaceutical action at tumor tissues with reduction of adverse effects. Polymeric micelles, as supramolecular assemblies of amphiphilic polymers, have been considerably developed as promising drug carrier candidates, and a number of clinical studies of anticancer drug-loaded polymeric micelle carriers for cancer chemotherapy applications are now in progress. However, these systems still face several issues; at present, the simultaneous control of target-selective delivery and release of incorporated drugs remains difficult. To resolve these points, the introduction of stimuli-responsive mechanisms to drug carrier systems is believed to be a promising approach to provide better solutions for future tumor drug targeting strategies. As possible trigger signals, biological acidic pH, light, heating/cooling and ultrasound actively play significant roles in signal-triggering drug release and carrier interaction with target cells. This review article summarizes several molecular designs for stimuli-responsive polymeric micelles in response to variation of pH, light and temperature and discusses their potentials as next-generation tumor drug targeting systems.

    17. Predict potential drug targets from the ion channel proteins based on SVM.

      Science.gov (United States)

      Huang, Chen; Zhang, Ruijie; Chen, Zhiqiang; Jiang, Yongshuai; Shang, Zhenwei; Sun, Peng; Zhang, Xuehong; Li, Xia

      2010-02-21

      The identification of molecular targets is a critical step in the drug discovery and development process. Ion channel proteins represent highly attractive drug targets implicated in a diverse range of disorders, in particular in the cardiovascular and central nervous systems. Due to the limits of experimental technique and low-throughput nature of patch-clamp electrophysiology, they remain a target class waiting to be exploited. In our study, we combined three types of protein features, primary sequence, secondary structure and subcellular localization to predict potential drug targets from ion channel proteins applying classical support vector machine (SVM) method. In addition, our prediction comprised two stages. In stage 1, we predicted ion channel target proteins based on whole-genome target protein characteristics. Firstly, we performed feature selection by Mann-Whitney U test, then made predictions to identify potential ion channel targets by SVM and designed a new evaluating indicator Q to prioritize results. In stage 2, we made a prediction based on known ion channel target protein characteristics. Genetic algorithm was used to select features and SVM was used to predict ion channel targets. Then, we integrated results of two stages, and found that five ion channel proteins appeared in both prediction results including CGMP-gated cation channel beta subunit and Gamma-aminobutyric acid receptor subunit alpha-5, etc., and four of which were relative to some nerve diseases. It suggests that these five proteins are potential targets for drug discovery and our prediction strategies are effective.

    18. Finding new drug targets for the treatment of migraine attacks

      DEFF Research Database (Denmark)

      Olesen, J; Olesen, Jes; Tfelt-Hansen, P

      2009-01-01

      No new preventive drugs specific to migraine have appeared for the last 20 years and existing acute therapies need improvement. Unfortunately, no animal models can predict the efficacy of new therapies for migraine. Because migraine attacks are fully reversible and can be aborted by therapy...

    19. Sensation Seeking and Targeting of Televised Anti-Drug PSAs.

      Science.gov (United States)

      Donohew, Lewis; And Others

      A study was conducted to determine how to reach out in an effective manner via televised public service announcements (PSAs) to particular at-risk audiences to motivate participation in drug abuse prevention programs. The subjects (207 young adults in Fayette County, Kentucky) responded to the M. Zuckerman sensation-seeking questionnaire. They…

    20. Drugs targeting the mitochondrial pore act as citotoxic and cytostatic agents in temozolomide-resistant glioma cells

      Directory of Open Access Journals (Sweden)

      Benvenuti Lucia

      2009-02-01

      Full Text Available Abstract Background High grade gliomas are one of the most difficult cancers to treat and despite surgery, radiotherapy and temozolomide-based chemotherapy, the prognosis of glioma patients is poor. Resistance to temozolomide is the major barrier to effective therapy. Alternative therapeutic approaches have been shown to be ineffective for the treatment of genetically unselected glioma patients. Thus, novel therapies are needed. Mitochondria-directed chemotherapy is an emerging tool to combat cancer, and inner mitochondrial permeability transition (MPT represents a target for the development of cytotoxic drugs. A number of agents are able to induce MPT and some of them target MPT-pore (MPTP components that are selectively up-regulated in cancer, making these agents putative cancer cell-specific drugs. Objective The aim of this paper is to report a comprehensive analysis of the effects produced by selected MPT-inducing drugs (Betulinic Acid, Lonidamine, CD437 in a temozolomide-resistant glioblastoma cell line (ADF cells. Methods EGFRvIII expression has been assayed by RT-PCR. EGFR amplification and PTEN deletion have been assayed by differential-PCR. Drugs effect on cell viability has been tested by crystal violet assay. MPT has been tested by JC1 staining. Drug cytostatic effect has been tested by mitotic index analysis. Drug cytotoxic effect has been tested by calcein AM staining. Apoptosis has been assayed by Hoechst incorporation and Annexine V binding assay. Authophagy has been tested by acridine orange staining. Results We performed a molecular and genetic characterization of ADF cells and demonstrated that this line does not express the EGFRvIII and does not show EGFR amplification. ADF cells do not show PTEN mutation but differential PCR data indicate a hemizygous deletion of PTEN gene. We analyzed the response of ADF cells to Betulinic Acid, Lonidamine, and CD437. Our data demonstrate that MPT-inducing agents produce concentration

    1. Molecular Communication Model for Targeted Drug Delivery in Multiple Disease Sites With Diversely Expressed Enzymes.

      Science.gov (United States)

      Chude-Okonkwo, Uche A K; Malekian, Reza; Maharaj, B T Sunil

      2016-04-01

      Targeted drug delivery (TDD) for disease therapy using liposomes as nanocarriers has received extensive attention in the literature. The liposome's ability to incorporate capabilities such as long circulation, stimuli responsiveness, and targeting characteristics, makes it a versatile nanocarrier. Timely drug release at the targeted site requires that trigger stimuli such as pH, light, and enzymes be uniquely overexpressed at the targeted site. However, in some cases, the targeted sites may not express trigger stimuli significantly, hence, achieving effective TDD at those sites is challenging. In this paper, we present a molecular communication-based TDD model for the delivery of therapeutic drugs to multiple sites that may or may not express trigger stimuli. The nanotransmitter and nanoreceiver models for the molecular communication system are presented. Here, the nanotransmitter and nanoreceiver are injected into the targeted body system's blood network. The compartmental pharmacokinetics model is employed to model the transportation of these therapeutic nanocarriers to the targeted sites where they are meant to anchor before the delivery process commences. We also provide analytical expressions for the delivered drug concentration. The effectiveness of the proposed model is investigated for drug delivery on tissue surfaces. Results show that the effectiveness of the proposed molecular communication-based TDD depends on parameters such as the total transmitter volume capacity, the receiver radius, the diffusion characteristic of the microenvironment of the targeted sites, and the concentration of the enzymes associated with the nanotransmitter and the nanoreceiver designs.

    2. Targeted Drug Delivery in Covalent Organic Nanosheets (CONs) via Sequential Postsynthesis.

      Science.gov (United States)

      Mitra, Shouvik; Sasmal, Himadri Sekhar; Kundu, Tanay; Kandambeth, Sharath; Illath, Kavya S; Díaz Díaz, David; Banerjee, Rahul

      2017-03-03

      Covalent organic nanosheets (CONs) have emerged as a new class of functional two-dimensional (2D) porous organic polymeric materials with a high accessible surface, diverse functionality and chemical stability. They could become a versa-tile candidate for targeted drug delivery. Despite their many advantages, there are limitations to use them for target specific drug delivery. We anticipated that these drawbacks could be overturned by judicious postsynthetic modification steps to use CONs for targeted drug delivery. The postsynthetic modification would not only produce the desired functionality, it would also help in exfoliation to CONs as well. In order to meet this requirement, we have developed a facile, salt-mediated synthesis of covalent organic frameworks (COFs) in presence of p-toluenesulphonic acid (PTSA). The COFs were subjected to sequential postsynthetic modifications to yield functionalized targeted CONs for targeted delivery of 5-fluorouracil to the breast cancer cells. This postsynthetic modification resulted in simultaneous chemical delamination and functionalization to targeted CONs. Targeted CONs showed sustained release of the drug to the cancer cells through receptor-mediated endocytosis, which led to cancer cell death via apoptosis. Considering easy and facile COF synthesis, functionality based postsynthetic modifications and chemical delamination to CONs for potential advantageous targeted drug delivery, this process can have a significant impact in biomedical applications.

    3. 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.

    4. Central nervous system myeloid cells as drug targets: current status and translational challenges.

      Science.gov (United States)

      Biber, Knut; Möller, Thomas; Boddeke, Erik; Prinz, Marco

      2016-02-01

      Myeloid cells of the central nervous system (CNS), which include parenchymal microglia, macrophages at CNS interfaces and monocytes recruited from the circulation during disease, are increasingly being recognized as targets for therapeutic intervention in neurological and psychiatric diseases. The origin of these cells in the immune system distinguishes them from ectodermal neurons and other glia and endows them with potential drug targets distinct from classical CNS target groups. However, despite the identification of several promising therapeutic approaches and molecular targets, no agents directly targeting these cells are currently available. Here, we assess strategies for targeting CNS myeloid cells and address key issues associated with their translation into the clinic.

    5. [Drug delivery systems to target the anterior segment of the eye: fundamental bases and clinical applications].

      Science.gov (United States)

      Behar-Cohen, F

      2002-05-01

      The development of new drug delivery systems to target the anterior segment of the eye may offer many advantages: to increase the biodisponibility of the drug, to allow the penetration of drug that cannot be formulated as solutions, to obtain constant and sustained drug release, to achieve higher local concentrations without systemic effects, to target more specifically one tissue or cell type, to reduce the frequency of instillation and therefore increase the observance and comfort of the patient while reducing side effects of frequent instillation. Several approaches are developed, aiming to increase the corneal contact time by modified formulation or reservoir systems, or by increasing the tissue permeability using iontophoresis. To date, no ocular drug delivery system is ideal for all purposes. To maximize treatment efficacy, careful evaluation of the specific pathological condition, the targeted Intraocular tissue and the location of the most severe pathology must be made before selecting the method of delivery most suitable for each individual patient.

    6. Serine Proteases of Malaria Parasite Plasmodium falciparum: Potential as Antimalarial Drug Targets

      Directory of Open Access Journals (Sweden)

      Asrar Alam

      2014-01-01

      Full Text Available Malaria is a major global parasitic disease and a cause of enormous mortality and morbidity. Widespread drug resistance against currently available antimalarials warrants the identification of novel drug targets and development of new drugs. Malarial proteases are a group of molecules that serve as potential drug targets because of their essentiality for parasite life cycle stages and feasibility of designing specific inhibitors against them. Proteases belonging to various mechanistic classes are found in P. falciparum, of which serine proteases are of particular interest due to their involvement in parasite-specific processes of egress and invasion. In P. falciparum, a number of serine proteases belonging to chymotrypsin, subtilisin, and rhomboid clans are found. This review focuses on the potential of P. falciparum serine proteases as antimalarial drug targets.

    7. “Bureaucracy & Beliefs”: Assessing the Barriers to Accessing Opioid Substitution Therapy by People Who Inject Drugs in Ukraine

      Science.gov (United States)

      Bojko, Martha J.; Mazhnaya, Alyona; Makarenko, Iuliia; Marcus, Ruthanne; Dvoriak, Sergii; Islam, Zahedul; Altice, Frederick L.

      2016-01-01

      Aims Opioid substitution therapy (OST) is an evidence-based HIV prevention strategy for people who inject drugs (PWIDs). Yet, only 2.7% of Ukraine’s estimated 310,000 PWIDs receive it despite free treatment since 2004. The multi-level barriers to entering OST among opioid dependent PWIDs have not been examined in Ukraine. Methods A multi-year mixed methods implementation science project included focus group discussions with 199 PWIDs in 5 major Ukrainian cities in 2013 covering drug treatment attitudes and beliefs and knowledge of and experiences with OST. Data were transcribed, translated into English and coded. Coded segments related to OST access, entry, knowledge, beliefs and attitudes were analyzed among 41 PWIDs who were eligible for but had never received OST. Findings A number of programmatic and structural barriers were mentioned by participants as barriers to entry to OST, including compulsory drug user registration, waiting lists, and limited number of treatment slots. Participants also voiced strong negative attitudes and beliefs about OST, especially methadone. Their perceptions about methadone’s side effects as well as the stigma of being a methadone client were expressed as obstacles to treatment. Conclusions Despite expressed interest in treatment, Ukrainian OST-naïve PWIDs evade OST for reasons that can be addressed through changes in program-level and governmental policies and social-marketing campaigns. Voiced OST barriers can effectively inform public health and policy directives related to HIV prevention and treatment in Ukraine to improve evidence-based treatment access and availability. PMID:27087758

    8. Targeting iron metabolism in drug discovery and delivery.

      Science.gov (United States)

      Crielaard, Bart J; Lammers, Twan; Rivella, Stefano

      2017-02-03

      Iron fulfils a central role in many essential biochemical processes in human physiology; thus, proper processing of iron is crucial. Although iron metabolism is subject to relatively strict physiological control, numerous disorders, such as cancer and neurodegenerative diseases, have recently been linked to deregulated iron homeostasis. Consequently, iron metabolism constitutes a promising and largely unexploited therapeutic target for the development of new pharmacological treatments for these diseases. Several iron metabolism-targeted therapies are already under clinical evaluation for haematological disorders, and these and newly developed therapeutic agents are likely to have substantial benefit in the clinical management of iron metabolism-associated diseases, for which few efficacious treatments are currently available.

    9. Tau-Centric Targets and Drugs in Clinical Development for the Treatment of Alzheimer's Disease

      OpenAIRE

      Francesco Panza; Vincenzo Solfrizzi; Davide Seripa; Imbimbo, Bruno P.; Madia Lozupone; Andrea Santamato; Chiara Zecca; Maria Rosaria Barulli; Antonello Bellomo; Alberto Pilotto; Antonio Daniele; Antonio Greco; Giancarlo Logroscino

      2016-01-01

      The failure of several Phase II/III clinical trials in Alzheimer’s disease (AD) with drugs targeting β-amyloid accumulation in the brain fuelled an increasing interest in alternative treatments against tau pathology, including approaches targeting tau phosphatases/kinases, active and passive immunization, and anti-tau aggregation. The most advanced tau aggregation inhibitor (TAI) is methylthioninium (MT), a drug existing in equilibrium between a reduced (leuco-methylthioninium) and oxidized f...

    10. An ex Vivo Model for Evaluating Blood-Brain Barrier Permeability, Efflux, and Drug Metabolism

      DEFF Research Database (Denmark)

      Hellman, Karin; Aadal Nielsen, Peter; Ek, Fredrik

      2016-01-01

      , risperidone, citalopram, fluoxetine, and haloperidol were studied, and one preselected metabolite for each drug was analyzed, identified, and quantified. Metabolite identification studies of clozapine and midazolam showed that the locust brain was highly metabolically active, and 18 and 14 metabolites......, respectively, were identified. The unbound drug fraction of clozapine, NDMC, carbamazepine, and risperidone was analyzed. In addition, coadministration of drugs with verapamil or fluvoxamine was performed to evaluate drug-drug interactions in all setups. All findings correlated well with the data...

    11. Molecularly targeted therapy for advanced hepatocellularcarcinoma - a drug development crisis?

      Institute of Scientific and Technical Information of China (English)

      2016-01-01

      Hepatocellular carcinoma is the fastest growing causeof cancer related death globally. Sorafenib, a multitargetedkinase inhibitor, is the only drug proven toimprove outcomes in patients with advanced diseaseoffering modest survival benefit. Although comprehensivegenomic mapping has improved understanding of thegenetic aberrations in hepatocellular cancer (HCC), thisknowledge has not yet impacted clinical care. The lastfew years have seen the failure of several first and secondline phase Ⅲ clinical trials of novel molecularly targetedtherapies, warranting a change in the way new therapiesare investigated in HCC. Potential reasons for thesefailures include clinical and molecular heterogeneity, trialdesign and a lack of biomarkers. This review discussesthe current crisis in HCC drug development and how weshould learn from recent trial failures to develop a moreeffective personalised treatment paradigm for patientswith HCC.

    12. Drug-loading capacity and nuclear targeting of multiwalled carbon nanotubes grafted with anionic amphiphilic copolymers

      Directory of Open Access Journals (Sweden)

      Tsai HC

      2013-11-01

      Full Text Available Hsieh-Chih Tsai,1,* Jeng-Yee Lin,2,* Faiza Maryani,1 Chun-Chiang Huang,1 Toyoko Imae1,31Graduate Institute of Applied Science and Technology, 2Division of Plastic Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei Medical University, 3Department of Chemical Engineering, National Taiwan University of Science and Technology, Taipei, Taiwan *These authors contributed equally to this work Abstract: In this study, three types of hybrid nanotubes (NTs, ie, oxidized multiwalled carbon NTs (COOH MWCNTs, heparin (Hep-conjugated MWCNTs (Hep MWCNTs, and diblock copolymer polyglycolic acid (PGA-co-heparin conjugated to MWCNTs (PGA MWCNTs, were synthesized with improved biocompatibility and drug-loading capacity. Hydrophilic Hep substituents on MWCNTs improved biocompatibility and acted as nucleus-sensitive segments on the CNT carrier, whereas the addition of PGA enhanced drug-loading capacity. In the PGA MWCNT system, the amphiphilic copolymer (PGA-Hep formed micelles on the side walls of CNTs, as confirmed by electron microscopy. The PGA system encapsulated the hydrophobic drug with high efficiency compared to the COOH MWCNT and Hep MWCNT systems. This is because the drug was loaded onto the PGA MWCNTs through hydrophobic forces and onto the CNTs by ∏–∏ stacking interactions. Additionally, most of the current drug-carrier designs that target cancer cells release the drug in the lysosome or cytoplasm. However, nuclear-targeted drug release is expected to kill cancer cells more directly and efficiently. In our study, PGA MWCNT carriers effectively delivered the active anticancer drug doxorubicin into targeted nuclei. This study may provide an effective strategy for the development of carbon-based drug carriers for nuclear-targeted drug delivery. Keywords: carbon nanotube, amphiphilic copolymer, drug loading, nucleus targeting, cancer therapy

    13. New development and application of ultrasound targeted microbubble destruction in gene therapy and drug delivery.

      Science.gov (United States)

      Chen, Zhi-Yi; Yang, Feng; Lin, Yan; Zhang, Jin-Shan; Qiu, Ri-Xiang; Jiang, Lan; Zhou, Xing-Xing; Yu, Jiang-Xiu

      2013-08-01

      Ultrasound is a common used technique for clinical imaging. In recent years, with the advances in preparation technology of microbubbles and the innovations in ultrasound imaging, ultrasound is no longer confined to detection of tissue perfusion, but extends to specific ultrasound molecular imaging and target therapy gradually. With the development of research, ultrasound molecular imaging and target therapy have made great progresses. Targeted microbubbles for molecular imaging are achieved by binding target molecules, specific antibody or ligand to the surface of microbubbles to obtain specific imaging by attaching to target tissues. Meanwhile, it can also achieve targeting gene therapy or drug delivery by ultrasound targeted microbubble destruction (UTMD) mediating genes or drugs to specific target sites. UTMD has a number of advantages, such as target-specific, highly effective, non-invasivity, relatively low-cost and no radiation, and has broad application prospects, which is regarded as one hot spot in medical studies. We reviewed the new development and application of UTMD in gene therapy and drug delivery in this paper. With further development of technology and research, the gene or drug delivery system and related methods will be widely used in application and researches.

    14. Is PDE4 too difficult a drug target?

      Science.gov (United States)

      Higgs, Gerry

      2010-05-01

      The search for selective inhibitors of PDE4 as novel anti-inflammatory drugs has continued for more than 30 years. Although several compounds have demonstrated therapeutic effects in diseases such as asthma, COPD, atopic dermatitis and psoriasis, none have reached the market. A persistent challenge in the development of PDE4 inhibitors has been drug-induced gastrointestinal adverse effects, such as nausea. However, extensive clinical trials with well-tolerated doses of roflumilast (Daxas; Nycomed/Mitsubishi Tanabe Pharma Corp/Forest Laboratories Inc) in COPD, a disease that is generally unresponsive to existing therapies, have demonstrated significant therapeutic improvements. In addition, GlaxoSmithKline plc is developing 256066, an inhaled formulation of a PDE4 inhibitor that has demonstrated efficacy in trials in asthma, and apremilast from Celgene Corp has been reported to be effective for the treatment of psoriasis. Despite the challenges and complications that have been encountered during the development of PDE4 inhibitors, these drugs may provide a genuinely novel class of anti-inflammatory agents, and there are several compounds in development that could fulfill that promise.

    15. Bioreducible carboxymethyl dextran nanoparticles for tumor-targeted drug delivery.

      Science.gov (United States)

      Thambi, Thavasyappan; You, Dong Gil; Han, Hwa Seung; Deepagan, V G; Jeon, Sang Min; Suh, Yung Doug; Choi, Ki Young; Kim, Kwangmeyung; Kwon, Ick Chan; Yi, Gi-Ra; Lee, Jun Young; Lee, Doo Sung; Park, Jae Hyung

      2014-11-01

      Bioreducible carboxymethyl dextran (CMD) derivatives are synthesized by the chemical modification of CMD with lithocholic acid (LCA) through a disulfide linkage. The hydrophobic nature of LCA allows the conjugates (CMD-SS-LCAs) to form self-assembled nanoparticles in aqueous conditions. Depending on the degree of LCA substitution, the particle diameters range from 163 to 242 nm. Doxorubicin (DOX), chosen as a model anticancer drug, is effectively encapsulated into the nanoparticles with high loading efficiency (>70%). In vitro optical imaging tests reveal that the fluorescence signal of DOX quenched in the bioreducible nanoparticles is highly recovered in the presence of glutathione (GSH), a tripeptide capable of reducing disulfide bonds in the intracellular compartments. Bioreducible nanoparticles rapidly release DOX when they are incubated with 10 mm GSH, whereas the drug release is greatly retarded in physiological buffer (pH 7.4). DOX-loaded bioreducible nanoparticles exhibit higher toxicity to SCC7 cancer cells than DOX-loaded nanoparticles without the disulfide bond. Confocal laser scanning microscopy observation demonstrate that bioreducible nanoparticles can effectively deliver DOX into the nuclei of SCC7 cells. In vivo biodistribution study indicates that Cy5.5-labeled CMD-SS-LCAs selectively accumulate at tumor sites after systemic administration into tumor-bearing mice. Notably, DOX-loaded bioreducible nanoparticles exhibit higher antitumor efficacy than reduction-insensitive control nanoparticles. Overall, it is evident that bioreducible CMD-SS-LCA nanoparticles are useful as a drug carrier for cancer therapy.

    16. Investigation on a Potential Targeting Drug Delivery System Consisting of Folate, Mitoxantrone and Human Serum Albumin

      Institute of Scientific and Technical Information of China (English)

      ZHOU Qiu-Jua; BI Ya-Jing; XIANG Jun-Feng; TANG Ya-Lin; YANG Qian-Fan; XU Guang-Zhi

      2008-01-01

      A potential targeting drug delivery system consisting of folate (FA), the targeting molecule, human serum al- bumin (HSA), the carrier, and mitoxantrone (MTO), the medicine, has been designed. Data obtained by UV absorp-tion, fluorescence, and NMR techniques indicated the formation of ternary complexes and possible application to building a targeting drug delivery system by using FA, MTO and HSA. Furthermore, cytotoxicity assay indicated that the toxicity of the FA-HSA-MTO against PC-3 cell line was 79.95%, which was much higher than that of free MTO tested in totally the same conditions. About 30% increase of the toxicity should be owed to the targeting ef-fect of FA. Thus, the feasibility and validity of a novel targeting drug delivery system, FA-HSA-MTO, was con-firmed.

    17. Grants4Targets - an innovative approach to translate ideas from basic research into novel drugs.

      Science.gov (United States)

      Lessl, Monika; Schoepe, Stefanie; Sommer, Anette; Schneider, Martin; Asadullah, Khusru

      2011-04-01

      Collaborations between industry and academia are steadily gaining importance. To combine expertises Bayer Healthcare has set up a novel open innovation approach called Grants4Targets. Ideas on novel drug targets can easily be submitted to http://www.grants4targets.com. After a review process, grants are provided to perform focused experiments to further validate the proposed targets. In addition to financial support specific know-how on target validation and drug discovery is provided. Experienced scientists are nominated as project partners and, depending on the project, tools or specific models are provided. Around 280 applications have been received and 41 projects granted. According to our experience, this type of bridging fund combined with joint efforts provides a valuable tool to foster drug discovery collaborations.

    18. The Research and Applications of Quantum Dots as Nano-Carriers for Targeted Drug Delivery and Cancer Therapy

      OpenAIRE

      Zhao, Mei-Xia; Zhu, Bing-Jie

      2016-01-01

      Quantum dots (QDs), nano-carriers for drugs, can help realize the targeting of drugs, and improve the bioavailability of drugs in biological fields. And, a QD nano-carrier system for drugs has the potential to realize early detection, monitoring, and localized treatments of specific disease sites. In addition, QD nano-carrier systems for drugs can improve stability of drugs, lengthen circulation time in vivo, enhance targeted absorption, and improve the distribution and metabolism process of ...

    19. Genome-wide identification of structural variants in genes encoding drug targets

      DEFF Research Database (Denmark)

      Rasmussen, Henrik Berg; Dahmcke, Christina Mackeprang

      2012-01-01

      The objective of the present study was to identify structural variants of drug target-encoding genes on a genome-wide scale. We also aimed at identifying drugs that are potentially amenable for individualization of treatments based on knowledge about structural variation in the genes encoding the...

    20. ROCK1 is a potential combinatorial drug target for BRAF mutant melanoma

      NARCIS (Netherlands)

      Smit, Marjon A; Maddalo, Gianluca; Greig, Kylie; Raaijmakers, Linsey M; Possik, Patricia A; van Breukelen, Bas; Cappadona, Salvatore; Heck, Albert Jr; Altelaar, Adrianus; Peeper, Daniel S

      2014-01-01

      Treatment of BRAF mutant melanomas with specific BRAF inhibitors leads to tumor remission. However, most patients eventually relapse due to drug resistance. Therefore, we designed an integrated strategy using (phospho)proteomic and functional genomic platforms to identify drug targets whose inhibiti

    1. Multifunctional magnetic silica nanotubes for MR imaging and targeted drug delivery.

      Science.gov (United States)

      Huang, Liang; Ao, Lijiao; Wang, Wei; Hu, Dehong; Sheng, Zonghai; Su, Wu

      2015-03-04

      A multifunctional drug delivery vehicle consisting of a tubular shaped silica host, a compact superparamagnetic iron oxide nanoparticle layer and a hyaluronic acid surface coating was developed as a theranostic platform, for in vivo MR imaging and magnetically guided/cancer targeted drug delivery.

    2. Protein target discovery of drug and its reactive intermediate metabolite by using proteomic strategy

      OpenAIRE

      Lianghai Hu; John Paul Fawcett; Jingkai Gu

      2012-01-01

      Identifying protein targets of bioactive compounds is an effective approach to discover unknown protein functions, identify molecular mechanisms of drug action, and obtain information for optimization of lead compounds. At the same time, metabolic activation of a drug can lead to cytotoxicities. Therefore, it is very important to systemically characterize the drug and its reactive intermediate. Mass spectrometry-based proteomic approach has emerged as the most efficient to study protein funct...

    3. Formulation, Evaluation and Optimization of Pectin- Bora Rice Beads for Colon Targeted Drug Delivery System

      Directory of Open Access Journals (Sweden)

      Kuldeep Hemraj Ramteke

      2014-03-01

      Full Text Available Purpose: The purpose of this research was to established new polysaccharide for the colon targeted drug delivery system, its formulation and in vitro and in vivo evaluation. Methods: Microspheres containing pectin and bora rice were prepared by ionotropic gelation technique using zinc acetate as cross linking agent and model drug used was glipizide. A 32 full factorial design was employed to study the effect of independent variables, polymer to drug ratio (A, and concentration of cross linking agent (B on dependent variables, particle size, swelling index, drug entrapment efficiency and percentage drug release. Results: Results of trial batches indicated that polymer to drug ratio and concentration of cross linking agent affects characteristics of beads. Beads were discrete, spherical and free flowing. Beads exhibited small particle size and showed higher percentage of drug entrapment efficiency. The optimized batch P2 exhibited satisfactory drug entrapment efficiency 68% and drug release was also controlled for more than 24 hours. The polymer to drug ratio had a more significant effect on the dependent variables. In vivo gamma scintigraphy study of optimized pectin-bora rice beads demonstrated degradation of beads whenever they reached to the colon. Conclusion: Bora rice is potential polysaccharide for colon targeted drug delivery system.

    4. The function of breast cancer resistance protein in epithelial barriers, stem cells and milk secretion of drugs and xenotoxins.

      Science.gov (United States)

      van Herwaarden, Antonius E; Schinkel, Alfred H

      2006-01-01

      The breast cancer resistance protein [BCRP (also known as ABCG2)] belongs to the ATP binding cassette (ABC) family of transmembrane drug transporters. BCRP has a broad substrate specificity and actively extrudes a wide variety of drugs, carcinogens and dietary toxins from cells. Situated in the apical plasma membrane of epithelial cells of the small and large intestine and renal proximal tubules and in the bile canalicular membrane of hepatocytes, BCRP decreases the oral availability and systemic exposure of its substrates. In several blood-tissue barriers BCRP reduces tissue penetration of its substrates and it protects haematopoietic stem cells from cytotoxic substrates. Moreover, BCRP is expressed in mammary gland alveolar epithelial cells during pregnancy and lactation, where it actively secretes a variety of drugs, toxins and carcinogens into milk. In apparent contradiction with the detoxifying role of BCRP in mothers, this contamination of milk exposes suckling infants and dairy consumers to xenotoxins. BCRP thus affects many important aspects of pharmacology and toxicology.

    5. Interactions of dendrimers with biological drug targets: reality or mystery - a gap in drug delivery and development research.

      Science.gov (United States)

      Ahmed, Shaimaa; Vepuri, Suresh B; Kalhapure, Rahul S; Govender, Thirumala

      2016-07-21

      Dendrimers have emerged as novel and efficient materials that can be used as therapeutic agents/drugs or as drug delivery carriers to enhance therapeutic outcomes. Molecular dendrimer interactions are central to their applications and realising their potential. The molecular interactions of dendrimers with drugs or other materials in drug delivery systems or drug conjugates have been extensively reported in the literature. However, despite the growing application of dendrimers as biologically active materials, research focusing on the mechanistic analysis of dendrimer interactions with therapeutic biological targets is currently lacking in the literature. This comprehensive review on dendrimers over the last 15 years therefore attempts to identify the reasons behind the apparent lack of dendrimer-receptor research and proposes approaches to address this issue. The structure, hierarchy and applications of dendrimers are briefly highlighted, followed by a review of their various applications, specifically as biologically active materials, with a focus on their interactions at the target site. It concludes with a technical guide to assist researchers on how to employ various molecular modelling and computational approaches for research on dendrimer interactions with biological targets at a molecular level. This review highlights the impact of a mechanistic analysis of dendrimer interactions on a molecular level, serves to guide and optimise their discovery as medicinal agents, and hopes to stimulate multidisciplinary research between scientific, experimental and molecular modelling research teams.

    6. Drug-loaded bubbles with matched focused ultrasound excitation for concurrent blood-brain barrier opening and brain-tumor drug delivery.

      Science.gov (United States)

      Fan, Ching-Hsiang; Ting, Chien-Yu; Chang, Yuan-Chih; Wei, Kuo-Chen; Liu, Hao-Li; Yeh, Chih-Kuang

      2015-03-01

      Focused ultrasound (FUS) with microbubbles has been used to achieve local blood-brain barrier opening (BBB opening) and increase the penetration of therapeutic drugs into brain tumors. However, inertial cavitation of microbubbles during FUS-induced BBB opening causes intracerebral hemorrhaging (ICH), leading to acute and chronic brain injury and limiting the efficiency of drug delivery. Here we investigated whether induction of drug (1,3-bis(2-chloroethyl)-1-nitrosourea, BCNU)-loaded bubbles (BCNU bubbles) to oscillate at their resonant frequency would reduce inertial cavitation during BBB opening, thereby eliminating ICH and enhancing drug delivery in a rat brain model. FUS was tested at 1 and 10 MHz, over a wide range of pressure (mechanical index ranging from 0.16 to 1.42) in the presence of BCNU bubbles. Excitation of BCNU bubbles by resonance frequency-matched FUS (10 MHz) resulted in predominantly stable cavitation and significantly reduced the occurrence of potential hazards of exposure to biological tissues during the BBB opening process. In addition, the drug release process could be monitored by acoustic emission obtained from ultrasound imaging. In tumor-bearing animals, BCNU bubbles with FUS showed significant control of tumor progression and improved maximum survival from 26 to 35 days. This study provides useful advancements toward the goal of successfully translating FUS theranostic bubble-enhanced brain drug delivery into clinical use.

    7. Notch signaling in glioblastoma: a developmental drug target?

      Directory of Open Access Journals (Sweden)

      Boulay Jean-Louis

      2010-11-01

      Full Text Available Abstract Malignant gliomas are among the most devastating tumors for which conventional therapies have not significantly improved patient outcome. Despite advances in imaging, surgery, chemotherapy and radiotherapy, survival is still less than 2 years from diagnosis and more targeted therapies are urgently needed. Notch signaling is central to the normal and neoplastic development of the central nervous system, playing important roles in proliferation, differentiation, apoptosis and cancer stem cell regulation. Notch is also involved in the regulation response to hypoxia and angiogenesis, which are typical tumor and more specifically glioblastoma multiforme (GBM features. Targeting Notch signaling is therefore a promising strategy for developing future therapies for the treatment of GBM. In this review we give an overview of the mechanisms of Notch signaling, its networking pathways in gliomas, and discuss its potential for designing novel therapeutic approaches.

    8. [New targets and new drugs in thoracic oncology].

      Science.gov (United States)

      Rouviere, D; Bousquet, E; Pons, E; Milia, J-D; Guibert, N; Mazieres, J

      2015-10-01

      A number of mechanisms that drive oncogenesis have been deciphered over the last 20 years. The main oncogenic factors in the field of thoracic oncology are mutations of EGFR, KRAS, and EML4-ALK translocation, which are most often reported in adenocarcinomas. However, new molecular targets have been highlighted recently including BRAF mutations, HER2 or PI3K, new translocations such as ROS1 or KIF5B-RET. Molecular abnormalities have also been identified in tumors other than adenocarcinoma (squamous and small cell carcinoma). Therapeutic strategies have been designed to inhibit these signaling pathways including monoclonal antibodies and tyrosine kinase inhibitors. Some of these molecules are now approved as therapies, others are currently undergoing testing in clinical trials. We here present a review of novel targeted agents for lung cancer.

    9. Targeting aerobic glycolysis: 3-bromopyruvate as a promising anticancer drug.

      Science.gov (United States)

      Cardaci, Simone; Desideri, Enrico; Ciriolo, Maria Rosa

      2012-02-01

      The Warburg effect refers to the phenomenon whereby cancer cells avidly take up glucose and produce lactic acid under aerobic conditions. Although the molecular mechanisms underlying tumor reliance on glycolysis remains not completely clear, its inhibition opens feasible therapeutic windows for cancer treatment. Indeed, several small molecules have emerged by combinatorial studies exhibiting promising anticancer activity both in vitro and in vivo, as a single agent or in combination with other therapeutic modalities. Therefore, besides reviewing the alterations of glycolysis that occur with malignant transformation, this manuscript aims at recapitulating the most effective pharmacological therapeutics of its targeting. In particular, we describe the principal mechanisms of action and the main targets of 3-bromopyruvate, an alkylating agent with impressive antitumor effects in several models of animal tumors. Moreover, we discuss the chemo-potentiating strategies that would make unparalleled the putative therapeutic efficacy of its use in clinical settings.

    10. Tailoring Lipid and Polymeric Nanoparticles as siRNA Carriers towards the Blood-Brain Barrier – from Targeting to Safe Administration

      DEFF Research Database (Denmark)

      Gomes, Maria João; Fernandes, Carlos; Martins, Susana

      2017-01-01

      Blood-brain barrier is a tightly packed layer of endothelial cells surrounding the brain that acts as the main obstacle for drugs enter the central nervous system (CNS), due to its unique features, as tight junctions and drug efflux systems. Therefore, since the incidence of CNS disorders is incr...

    11. Mining predicted essential genes of Brugia malayi for nematode drug targets.

      Directory of Open Access Journals (Sweden)

      Sanjay Kumar

      Full Text Available We report results from the first genome-wide application of a rational drug target selection methodology to a metazoan pathogen genome, the completed draft sequence of Brugia malayi, a parasitic nematode responsible for human lymphatic filariasis. More than 1.5 billion people worldwide are at risk of contracting lymphatic filariasis and onchocerciasis, a related filarial disease. Drug treatments for filariasis have not changed significantly in over 20 years, and with the risk of resistance rising, there is an urgent need for the development of new anti-filarial drug therapies. The recent publication of the draft genomic sequence for B. malayi enables a genome-wide search for new drug targets. However, there is no functional genomics data in B. malayi to guide the selection of potential drug targets. To circumvent this problem, we have utilized the free-living model nematode Caenorhabditis elegans as a surrogate for B. malayi. Sequence comparisons between the two genomes allow us to map C. elegans orthologs to B. malayi genes. Using these orthology mappings and by incorporating the extensive genomic and functional genomic data, including genome-wide RNAi screens, that already exist for C. elegans, we identify potentially essential genes in B. malayi. Further incorporation of human host genome sequence data and a custom algorithm for prioritization enables us to collect and rank nearly 600 drug target candidates. Previously identified potential drug targets cluster near the top of our prioritized list, lending credibility to our methodology. Over-represented Gene Ontology terms, predicted InterPro domains, and RNAi phenotypes of C. elegans orthologs associated with the potential target pool are identified. By virtue of the selection procedure, the potential B. malayi drug targets highlight components of key processes in nematode biology such as central metabolism, molting and regulation of gene expression.

    12. Mining predicted essential genes of Brugia malayi for nematode drug targets.

      Science.gov (United States)

      Kumar, Sanjay; Chaudhary, Kshitiz; Foster, Jeremy M; Novelli, Jacopo F; Zhang, Yinhua; Wang, Shiliang; Spiro, David; Ghedin, Elodie; Carlow, Clotilde K S

      2007-01-01

      We report results from the first genome-wide application of a rational drug target selection methodology to a metazoan pathogen genome, the completed draft sequence of Brugia malayi, a parasitic nematode responsible for human lymphatic filariasis. More than 1.5 billion people worldwide are at risk of contracting lymphatic filariasis and onchocerciasis, a related filarial disease. Drug treatments for filariasis have not changed significantly in over 20 years, and with the risk of resistance rising, there is an urgent need for the development of new anti-filarial drug therapies. The recent publication of the draft genomic sequence for B. malayi enables a genome-wide search for new drug targets. However, there is no functional genomics data in B. malayi to guide the selection of potential drug targets. To circumvent this problem, we have utilized the free-living model nematode Caenorhabditis elegans as a surrogate for B. malayi. Sequence comparisons between the two genomes allow us to map C. elegans orthologs to B. malayi genes. Using these orthology mappings and by incorporating the extensive genomic and functional genomic data, including genome-wide RNAi screens, that already exist for C. elegans, we identify potentially essential genes in B. malayi. Further incorporation of human host genome sequence data and a custom algorithm for prioritization enables us to collect and rank nearly 600 drug target candidates. Previously identified potential drug targets cluster near the top of our prioritized list, lending credibility to our methodology. Over-represented Gene Ontology terms, predicted InterPro domains, and RNAi phenotypes of C. elegans orthologs associated with the potential target pool are identified. By virtue of the selection procedure, the potential B. malayi drug targets highlight components of key processes in nematode biology such as central metabolism, molting and regulation of gene expression.

    13. Targeted CNx Nanowire-Drug Complexes for Enhanced Chemotherapeutic Efficacy

      Science.gov (United States)

      2009-09-01

      Zhongrui Li‡ and Alexandru S. Biris‡ (2008). Temperature Measurement of Carbon Nanotubes Using Infrared Thermography Chemistry of Materials 20, 4011...The relative efficiency of conversion of nIR irradiation into heat for DNA-encased MWNTs relative to non-DNA-encased MWNTs and other materials is...successful, the use of aptamers. Details of the successful approach to building N-MWNTs with targeting molecule: Raw, carbon vapor deposition (CVD) MWNTs

    14. Sphingolipids Are Dual Specific Drug Targets for the Management of Pulmonary Infections: Perspective

      Science.gov (United States)

      Sharma, Lalita; Prakash, Hridayesh

      2017-01-01

      bactericidal potential in macrophages for the control of TB. In this review, we have discussed and emphasized that sphingolipids may represent effective novel, yet dual specific drug targets for controlling pulmonary infections.

    15. Candidate Targets for New Anti-Virulence Drugs: Selected Cases of Bacterial Adhesion and Biofilm Formation

      DEFF Research Database (Denmark)

      Klemm, Per; Hancock, Viktoria; Kvist, Malin;

      2007-01-01

      formation are highly attractive targets for new drugs. Specific adhesion provides bacteria with target selection and prevents removal by hydrodynamic flow forces. Bacterial adhesion is of paramount importance for bacterial pathogenesis. Adhesion is also the first step in biofilm formation. Biofilm formation...

    16. Adaptation of targeted nanocarriers to changing requirements in antimalarial drug delivery

      OpenAIRE

      Marques, Joana; Valle-Delgado, Juan J.; Urbán, Patricia; Baró, Elisabet; Prohens, Rafel; Mayor, Alfredo; Cisteró, Pau; Delves, Michael; Robert E Sinden; Grandfils, Christian; de Paz, José L.; García-Salcedo, José A.; Fernández-Busquets, Xavier

      2016-01-01

      The adaptation of existing antimalarial nanocarriers to new Plasmodium stages, drugs, targeting molecules, or encapsulating structures is a strategy that can provide new nanotechnology-based, cost-efficient therapies against malaria. We have explored the modification of different liposome prototypes that had been developed in our group for the targeted delivery of antimalarial dru...

    17. Label-free integrative pharmacology on-target of drugs at the β2-adrenergic receptor

      Science.gov (United States)

      Ferrie, Ann M.; Sun, Haiyan; Fang, Ye

      2011-07-01

      We describe a label-free integrative pharmacology on-target (iPOT) method to assess the pharmacology of drugs at the β2-adrenergic receptor. This method combines dynamic mass redistribution (DMR) assays using an array of probe molecule-hijacked cells with similarity analysis. The whole cell DMR assays track cell system-based, ligand-directed, and kinetics-dependent biased activities of the drugs, and translates their on-target pharmacology into numerical descriptors which are subject to similarity analysis. We demonstrate that the approach establishes an effective link between the label-free pharmacology and in vivo therapeutic indications of drugs.

    18. Endocrine function as a target of perinatal drug effects: methodologic issues.

      Science.gov (United States)

      Kuhn, C; Ignar, D; Windh, R

      1991-01-01

      The goal of this chapter is to indicate potential endocrine targets of perinatal drug exposure, to describe the methodologic issues involved in detecting changes in hormone secretion, and to provide examples of several endocrine systems in which exposure to drugs during development significantly impaired normal endocrine development. Finally, we attempted to show that endocrine function is both a target and useful marker for detecting effects of drug of abuse on development that provides the advantages of accurate quantitation and relative response stability across ontogeny.

    19. Anti-cancer drug loaded iron-gold core-shell nanoparticles (Fe@Au) for magnetic drug targeting.

      Science.gov (United States)

      Kayal, Sibnath; Ramanujan, Raju Vijayaraghavan

      2010-09-01

      Magnetic drug targeting, using core-shell magnetic carrier particles loaded with anti-cancer drugs, is an emerging and significant method of cancer treatment. Gold shell-iron core nanoparticles (Fe@Au) were synthesized by the reverse micelle method with aqueous reactants, surfactant, co-surfactant and oil phase. XRD, XPS, TEM and magnetic property measurements were utilized to characterize these core-shell nanoparticles. Magnetic measurements showed that the particles were superparamagnetic at room temperature and that the saturation magnetization decreased with increasing gold concentration. The anti-cancer drug doxorubicin (DOX) was loaded onto these Fe@Au nanoparticle carriers and the drug release profiles showed that upto 25% of adsorbed drug was released in 80 h. It was found that the amine (-NH2) group of DOX binds to the gold shell. An in vitro apparatus simulating the human circulatory system was used to determine the retention of these nanoparticle carriers when exposed to an external magnetic field. A high percentage of magnetic carriers could be retained for physiologically relevant flow speeds of fluid. The present findings show that DOX loaded gold coated iron nanoparticles are promising for magnetically targeted drug delivery.

    20. Nitric oxide-related drug targets in headache

      DEFF Research Database (Denmark)

      Olesen, Jes

      2010-01-01

      SUMMARY: Nitric oxide (NO) is a very important molecule in the regulation of cerebral and extra cerebral cranial blood flow and arterial diameters. It is also involved in nociceptive processing. Glyceryl trinitrate (GTN), a pro-drug for NO, causes headache in normal volunteers and a so-called del......SUMMARY: Nitric oxide (NO) is a very important molecule in the regulation of cerebral and extra cerebral cranial blood flow and arterial diameters. It is also involved in nociceptive processing. Glyceryl trinitrate (GTN), a pro-drug for NO, causes headache in normal volunteers and a so......-called delayed headache that fulfils criteria for migraine without aura in migraine sufferers. Blockade of nitric oxide synthases (NOS) by L-nitromonomethylarginine effectively treats attacks of migraine without aura. Similar results have been obtained for chronic the tension-type headache and cluster headache....... Inhibition of the breakdown of cyclic guanylate phosphate (cGMP) also provokes migraine in sufferers, indicating that cGMP is the effector of NO-induced migraine. Similar evidence suggests an important role of NO in the tension-type headache and cluster headache. These very strong data from human...

    1. Stabilising cubosomes with Tween 80 as a step towards targeting lipid nanocarriers to the blood-brain barrier.

      Science.gov (United States)

      Azhari, Hanisah; Strauss, Mike; Hook, Sarah; Boyd, Ben J; Rizwan, Shakila B

      2016-07-01

      Coating nanoparticles with the surfactant Tween 80 have been previously shown to enhance drug delivery across the blood-brain barrier (BBB). The aim of this study was to investigate whether Tween 80 could be used to stabilise phytantriol-based cubosomes thereby enabling potential application in delivering macromolecular therapeutics to the brain. Cubosome particles with their large internal and external surface area by virtue of their nanostructure are ideal for delivery of macromolecules. Phase behaviour studies were conducted using a combination of optical microscopy and small-angle X-ray scattering (SAXS) and the addition of Tween 80 to mixtures of phytantriol and water resulted in a rich array of lyotropic mesophases. In particular, a large cubic phase region and a two-phase region of readily dispersed cubosomes is observed. Cubosomes with different concentrations of Tween 80 and phytantriol as the liquid crystal forming lipid were prepared using the solvent precursor method and their physical properties were investigated. A combination of dynamic light scattering, cryogenic electron tomography and SAXS shows formation of well-defined cubosomes with a narrow size distribution and the Im3m cubic structure. Collectively, the results confirm that Tween 80 can effectively stabilize phytantriol cubosomes, opening the possibility for future application in drug delivery across the BBB. Moreover, well-defined, homogenous cubosome formulations prepared using the mild solvent precursor dilution method has significant implications for large-scale production of cubosomes, which currently is a major barrier to the application of cubosomes in the clinic.

    2. Autophagy enhances intestinal epithelial tight junction barrier function by targeting claudin-2 protein degradation.

      Science.gov (United States)

      Nighot, Prashant K; Hu, Chien-An Andy; Ma, Thomas Y

      2015-03-13

      Autophagy is an intracellular degradation pathway and is considered to be an essential cell survival mechanism. Defects in autophagy are implicated in many pathological processes, including inflammatory bowel disease. Among the innate defense mechanisms of intestinal mucosa, a defective tight junction (TJ) barrier has been postulated as a key pathogenic factor in the causation and progression of inflammatory bowel disease by allowing increased antigenic permeation. The cross-talk between autophagy and the TJ barrier has not yet been described. In this study, we present the novel finding that autophagy enhances TJ barrier function in Caco-2 intestinal epithelial cells. Nutrient starvation-induced autophagy significantly increased transepithelial electrical resistance and reduced the ratio of sodium/chloride paracellular permeability. Nutrient starvation reduced the paracellular permeability of small-sized urea but not larger molecules. The role of autophagy in the modulation of paracellular permeability was confirmed by pharmacological induction as well as pharmacological and genetic inhibition of autophagy. Consistent with the autophagy-induced reduction in paracellular permeability, a marked decrease in the level of the cation-selective, pore-forming TJ protein claudin-2 was observed after cell starvation. Starvation reduced the membrane presence of claudin-2 and increased its cytoplasmic, lysosomal localization. Therefore, our data show that autophagy selectively reduces epithelial TJ permeability of ions and small molecules by lysosomal degradation of the TJ protein claudin-2.

    3. Endothelial cells of the blood-brain barrier: a target for glucocorticoids and estrogens?

      Science.gov (United States)

      Dietrich, Jean-Bernard

      2004-01-01

      Adhesion molecules are involved in the leukocyte recruitment of leukocytes at the blood-brain barrier. For this reason, it is important to understand how the regulation of their gene expression controls lymphocyte adhesion to endothelial cells in microvessels. Indeed, due to their specificity and diversity, adhesion molecules involved in extravasation play an essential role in the recruitment of activated leukocytes and activation of inflammation. Multiple sclerosis results from a chronic inflammation of the CNS which is mediated by infiltration of inflammatory cells from the immune system. Administration of glucocorticoids is a routine method to control multiple sclerosis since naturally derived or synthetic glucocorticoids are potent immunosuppressive and anti-inflammatory agents. Glucocorticoids also have beneficial effects in stabilizing the blood-brain barrier, as steroid hormones regulate the expression of adhesion molecule genes in endothelial cells. Other hormones such as estrogens modulate many endothelial cell biological activities, among them adhesion to leukocytes. They regulate expression of adhesion molecules genes on endothelial cells and are useful for the treatment of experimental autoimmune encephalomyelitis, the animal model of multiple sclerosis. The effects of glucocorticoids and estrogens on the expression of adhesion molecules on endothelial cells, including microvascular endothelial cells of the blood-brain barrier, are reviewed in this paper, as well as the involvement of these hormones in the therapy of experimental autoimmune encephalomyelitis and multiple sclerosis.

    4. Chemical Genomics and Emerging DNA Technologies in the Identification of Drug Mechanisms and Drug Targets

      DEFF Research Database (Denmark)

      Olsen, Louise Cathrine Braun; Færgeman, Nils J.

      2012-01-01

      critical roles in the genomic age of biological research and drug discovery. In the present review we discuss how simple biological model organisms can be used as screening platforms in combination with emerging genomic technologies to advance the identification of potential drugs and their molecular...

    5. Novel Methods for Drug-Target Interaction Prediction using Graph Mining

      KAUST Repository

      Ba Alawi, Wail

      2016-08-31

      The problem of developing drugs that can be used to cure diseases is important and requires a careful approach. Since pursuing the wrong candidate drug for a particular disease could be very costly in terms of time and money, there is a strong interest in minimizing such risks. Drug repositioning has become a hot topic of research, as it helps reduce these risks significantly at the early stages of drug development by reusing an approved drug for the treatment of a different disease. Still, finding new usage for a drug is non-trivial, as it is necessary to find out strong supporting evidence that the proposed new uses of drugs are plausible. Many computational approaches were developed to narrow the list of possible candidate drug-target interactions (DTIs) before any experiments are done. However, many of these approaches suffer from unacceptable levels of false positives. We developed two novel methods based on graph mining networks of drugs and targets. The first method (DASPfind) finds all non-cyclic paths that connect a drug and a target, and using a function that we define, calculates a score from all the paths. This score describes our confidence that DTI is correct. We show that DASPfind significantly outperforms other state-of-the-art methods in predicting the top ranked target for each drug. We demonstrate the utility of DASPfind by predicting 15 novel DTIs over a set of ion channel proteins, and confirming 12 out of these 15 DTIs through experimental evidence reported in literature and online drug databases. The second method (DASPfind+) modifies DASPfind in order to increase the confidence and reliability of the resultant predictions. Based on the structure of the drug-target interaction (DTI) networks, we introduced an optimization scheme that incrementally alters the network structure locally for each drug to achieve more robust top 1 ranked predictions. Moreover, we explored effects of several similarity measures between the targets on the prediction

    6. Targeting Energy Metabolism in Mycobacterium tuberculosis, a New Paradigm in Antimycobacterial Drug Discovery

      Science.gov (United States)

      Villellas, Cristina; Lu, Ping

      2017-01-01

      ABSTRACT Drug-resistant mycobacterial infections are a serious global health challenge, leading to high mortality and socioeconomic burdens in developing countries worldwide. New innovative approaches, from identification of new targets to discovery of novel chemical scaffolds, are urgently needed. Recently, energy metabolism in mycobacteria, in particular the oxidative phosphorylation pathway, has emerged as an object of intense microbiological investigation and as a novel target pathway in drug discovery. New classes of antibacterials interfering with elements of the oxidative phosphorylation pathway are highly active in combating dormant or latent mycobacterial infections, with a promise of shortening tuberculosis chemotherapy. The regulatory approval of the ATP synthase inhibitor bedaquiline and the discovery of Q203, a candidate drug targeting the cytochrome bc1 complex, have highlighted the central importance of this new target pathway. In this review, we discuss key features and potential applications of inhibiting energy metabolism in our quest for discovering potent novel and sterilizing drug combinations for combating tuberculosis. We believe that the combination of drugs targeting elements of the oxidative phosphorylation pathway can lead to a completely new regimen for drug-susceptible and multidrug-resistant tuberculosis.

    7. Improved prediction of drug-target interactions using regularized least squares integrating with kernel fusion technique

      Energy Technology Data Exchange (ETDEWEB)

      Hao, Ming; Wang, Yanli, E-mail: ywang@ncbi.nlm.nih.gov; Bryant, Stephen H., E-mail: bryant@ncbi.nlm.nih.gov

      2016-02-25

      Identification of drug-target interactions (DTI) is a central task in drug discovery processes. In this work, a simple but effective regularized least squares integrating with nonlinear kernel fusion (RLS-KF) algorithm is proposed to perform DTI predictions. Using benchmark DTI datasets, our proposed algorithm achieves the state-of-the-art results with area under precision–recall curve (AUPR) of 0.915, 0.925, 0.853 and 0.909 for enzymes, ion channels (IC), G protein-coupled receptors (GPCR) and nuclear receptors (NR) based on 10 fold cross-validation. The performance can further be improved by using a recalculated kernel matrix, especially for the small set of nuclear receptors with AUPR of 0.945. Importantly, most of the top ranked interaction predictions can be validated by experimental data reported in the literature, bioassay results in the PubChem BioAssay database, as well as other previous studies. Our analysis suggests that the proposed RLS-KF is helpful for studying DTI, drug repositioning as well as polypharmacology, and may help to accelerate drug discovery by identifying novel drug targets. - Graphical abstract: Flowchart of the proposed RLS-KF algorithm for drug-target interaction predictions. - Highlights: • A nonlinear kernel fusion algorithm is proposed to perform drug-target interaction predictions. • Performance can further be improved by using the recalculated kernel. • Top predictions can be validated by experimental data.

    8. Hedgehog pathway as a drug target: Smoothened inhibitors in development

      Directory of Open Access Journals (Sweden)

      Lin TL

      2012-03-01

      Full Text Available Tara L Lin1, William Matsui21Division of Hematology/Oncology, Department of Internal Medicine, University of Kansas, Kansas City, MO, USA; 2Division of Hematologic Malignancies, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USAAbstract: Emerging laboratory and clinical investigations demonstrate that Hedgehog signaling (Hh represents a novel therapeutic target in various human cancers. This conserved signaling pathway precisely regulates self-renewal and terminal differentiation in embryonic development, but is typically silenced in adult tissues, with reactivation usually only during tissue repair. Aberrant Hh pathway signaling has been implicated in the pathogenesis, self-renewal, and chemotherapy resistance of a growing number of solid and hematologic malignancies. Major components of the Hh pathway include the Hh ligands (Sonic, Desert, and Indian, the transmembrane receptor Patched, the signal transducer Smoothened (Smo, and transcription factors Gli1–3 which regulate the transcription of Hh target genes. Mutations in Hh pathway genes, increased Hh signaling in tumor stroma, and Hh overexpression in self-renewing cells (cancer stem cells have been described, and these different modes of Hh signaling have implications for the design of Hh pathway inhibitors and their integration into conventional treatment regimens. Discovery of a naturally-occurring Smo inhibitor, cyclopamine, and the identification of Hh pathway mutations and over expression in cancer cells prompted the development of several cyclopamine derivatives. Encouraging laboratory and in vivo data has resulted in Phase I and II clinical trials of Smo inhibitors. In this review, we will discuss the current understanding of Hh pathway signaling in malignancy and Smo antagonists in development. Recent data with these agents shows that they are well-tolerated and may be effective for subsets of patients. Challenges remain

    9. E2F-1 as an anticancer drug target

      Directory of Open Access Journals (Sweden)

      Joseph R. Bertino

      2011-12-01

      Full Text Available Mounting evidence indicates that the E2F transcription factors play an essential role in all aspects of cellular functions. Many human malignancies have been shown to overexpress one or more of the ‘‘activating’’ E2Fs. In some circumstances, down regulation as well as overexpression of E2F-1, leads to inhibition of cell growth. The emphasis in this review is placed on new data implicating microRNAs in the regulation of E2F activity and the efforts thus far to target this activity in order to cause tumor regression.

    10. Estimation of Liposome Penetration Barriers of Drug Molecules with All-Atom and Coarse-Grained Models.

      Science.gov (United States)

      Genheden, Samuel; Eriksson, Leif A

      2016-09-13

      Liposomes are common carriers of drug molecules, providing enhanced delivery and accumulation of hydrophilic agents or larger biomolecules. Molecular simulations can be used to estimate key features of the drug molecules upon interaction with the liposomes, such as penetration barriers and localization. Herein, we investigate several aspects of the computational estimation of penetration barriers, viz. the potential of mean force (PMFs) along a vector spanning the membrane. First, we provide an evaluation of the all-atom (AA) and coarse-grained (CG) parametrization of 5-aminolevulinic acid (5-ALA) and two of its alkyl esters by computing n-octanol/water partition coefficients. We find that the CG parametrization of the esters performs significantly better than the CG model of 5-ALA, highlighting the difficulty to coarse-grain small, polar molecules. However, the expected trend in partition coefficients is reproduced also with the CG models. Second, we compare PMFs in a small membrane slab described with either the AA or CG models. Here, we are able to reproduce the all-atom PMF of 5-ALA with CG. However, for the alkyl esters it is unfortunately not possible to correctly reproduce both the depth and the penetration barrier of the PMF seen in the AA simulations with any of the tested CG models. We argue that it is more important to choose a CG parametrization that reproduces the depth of the PMF. Third, we compare, using the CG model, PMFs in the membrane slab with PMFs in a large, realistic liposome. We find similar depths but slightly different penetration barriers most likely due to differences in the lipid density along the membrane axis. Finally, we compute PMFs in liposomes with three different lipid compositions. Unfortunately, differences in the PMFs could not be quantified, and it remains to be investigated to what extent liposome simulations can fully reproduce experimental findings.

    11. Prediction of drug-target interaction by label propagation with mutual interaction information derived from heterogeneous network.

      Science.gov (United States)

      Yan, Xiao-Ying; Zhang, Shao-Wu; Zhang, Song-Yao

      2016-02-01

      The identification of potential drug-target interaction pairs is very important, which is useful not only for providing greater understanding of protein function, but also for enhancing drug research, especially for drug function repositioning. Recently, numerous machine learning-based algorithms (e.g. kernel-based, matrix factorization-based and network-based inference methods) have been developed for predicting drug-target interactions. All these methods implicitly utilize the assumption that similar drugs tend to target similar proteins and yield better results for predicting interactions between drugs and target proteins. To further improve the accuracy of prediction, a new method of network-based label propagation with mutual interaction information derived from heterogeneous networks, namely LPMIHN, is proposed to infer the potential drug-target interactions. LPMIHN separately performs label propagation on drug and target similarity networks, but the initial label information of the target (or drug) network comes from the drug (or target) label network and the known drug-target interaction bipartite network. The independent label propagation on each similarity network explores the cluster structure in its network, and the label information from the other network is used to capture mutual interactions (bicluster structures) between the nodes in each pair of the similarity networks. As compared to other recent state-of-the-art methods on the four popular benchmark datasets of binary drug-target interactions and two quantitative kinase bioactivity datasets, LPMIHN achieves the best results in terms of AUC and AUPR. In addition, many of the promising drug-target pairs predicted from LPMIHN are also confirmed on the latest publicly available drug-target databases such as ChEMBL, KEGG, SuperTarget and Drugbank. These results demonstrate the effectiveness of our LPMIHN method, indicating that LPMIHN has a great potential for predicting drug-target interactions.

    12. Nitric oxide-related drug targets in headache

      DEFF Research Database (Denmark)

      Olesen, Jes

      2010-01-01

      -called delayed headache that fulfils criteria for migraine without aura in migraine sufferers. Blockade of nitric oxide synthases (NOS) by L-nitromonomethylarginine effectively treats attacks of migraine without aura. Similar results have been obtained for chronic the tension-type headache and cluster headache....... Inhibition of the breakdown of cyclic guanylate phosphate (cGMP) also provokes migraine in sufferers, indicating that cGMP is the effector of NO-induced migraine. Similar evidence suggests an important role of NO in the tension-type headache and cluster headache. These very strong data from human......SUMMARY: Nitric oxide (NO) is a very important molecule in the regulation of cerebral and extra cerebral cranial blood flow and arterial diameters. It is also involved in nociceptive processing. Glyceryl trinitrate (GTN), a pro-drug for NO, causes headache in normal volunteers and a so...

    13. Representation of target-bound drugs by computed conformers: implications for conformational libraries

      Directory of Open Access Journals (Sweden)

      Goede Andrean

      2006-06-01

      Full Text Available Abstract Background The increasing number of known protein structures provides valuable information about pharmaceutical targets. Drug binding sites are identifiable and suitable lead compounds can be proposed. The flexibility of ligands is a critical point for the selection of potential drugs. Since computed 3D structures of millions of compounds are available, the knowledge of their binding conformations would be a great benefit for the development of efficient screening methods. Results Integration of two public databases allowed superposition of conformers for 193 approved drugs with 5507 crystallised target-bound counterparts. The generation of 9600 drug conformers using an atomic force field was carried out to obtain an optimal coverage of the conformational space. Bioactive conformations are best described by a conformational ensemble: half of all drugs exhibit multiple active states, distributed over the entire range of the reachable energy and conformational space. A number of up to 100 conformers per drug enabled us to reproduce the bound states within a similarity threshold of 1.0 Å in 70% of all cases. This fraction rises to about 90% for smaller or average sized drugs. Conclusion Single drugs adopt multiple bioactive conformations if they interact with different target proteins. Due to the structural diversity of binding sites they adopt conformations that are distributed over a broad conformational space and wide energy range. Since the majority of drugs is well represented by a predefined low number of conformers (up to 100 this procedure is a valuable method to compare compounds by three-dimensional features or for fast similarity searches starting with pharmacophores. The underlying 9600 generated drug conformers are downloadable from the Super Drug Web site 1. All superpositions are visualised at the same source. Additional conformers (110,000 of 2400 classified WHO-drugs are also available.

    14. Muscarinic Acetylcholine Receptor Subtypes as Potential Drug Targets for the Treatment of Schizophrenia, Drug Abuse and Parkinson's Disease

      DEFF Research Database (Denmark)

      Dencker, Ditte; Thomsen, Morgane; Wörtwein, Gitta

      2011-01-01

      's disease and drug abuse. Dopaminergic systems are regulated by cholinergic, especially muscarinic, input. Not surprisingly, increasing evidence implicates muscarinic acetylcholine receptor-mediated pathways as potential targets for the treatment of these disorders classically viewed as "dopamine based...... site. Such agents may lead to the development of novel classes of drugs useful for the treatment of psychosis, drug abuse and Parkinson's disease. The present review highlights recent studies carried out using muscarinic receptor knock-out mice and new subtype-selective allosteric ligands to assess...... the roles of M(1), M(4), and M(5) receptors in various central processes that are under strong dopaminergic control. The outcome of these studies opens new perspectives for the use of novel muscarinic drugs for several severe disorders of the CNS....

    15. IAP proteins as targets for drug development in oncology

      Directory of Open Access Journals (Sweden)

      Dubrez L

      2013-09-01

      Full Text Available Laurence Dubrez,1,2 Jean Berthelet,1,2 Valérie Glorian,1,21Institut National de la Santé et de la Recherche Médicale (Inserm, Dijon, France; 2Université de Bourgogne, Dijon, FranceAbstract: The inhibitors of apoptosis (IAPs constitute a family of proteins involved in the regulation of various cellular processes, including cell death, immune and inflammatory responses, cell proliferation, cell differentiation, and cell motility. There is accumulating evidence supporting IAP-targeting in tumors: IAPs regulate various cellular processes that contribute to tumor development, such as cell death, cell proliferation, and cell migration; their expression is increased in a number of human tumor samples, and IAP overexpression has been correlated with tumor growth, and poor prognosis or low response to treatment; and IAP expression can be rapidly induced in response to chemotherapy or radiotherapy because of the presence of an internal ribosome entry site (IRES-dependent mechanism of translation initiation, which could contribute to resistance to antitumor therapy. The development of IAP antagonists is an important challenge and was subject to intense research over the past decade. Six molecules are currently in clinical trials. This review focuses on the role of IAPs in tumors and the development of IAP-targeting molecules for anticancer therapy.Keywords: Smac mimetics, apoptosis, antitumor therapy

    16. Mechanism-Based Tumor-Targeting Drug Delivery System. Validation of Efficient Vitamin Receptor-Mediated Endocytosis and Drug Release

      Energy Technology Data Exchange (ETDEWEB)

      Chen, S.; Wong, S.; Zhao, X.; Chen, J.; Chen, J.; Kuznetsova, L.; Ojima, I.

      2010-05-01

      An efficient mechanism-based tumor-targeting drug delivery system, based on tumor-specific vitamin-receptor mediated endocytosis, has been developed. The tumor-targeting drug delivery system is a conjugate of a tumor-targeting molecule (biotin: vitamin H or vitamin B-7), a mechanism-based self-immolative linker and a second-generation taxoid (SB-T-1214) as the cytotoxic agent. This conjugate (1) is designed to be (i) specific to the vitamin receptors overexpressed on tumor cell surface and (ii) internalized efficiently through receptor-mediated endocytosis, followed by smooth drug release via glutathione-triggered self-immolation of the linker. In order to monitor and validate the sequence of events hypothesized, i.e., receptor-mediated endocytosis of the conjugate, drug release, and drug-binding to the target protein (microtubules), three fluorescent/fluorogenic molecular probes (2, 3, and 4) were designed and synthesized. The actual occurrence of these processes was unambiguously confirmed by means of confocal fluorescence microscopy (CFM) and flow cytometry using L1210FR leukemia cells, overexpressing biotin receptors. The molecular probe 4, bearing the taxoid linked to fluorescein, was also used to examine the cell specificity (i.e., efficacy of receptor-based cell targeting) for three cell lines, L1210FR (biotin receptors overexpressed), L1210 (biotin receptors not overexpressed), and WI38 (normal human lung fibroblast, biotin receptor negative). As anticipated, the molecular probe 4 exhibited high specificity only to L1210FR. To confirm the direct correlation between the cell-specific drug delivery and anticancer activity of the probe 4, its cytotoxicity against these three cell lines was also examined. The results clearly showed a good correlation between the two methods. In the same manner, excellent cell-specific cytotoxicity of the conjugate 1 (without fluorescein attachment to the taxoid) against the same three cell lines was confirmed. This mechanism

    17. Inhibition of Glutamine Synthetase: A Potential Drug Target in Mycobacterium tuberculosis

      Directory of Open Access Journals (Sweden)

      Sherry L. Mowbray

      2014-08-01

      Full Text Available Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis. Globally, tuberculosis is second only to AIDS in mortality and the disease is responsible for over 1.3 million deaths each year. The impractically long treatment schedules (generally 6–9 months and unpleasant side effects of the current drugs often lead to poor patient compliance, which in turn has resulted in the emergence of multi-, extensively- and totally-drug resistant strains. The development of new classes of anti-tuberculosis drugs and new drug targets is of global importance, since attacking the bacterium using multiple strategies provides the best means to prevent resistance. This review presents an overview of the various strategies and compounds utilized to inhibit glutamine synthetase, a promising target for the development of drugs for TB therapy.

    18. Target engagement and drug residence time can be observed in living cells with BRET.

      Science.gov (United States)

      Robers, Matthew B; Dart, Melanie L; Woodroofe, Carolyn C; Zimprich, Chad A; Kirkland, Thomas A; Machleidt, Thomas; Kupcho, Kevin R; Levin, Sergiy; Hartnett, James R; Zimmerman, Kristopher; Niles, Andrew L; Ohana, Rachel Friedman; Daniels, Danette L; Slater, Michael; Wood, Monika G; Cong, Mei; Cheng, Yi-Qiang; Wood, Keith V

      2015-12-03

      The therapeutic action of drugs is predicated on their physical engagement with cellular targets. Here we describe a broadly applicable method using bioluminescence resonance energy transfer (BRET) to reveal the binding characteristics of a drug with selected targets within intact cells. Cell-permeable fluorescent tracers are used in a competitive binding format to quantify drug engagement with the target proteins fused to Nanoluc luciferase. The approach enabled us to profile isozyme-specific engagement and binding kinetics for a panel of histone deacetylase (HDAC) inhibitors. Our analysis was directed particularly to the clinically approved prodrug FK228 (Istodax/Romidepsin) because of its unique and largely unexplained mechanism of sustained intracellular action. Analysis of the binding kinetics by BRET revealed remarkably long intracellular residence times for FK228 at HDAC1, explaining the protracted intracellular behaviour of this prodrug. Our results demonstrate a novel application of BRET for assessing target engagement within the complex milieu of the intracellular environment.

    19. Hyaluronic acid modified mesoporous carbon nanoparticles for targeted drug delivery to CD44-overexpressing cancer cells

      Science.gov (United States)

      Wan, Long; Jiao, Jian; Cui, Yu; Guo, Jingwen; Han, Ning; Di, Donghua; Chang, Di; Wang, Pu; Jiang, Tongying; Wang, Siling

      2016-04-01

      In this paper, hyaluronic acid (HA) functionalized uniform mesoporous carbon spheres (UMCS) were synthesized for targeted enzyme responsive drug delivery using a facile electrostatic attraction strategy. This HA modification ensured stable drug encapsulation in mesoporous carbon nanoparticles in an extracellular environment while increasing colloidal stability, biocompatibility, cell-targeting ability, and controlled cargo release. The cellular uptake experiments of fluorescently labeled mesoporous carbon nanoparticles, with or without HA functionalization, demonstrated that HA-UMCS are able to specifically target cancer cells overexpressing CD44 receptors. Moreover, the cargo loaded doxorubicin (DOX) and verapamil (VER) exhibited a dual pH and hyaluronidase-1 responsive release in the tumor microenvironment. In addition, VER/DOX/HA-UMCS exhibited a superior therapeutic effect on an in vivo HCT-116 tumor in BALB/c nude mice. In summary, it is expected that HA-UMCS will offer a new method for targeted co-delivery of drugs to tumors overexpressing CD44 receptors.

    20. A review of recent patents on the protozoan parasite HSP90 as a drug target.

      Science.gov (United States)

      Angel, Sergio O; Matrajt, Mariana; Echeverria, Pablo C

      2013-04-01

      Diseases caused by protozoan parasites are still an important health problem. These parasites can cause a wide spectrum of diseases, some of which are severe and have high morbidity or mortality if untreated. Since they are still uncontrolled, it is important to find novel drug targets and develop new therapies to decrease their remarkable social and economic impact on human societies. In the past years, human HSP90 has become an interesting drug target that has led to a large number of investigations both at state organizations and pharmaceutical companies, followed by clinical trials. The finding that HSP90 has important biological roles in some protozoan parasites like Plasmodium spp, Toxoplasma gondii and trypanosomatids has allowed the expansion of the results obtained in human cancer to these infections. This review summarizes the latest important findings showing protozoan HSP90 as a drug target and presents three patents targeting T. gondii, P. falciparum and trypanosomatids HSP90.

    1. Discovery of novel drug targets and their functions using phenotypic screening of natural products.

      Science.gov (United States)

      Chang, Junghwa; Kwon, Ho Jeong

      2016-03-01

      Natural products are valuable resources that provide a variety of bioactive compounds and natural pharmacophores in modern drug discovery. Discovery of biologically active natural products and unraveling their target proteins to understand their mode of action have always been critical hurdles for their development into clinical drugs. For effective discovery and development of bioactive natural products into novel therapeutic drugs, comprehensive screening and identification of target proteins are indispensable. In this review, a systematic approach to understanding the mode of action of natural products isolated using phenotypic screening involving chemical proteomics-based target identification is introduced. This review highlights three natural products recently discovered via phenotypic screening, namely glucopiericidin A, ecumicin, and terpestacin, as representative case studies to revisit the pivotal role of natural products as powerful tools in discovering the novel functions and druggability of targets in biological systems and pathological diseases of interest.

    2. A RNA-DNA Hybrid Aptamer for Nanoparticle-Based Prostate Tumor Targeted Drug Delivery

      Directory of Open Access Journals (Sweden)

      John C. Leach

      2016-03-01

      Full Text Available The side effects of radio- and chemo-therapy pose long-term challenges on a cancer patient’s health. It is, therefore, highly desirable to develop more effective therapies that can specifically target carcinoma cells without damaging normal and healthy cells. Tremendous efforts have been made in the past to develop targeted drug delivery systems for solid cancer treatment. In this study, a new aptamer, A10-3-J1, which recognizes the extracellular domain of the prostate specific membrane antigen (PSMA, was designed. A super paramagnetic iron oxide nanoparticle-aptamer-doxorubicin (SPIO-Apt-Dox was fabricated and employed as a targeted drug delivery platform for cancer therapy. This DNA RNA hybridized aptamer antitumor agent was able to enhance the cytotoxicity of targeted cells while minimizing collateral damage to non-targeted cells. This SPIO-Apt-Dox nanoparticle has specificity to PSMA+ prostate cancer cells. Aptamer inhibited nonspecific uptake of membrane-permeable doxorubic to the non-target cells, leading to reduced untargeted cytotoxicity and endocytic uptake while enhancing targeted cytotoxicity and endocytic uptake. The experimental results indicate that the drug delivery platform can yield statistically significant effectiveness being more cytotoxic to the targeted cells as opposed to the non-targeted cells.

    3. Targeted brain derived neurotropic factors (BDNF delivery across the blood-brain barrier for neuro-protection using magnetic nano carriers: an in-vitro study.

      Directory of Open Access Journals (Sweden)

      Sudheesh Pilakka-Kanthikeel

      Full Text Available Parenteral use of drugs; such as opiates exert immunomodulatory effects and serve as a cofactor in the progression of HIV-1 infection, thereby potentiating HIV related neurotoxicity ultimately leading to progression of NeuroAIDS. Morphine exposure is known to induce apoptosis, down regulate cAMP response element-binding (CREB expression and decrease in dendritic branching and spine density in cultured cells. Use of neuroprotective agent; brain derived neurotropic factor (BDNF, which protects neurons against these effects, could be of therapeutic benefit in the treatment of opiate addiction. Previous studies have shown that BDNF was not transported through the blood brain barrier (BBB in-vivo.; and hence it is not effective in-vivo. Therefore development of a drug delivery system that can cross BBB may have significant therapeutic advantage. In the present study, we hypothesized that magnetically guided nanocarrier may provide a viable approach for targeting BDNF across the BBB. We developed a magnetic nanoparticle (MNP based carrier bound to BDNF and evaluated its efficacy and ability to transmigrate across the BBB using an in-vitro BBB model. The end point determinations of BDNF that crossed BBB were apoptosis, CREB expression and dendritic spine density measurement. We found that transmigrated BDNF was effective in suppressing the morphine induced apoptosis, inducing CREB expression and restoring the spine density. Our results suggest that the developed nanocarrier will provide a potential therapeutic approach to treat opiate addiction, protect neurotoxicity and synaptic density degeneration.

    4. New tuberculostatic agents targeting nucleic acid biosynthesis: drug design using QSAR approaches.

      Science.gov (United States)

      Bueno, Renata V; Braga, Rodolpho C; Segretti, Natanael D; Ferreira, Elizabeth I; Trossini, Gustavo H G; Andrade, Carolina H

      2014-01-01

      Worldwide, tuberculosis (TB) is the leading cause of death among curable infectious diseases. The emergence of multidrug resistant (MDR) and extensively drug resistant (XDR) TB is a growing global health concern and there is an urgent need for new anti-TB drugs. Enzymes involved in DNA and ATP biosynthesis are potential targets for tuberculostatic drug design, since these enzymes are essential for Mycobacterium tuberculosis growth. This review presents the current progress and applications of structure-activity relationship analysis for the discovery of innovative tuberculostatic agents as inhibitors of ribonucleotide reductase, DNA gyrase, ATP synthase, and thymidylate kinase enzymes, highlighting present challenges and new opportunities in TB drug design.

    5. Crucial role of the biological barrier at the primary targeted organs in controlling the translocation and toxicity of multi-walled carbon nanotubes in the nematode Caenorhabditis elegans

      Science.gov (United States)

      Wu, Qiuli; Li, Yinxia; Li, Yiping; Zhao, Yunli; Ge, Ling; Wang, Haifang; Wang, Dayong

      2013-10-01

      Multi-walled carbon nanotubes (MWCNTs) can be translocated into the targeted organs of organisms. We employed a model organism of the nematode Caenorhabditis elegans to investigate the role of a biological barrier at the primary targeted organs in regulating the translocation and toxicity formation of MWCNTs. A prolonged exposure to MWCNTs at predicted environmental relevant concentrations caused adverse effects associated with both the primary and secondary targeted organs on nematodes. The function of PEGylated modification in reducing MWCNTs toxicity might be mainly due to the suppression of their translocation into secondary targeted organs through the primary targeted organs. A biological barrier at the primary targeted organs contributed greatly to the control of MWCNTs translocation into secondary targeted organs, as indicated by functions of Mn-SODs required for prevention of oxidative stress in the primary targeted organs. Over-expression of Mn-SODs in primary targeted organs effectively suppressed the translocation and toxicity of MWCNTs. Our work highlights the crucial role of the biological barrier at the primary targeted organs in regulating the translocation and toxicity formation of MWCNTs. Our data also shed light on the future development of engineered nanomaterials (ENMs) with improved biocompatibility and design of prevention strategies against ENMs toxicity.Multi-walled carbon nanotubes (MWCNTs) can be translocated into the targeted organs of organisms. We employed a model organism of the nematode Caenorhabditis elegans to investigate the role of a biological barrier at the primary targeted organs in regulating the translocation and toxicity formation of MWCNTs. A prolonged exposure to MWCNTs at predicted environmental relevant concentrations caused adverse effects associated with both the primary and secondary targeted organs on nematodes. The function of PEGylated modification in reducing MWCNTs toxicity might be mainly due to the suppression

    6. The AEROPATH project targeting Pseudomonas aeruginosa: crystallographic studies for assessment of potential targets in early-stage drug discovery

      Science.gov (United States)

      Moynie, Lucille; Schnell, Robert; McMahon, Stephen A.; Sandalova, Tatyana; Boulkerou, Wassila Abdelli; Schmidberger, Jason W.; Alphey, Magnus; Cukier, Cyprian; Duthie, Fraser; Kopec, Jolanta; Liu, Huanting; Jacewicz, Agata; Hunter, William N.; Naismith, James H.; Schneider, Gunter

      2013-01-01

      Bacterial infections are increasingly difficult to treat owing to the spread of antibiotic resistance. A major concern is Gram-negative bacteria, for which the discovery of new antimicrobial drugs has been particularly scarce. In an effort to accelerate early steps in drug discovery, the EU-funded AEROPATH project aims to identify novel targets in the opportunistic pathogen Pseudomonas aeruginosa by applying a multidisciplinary approach encompassing target validation, structural characterization, assay development and hit identification from small-molecule libraries. Here, the strategies used for target selection are described and progress in protein production and structure analysis is reported. Of the 102 selected targets, 84 could be produced in soluble form and the de novo structures of 39 proteins have been determined. The crystal structures of eight of these targets, ranging from hypothetical unknown proteins to metabolic enzymes from different functional classes (PA1645, PA1648, PA2169, PA3770, PA4098, PA4485, PA4992 and PA5259), are reported here. The structural information is expected to provide a firm basis for the improvement of hit compounds identified from fragment-based and high-throughput screening campaigns. PMID:23295481

    7. Effect of cryoprotectants for maintaining drug permeability barriers in porcine buccal mucosa

      DEFF Research Database (Denmark)

      Marxen, Eva; Axelsen, Mary Carlos; Pedersen, Anne Marie Lynge;

      2016-01-01

      if permeability barriers for small molecules (nicotine and diazepam) were maintained after freezing porcine buccal mucosa with cryoprotectants to -80°C. Combinations of dimethyl sulfoxide, bovine serum albumin, glycerol and sucrose were used as cryoprotectants. The permeability of nicotine and diazepam across...... tissue. Freezing with or without cryoprotectants did not significantly affect the flux of diazepam compared to fresh tissue. Only minor histological changes were seen in frozen/thawed porcine buccal mucosa compared to fresh tissue. In conclusion, permeability barriers for nicotine and diazepam were...

    8. Nanomedicine Faces Barriers

      Directory of Open Access Journals (Sweden)

      Paul Debbage

      2010-10-01

      Full Text Available Targeted nanoparticles have the potential to improve drug delivery efficiencies by more than two orders of magnitude, from the ~ 0.1% which is common today. Most pharmacologically agents on the market today are small drug molecules, which diffuse across the body’s blood-tissue barriers and distribute not only into the lesion, but into almost all organs. Drug actions in the non-lesion organs are an inescapable part of the drug delivery principle, causing “side-effects” which limit the maximally tolerable doses and result in inadequate therapy of many lesions. Nanoparticles only cross barriers by design, so side-effects are not built into their mode of operation. Delivery rates of almost 90% have been reported. This review examines the significance of these statements and checks how far they need qualification. What type of targeting is required? Is a single targeting sufficient? What new types of clinical challenge, such as immunogenicity, might attend the use of targeted nanoparticles?

    9. Specific Cell Targeting Therapy Bypasses Drug Resistance Mechanisms in African Trypanosomiasis

      Science.gov (United States)

      Unciti-Broceta, Juan D.; Arias, José L.; Maceira, José; Soriano, Miguel; Ortiz-González, Matilde; Hernández-Quero, José; Muñóz-Torres, Manuel; de Koning, Harry P.; Magez, Stefan; Garcia-Salcedo, José A.

      2015-01-01

      African trypanosomiasis is a deadly neglected disease caused by the extracellular parasite Trypanosoma brucei. Current therapies are characterized by high drug toxicity and increasing drug resistance mainly associated with loss-of-function mutations in the transporters involved in drug import. The introduction of new antiparasitic drugs into therapeutic use is a slow and expensive process. In contrast, specific targeting of existing drugs could represent a more rapid and cost-effective approach for neglected disease treatment, impacting through reduced systemic toxicity and circumventing resistance acquired through impaired compound uptake. We have generated nanoparticles of chitosan loaded with the trypanocidal drug pentamidine and coated by a single domain nanobody that specifically targets the surface of African trypanosomes. Once loaded into this nanocarrier, pentamidine enters trypanosomes through endocytosis instead of via classical cell surface transporters. The curative dose of pentamidine-loaded nanobody-chitosan nanoparticles was 100-fold lower than pentamidine alone in a murine model of acute African trypanosomiasis. Crucially, this new formulation displayed undiminished in vitro and in vivo activity against a trypanosome cell line resistant to pentamidine as a result of mutations in the surface transporter aquaglyceroporin 2. We conclude that this new drug delivery system increases drug efficacy and has the ability to overcome resistance to some anti-protozoal drugs. PMID:26110623

    10. Specific Cell Targeting Therapy Bypasses Drug Resistance Mechanisms in African Trypanosomiasis.

      Science.gov (United States)

      Unciti-Broceta, Juan D; Arias, José L; Maceira, José; Soriano, Miguel; Ortiz-González, Matilde; Hernández-Quero, José; Muñóz-Torres, Manuel; de Koning, Harry P; Magez, Stefan; Garcia-Salcedo, José A

      2015-06-01

      African trypanosomiasis is a deadly neglected disease caused by the extracellular parasite Trypanosoma brucei. Current therapies are characterized by high drug toxicity and increasing drug resistance mainly associated with loss-of-function mutations in the transporters involved in drug import. The introduction of new antiparasitic drugs into therapeutic use is a slow and expensive process. In contrast, specific targeting of existing drugs could represent a more rapid and cost-effective approach for neglected disease treatment, impacting through reduced systemic toxicity and circumventing resistance acquired through impaired compound uptake. We have generated nanoparticles of chitosan loaded with the trypanocidal drug pentamidine and coated by a single domain nanobody that specifically targets the surface of African trypanosomes. Once loaded into this nanocarrier, pentamidine enters trypanosomes through endocytosis instead of via classical cell surface transporters. The curative dose of pentamidine-loaded nanobody-chitosan nanoparticles was 100-fold lower than pentamidine alone in a murine model of acute African trypanosomiasis. Crucially, this new formulation displayed undiminished in vitro and in vivo activity against a trypanosome cell line resistant to pentamidine as a result of mutations in the surface transporter aquaglyceroporin 2. We conclude that this new drug delivery system increases drug efficacy and has the ability to overcome resistance to some anti-protozoal drugs.

    11. Specific Cell Targeting Therapy Bypasses Drug Resistance Mechanisms in African Trypanosomiasis.

      Directory of Open Access Journals (Sweden)

      Juan D Unciti-Broceta

      2015-06-01

      Full Text Available African trypanosomiasis is a deadly neglected disease caused by the extracellular parasite Trypanosoma brucei. Current therapies are characterized by high drug toxicity and increasing drug resistance mainly associated with loss-of-function mutations in the transporters involved in drug import. The introduction of new antiparasitic drugs into therapeutic use is a slow and expensive process. In contrast, specific targeting of existing drugs could represent a more rapid and cost-effective approach for neglected disease treatment, impacting through reduced systemic toxicity and circumventing resistance acquired through impaired compound uptake. We have generated nanoparticles of chitosan loaded with the trypanocidal drug pentamidine and coated by a single domain nanobody that specifically targets the surface of African trypanosomes. Once loaded into this nanocarrier, pentamidine enters trypanosomes through endocytosis instead of via classical cell surface transporters. The curative dose of pentamidine-loaded nanobody-chitosan nanoparticles was 100-fold lower than pentamidine alone in a murine model of acute African trypanosomiasis. Crucially, this new formulation displayed undiminished in vitro and in vivo activity against a trypanosome cell line resistant to pentamidine as a result of mutations in the surface transporter aquaglyceroporin 2. We conclude that this new drug delivery system increases drug efficacy and has the ability to overcome resistance to some anti-protozoal drugs.

    12. The RAS-Effector Interaction as a Drug Target.

      Science.gov (United States)

      Keeton, Adam B; Salter, E Alan; Piazza, Gary A

      2017-01-15

      About a third of all human cancers harbor mutations in one of the K-, N-, or HRAS genes that encode an abnormal RAS protein locked in a constitutively activated state to drive malignant transformation and tumor growth. Despite more than three decades of intensive research aimed at the discovery of RAS-directed therapeutics, there are no FDA-approved drugs that are broadly effective against RAS-driven cancers. Although RAS proteins are often said to be "undruggable," there is mounting evidence suggesting it may be feasible to develop direct inhibitors of RAS proteins. Here, we review this evidence with a focus on compounds capable of inhibiting the interaction of RAS proteins with their effectors that transduce the signals of RAS and that drive and sustain malignant transformation and tumor growth. These reports of direct-acting RAS inhibitors provide valuable insight for further discovery and development of clinical candidates for RAS-driven cancers involving mutations in RAS genes or otherwise activated RAS proteins. Cancer Res; 77(2); 221-6. ©2017 AACR.

    13. Imaging of a targeted PDT drug with fluorescence tomography

      Science.gov (United States)

      Muffoletto, Dan; Gupta, Anurag; Xu, Zhiqiang; Mahrer, Chris; Bauer, Gretchen; Galas, Scott; Pandey, Ravindra K.; Sunar, Ulas

      2009-02-01

      We constructed a whole-body fluorescence tomography instrument to monitor novel bifunctional phototherapeutic drugs (e.g., HPPH-Cyanine dye conjugate) in small animals. The instrument allows dense source and detector sampling with a fast galvo scanner and a CCD detector for improved resolution and sensitivity (Patwardhan et al., 2005). Here we report tissue phantom measurements to evaluate the imaging performance with a newly constructed tomography instrument. Phantom measurements showed that strong fluorescence generated by HPPH-Cyanine dye (HPPH-CD), having high fluorescence quantum yield and long wavelength fluorescence emission, allowed deep tissue imaging. We also report in vivo fluorescence measurements of the conjugate in Nude mice bearing A549 human non-small cell lung carcinoma (NSCLC) tumors at 24 hr post injection to evaluate tumor detection ability of the conjugate. Our results indicate that the HPPH-CD shows preferential uptake in tumors compared to surrounding normal tissue at 24 hr post injection. This study demonstrates a potential use of HPPH-CD in detection (fluorescence imaging) and treatment (PDT) of deeply seated tumors.

    14. Epigenetic Modifications, Alcoholic Brain and Potential Drug Targets

      Science.gov (United States)

      Jangra, Ashok; Sriram, Chandra Shaker; Pandey, Suryanarayan; Choubey, Priyansha; Rajput, Prabha; Saroha, Babita; Bezbaruah, Babul Kumar; Lahkar, Mangala

      2016-01-01

      Acute and chronic alcohol exposure evidently influences epigenetic changes, both transiently and permanently, and these changes in turn influence a variety of cells and organ systems throughout the body. Many of the alcohol-induced epigenetic modifications can contribute to cellular adaptations that ultimately lead to behavioral tolerance and alcohol dependence. The persistence of behavioral changes demonstrates that long-lasting changes in gene expression, within particular regions of the brain, may contribute importantly to the addiction phenotype. The research activities over the past years have demonstrated a crucial role of epigenetic mechanisms in causing long lasting and transient changes in the expression of several genes in diverse tissues, including brain. This has stimulated recent research work that is aimed at characterizing the influence of epigenetic regulatory events in mediating the long lasting and transient effects of alcohol abuse on the brain in humans and animal models of alcohol addiction. In this study, we update our current understanding of the impact of alcohol exposure on epigenetic mechanisms in the brain and refurbish the knowledge of epigenetics in the direction of new drugs development. PMID:27780992

    15. Discovery of cancer drug targets by CRISPR-Cas9 screening of protein domains.

      Science.gov (United States)

      Shi, Junwei; Wang, Eric; Milazzo, Joseph P; Wang, Zihua; Kinney, Justin B; Vakoc, Christopher R

      2015-06-01

      CRISPR-Cas9 genome editing technology holds great promise for discovering therapeutic targets in cancer and other diseases. Current screening strategies target CRISPR-Cas9-induced mutations to the 5' exons of candidate genes, but this approach often produces in-frame variants that retain functionality, which can obscure even strong genetic dependencies. Here we overcome this limitation by targeting CRISPR-Cas9 mutagenesis to exons encoding functional protein domains. This generates a higher proportion of null mutations and substantially increases the potency of negative selection. We also show that the magnitude of negative selection can be used to infer the functional importance of individual protein domains of interest. A screen of 192 chromatin regulatory domains in murine acute myeloid leukemia cells identifies six known drug targets and 19 additional dependencies. A broader application of this approach may allow comprehensive identification of protein domains that sustain cancer cells and are suitable for drug targeting.

    16. 'One-pot' synthesis of multifunctional GSH-CdTe quantum dots for targeted drug delivery.

      Science.gov (United States)

      Chen, Xiaoqin; Tang, Yajun; Cai, Bing; Fan, Hongsong

      2014-06-13

      A novel quantum dots-based multifunctional nanovehicle (DOX-QD-PEG-FA) was designed for targeted drug delivery, fluorescent imaging, tracking, and cancer therapy, in which the GSH-CdTe quantum dots play a key role in imaging and drug delivery. To exert curative effects, the antineoplastic drug doxorubicin hydrochloride (DOX) was loaded on the GSH-CdTe quantum dots through a condensation reaction. Meanwhile, a polyethylene glycol (PEG) shell was introduced to wrap the DOX-QD, thus stabilizing the structure and preventing clearance and drug release during systemic circulation. To actively target cancer cells and prevent the nanovehicles from being absorbed by normal cells, the nanoparticles were further decorated with folic acid (FA), allowing them to target HeLa cells that express the FA receptor. The multifunctional DOX-QD-PEG-FA conjugates were simply prepared using the 'one pot' method. In vitro study demonstrated that this simple, multifunctional nanovehicle can deliver DOX to the targeted cancer cells and localize the nanoparticles. After reaching the tumor cells, the FA on the DOX-QD-PEG surface allowed folate receptor recognition and increased the drug concentration to realize a higher curative effect. This novel, multifunctional DOX-QD-PEG-FA system shows great potential for tumor imaging, targeting, and therapy.

    17. Predicting drug-target interactions by dual-network integrated logistic matrix factorization

      Science.gov (United States)

      Hao, Ming; Bryant, Stephen H.; Wang, Yanli

      2017-01-01

      In this work, we propose a dual-network integrated logistic matrix factorization (DNILMF) algorithm to predict potential drug-target interactions (DTI). The prediction procedure consists of four steps: (1) inferring new drug/target profiles and constructing profile kernel matrix; (2) diffusing drug profile kernel matrix with drug structure kernel matrix; (3) diffusing target profile kernel matrix with target sequence kernel matrix; and (4) building DNILMF model and smoothing new drug/target predictions based on their neighbors. We compare our algorithm with the state-of-the-art method based on the benchmark dataset. Results indicate that the DNILMF algorithm outperforms the previously reported approaches in terms of AUPR (area under precision-recall curve) and AUC (area under curve of receiver operating characteristic) based on the 5 trials of 10-fold cross-validation. We conclude that the performance improvement depends on not only the proposed objective function, but also the used nonlinear diffusion technique which is important but under studied in the DTI prediction field. In addition, we also compile a new DTI dataset for increasing the diversity of currently available benchmark datasets. The top prediction results for the new dataset are confirmed by experimental studies or supported by other computational research.

    18. Magnetic graphene oxide as a carrier for targeted delivery of chemotherapy drugs in cancer therapy

      Science.gov (United States)

      Huang, Ya-Shu; Lu, Yu-Jen; Chen, Jyh-Ping

      2017-04-01

      A magnetic targeted functionalized graphene oxide (GO) complex is constituted as a nanocarrier for targeted delivery and pH-responsive controlled release of chemotherapy drugs to cancer cells. Magnetic graphene oxide (mGO) was prepared by chemical co-precipitation of Fe3O4 magnetic nanoparticles on GO nano-platelets. The mGO was successively modified by chitosan and mPEG-NHS through covalent bindings to synthesize mGOC-PEG. The polyethylene glycol (PEG) moiety is expected to prolong the circulation time of mGO by reducing the reticuloendothelial system clearance. Irinotecan (CPT-11) or doxorubicin (DOX) was loaded to mGOC-PEG through π-π stacking interactions for magnetic targeted delivery of the cancer chemotherapy drug. The best values of loading efficiency and loading content of CPT-11 were 54% and 2.7% respectively; whereas for DOX, they were 65% and 393% The pH-dependent drug release profile was further experimented at different pHs, in which 60% of DOX was released at pH 5.4 and 10% was released at pH 7.4. In contrast, 90% CPT-11 was released at pH 5.4 and 70% at pH 7.4. Based on the drug loading and release characteristics, mGOC-PEG/DOX was further chosen for in vitro cytotoxicity tests against U87 human glioblastoma cell line. The IC50 value of mGOC-PEG/DOX was found to be similar to that of free DOX but was reduced dramatically when subject to magnetic targeting. It is concluded that with the high drug loading and pH-dependent drug release properties, mGOC-PEG will be a promising drug carrier for targeted delivery of chemotherapy drugs in cancer therapy.

    19. Smart Cancer Cell Targeting Imaging and Drug Delivery System by Systematically Engineering Periodic Mesoporous Organosilica Nanoparticles.

      Science.gov (United States)

      Lu, Nan; Tian, Ying; Tian, Wei; Huang, Peng; Liu, Ying; Tang, Yuxia; Wang, Chunyan; Wang, Shouju; Su, Yunyan; Zhang, Yunlei; Pan, Jing; Teng, Zhaogang; Lu, Guangming

      2016-02-10

      The integration of diagnosis and therapy into one nanoplatform, known as theranostics, has attracted increasing attention in the biomedical areas. Herein, we first present a cancer cell targeting imaging and drug delivery system based on engineered thioether-bridged periodic mesoporous organosilica nanoparticles (PMOs). The PMOs are stably and selectively conjugated with near-infrared fluorescence (NIRF) dye Cyanine 5.5 (Cy5.5) and anti-Her2 affibody on the outer surfaces to endow them with excellent NIRF imaging and cancer targeting properties. Also, taking the advantage of the thioether-group-incorporated mesopores, the release of chemotherapy drug doxorubicin (DOX) loaded in the PMOs is responsive to the tumor-related molecule glutathione (GSH). The drug release percentage reaches 84.8% in 10 mM of GSH solution within 24 h, which is more than 2-fold higher than that without GSH. In addition, the drug release also exhibits pH-responsive, which reaches 53.6% at pH 5 and 31.7% at pH 7.4 within 24 h. Confocal laser scanning microscopy and flow cytometry analysis demonstrate that the PMOs-based theranostic platforms can efficiently target to and enter Her2 positive tumor cells. Thus, the smart imaging and drug delivery nanoplatforms induce high tumor cell growth inhibition. Meanwhile, the Cy5.5 conjugated PMOs perform great NIRF imaging ability, which could monitor the intracellular distribution, delivery and release of the chemotherapy drug. In addition, cell viability and histological assessments show the engineered PMOs have good biocompatibility, further encouraging the following biomedical applications. Over all, the systemically engineered PMOs can serve as a novel cancer cell targeting imaging and drug delivery platform with NIRF imaging, GSH and pH dual-responsive drug release, and high tumor cell targeting ability.

    20. IPC synthase as a useful target for antifungal drugs.

      Science.gov (United States)

      Sugimoto, Yuichi; Sakoh, Hiroki; Yamada, Koji

      2004-12-01

      Inositol phosphorylceramide (IPC) synthase is a common and essential enzyme in fungi and plants, which catalyzes the transfer of phosphoinositol to the C-1 hydroxy of ceramide to produce IPC. This reaction is a key step in fungal sphingolipid biosynthesis, therefore the enzyme is a potential target for the development of nontoxic therapeutic antifungal agents. Natural products with a desired biological activity, aureobasidin A (AbA), khafrefungin, and galbonolide A, have been reported. AbA, a cyclic depsipeptide containing 8 amino acids and a hydroxyl acid, is a broad spectrum antifungal with strong activity against many pathogenic fungi such as Candida spp., Cryptococcus neoformans, and some Aspergillus spp. Khafrefungin, an aldonic acid ester with a C22 long alkyl chain, has antifungal activity against C. albicans, Cr. Neoformans, and Saccharomyces cerevisiae. Galbonolide A is a 14-membered macrolide with fungicidal activity against clinically important strains, and is especially potent against Cr. neoformans. These classes of natural products are potent and specific antifungal agents. We review current progress in the development of IPC synthase inhibitors with antifungal activities, and present structure-activity relationships (SAR), physicochemical and structural properties, and synthetic methodology for chemical modification.

    1. Identification of the platelet ADP receptor targeted by antithrombotic drugs.

      Science.gov (United States)

      Hollopeter, G; Jantzen, H M; Vincent, D; Li, G; England, L; Ramakrishnan, V; Yang, R B; Nurden, P; Nurden, A; Julius, D; Conley, P B

      2001-01-11

      Platelets have a crucial role in the maintenance of normal haemostasis, and perturbations of this system can lead to pathological thrombus formation and vascular occlusion, resulting in stroke, myocardial infarction and unstable angina. ADP released from damaged vessels and red blood cells induces platelet aggregation through activation of the integrin GPIIb-IIIa and subsequent binding of fibrinogen. ADP is also secreted from platelets on activation, providing positive feedback that potentiates the actions of many platelet activators. ADP mediates platelet aggregation through its action on two G-protein-coupled receptor subtypes. The P2Y1 receptor couples to Gq and mobilizes intracellular calcium ions to mediate platelet shape change and aggregation. The second ADP receptor required for aggregation (variously called P2Y(ADP), P2Y(AC), P2Ycyc or P2T(AC)) is coupled to the inhibition of adenylyl cyclase through Gi. The molecular identity of the Gi-linked receptor is still elusive, even though it is the target of efficacious antithrombotic agents, such as ticlopidine and clopidogrel and AR-C66096 (ref. 9). Here we describe the cloning of this receptor, designated P2Y12, and provide evidence that a patient with a bleeding disorder has a defect in this gene. Cloning of the P2Y12 receptor should facilitate the development of better antiplatelet agents to treat cardiovascular diseases.

    2. Potential therapeutic targets and the role of technology in developing novel cannabinoid drugs from cyanobacteria.

      Science.gov (United States)

      Vijayakumar, S; Manogar, P; Prabhu, S

      2016-10-01

      Cyanobacteria find several applications in pharmacology as potential candidates for drug design. The need for new compounds that can be used as drugs has always been on the rise in therapeutics. Cyanobacteria have been identified as promising targets of research in the quest for new pharmaceutical compounds as they can produce secondary metabolites with novel chemical structures. Cyanobacteria is now recognized as a vital source of bioactive molecules like Curacin A, Largazole and Apratoxin which have succeeded in reaching Phase II and Phase III into clinical trials. The discovery of several new clinical cannabinoid drugs in the past decade from diverse marine life should translate into a number of new drugs for cannabinoid in the years to come. Conventional cannabinoid drugs have high toxicity and as a result, they affect the efficacy of chemotherapy and patients' life very much. The present review focuses on how potential, safe and affordable drugs used for cannabinoid treatment could be developed from cyanobacteria.

    3. PET studies on P-glycoprotein function in the blood-brain barrier : How it affects uptake and binding of drugs within the CNS

      NARCIS (Netherlands)

      Elsinga, PH; Hendrikse, Nelis; Bart, J; Vaalburg, W; van Waarde, A

      2004-01-01

      Permeability of the blood-brain barrier (BBB) is one of the factors determining the bioavailability of therapeutic drugs. The BBB only allows entry of lipophilic compounds with low molecular weights by passive diffusion. However, many lipophilic drugs show negligible brain uptake. They are substrate

    4. From drug response profiling to target addiction scoring in cancer cell models

      Directory of Open Access Journals (Sweden)

      Bhagwan Yadav

      2015-10-01

      Full Text Available Deconvoluting the molecular target signals behind observed drug response phenotypes is an important part of phenotype-based drug discovery and repurposing efforts. We demonstrate here how our network-based deconvolution approach, named target addiction score (TAS, provides insights into the functional importance of druggable protein targets in cell-based drug sensitivity testing experiments. Using cancer cell line profiling data sets, we constructed a functional classification across 107 cancer cell models, based on their common and unique target addiction signatures. The pan-cancer addiction correlations could not be explained by the tissue of origin, and only correlated in part with molecular and genomic signatures of the heterogeneous cancer cells. The TAS-based cancer cell classification was also shown to be robust to drug response data resampling, as well as predictive of the transcriptomic patterns in an independent set of cancer cells that shared similar addiction signatures with the 107 cancers. The critical protein targets identified by the integrated approach were also shown to have clinically relevant mutation frequencies in patients with various cancer subtypes, including not only well-established pan-cancer genes, such as PTEN tumor suppressor, but also a number of targets that are less frequently mutated in specific cancer types, including ABL1 oncoprotein in acute myeloid leukemia. An application to leukemia patient primary cell models demonstrated how the target deconvolution approach offers functional insights into patient-specific addiction patterns, such as those indicative of their receptor-type tyrosine-protein kinase FLT3 internal tandem duplication (FLT3-ITD status and co-addiction partners, which may lead to clinically actionable, personalized drug treatment developments. To promote its application to the future drug testing studies, we have made available an open-source implementation of the TAS calculation in the form

    5. Receptor binding peptides for target-selective delivery of nanoparticles encapsulated drugs

      Directory of Open Access Journals (Sweden)

      Accardo A

      2014-03-01

      Full Text Available Antonella Accardo,1 Luigi Aloj,2 Michela Aurilio,2 Giancarlo Morelli,1 Diego Tesauro11Centro interuniversitario di Ricerca sui Peptidi Bioattivi (CIRPeB, Department of Pharmacy and Istituto di Biostrutture e Bioimmagini - Consiglio Nazionale delle Ricerche (IBB CNR, University of Naples “Federico II”, 2Department of Nuclear Medicine, Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione “G. Pascale”, Napoli, ItalyAbstract: Active targeting by means of drug encapsulated nanoparticles decorated with targeting bioactive moieties represents the next frontier in drug delivery; it reduces drug side effects and increases the therapeutic index. Peptides, based on their chemical and biological properties, could have a prevalent role to direct drug encapsulated nanoparticles, such as liposomes, micelles, or hard nanoparticles, toward the tumor tissues. A considerable number of molecular targets for peptides are either exclusively expressed or overexpressed on both cancer vasculature and cancer cells. They can be classified into three wide categories: integrins; growth factor receptors (GFRs; and G-protein coupled receptors (GPCRs. Therapeutic agents based on nanovectors decorated with peptides targeting membrane receptors belonging to the GPCR family overexpressed by cancer cells are reviewed in this article. The most studied targeting membrane receptors are considered: somatostatin receptors; cholecystokinin receptors; receptors associated with the Bombesin like peptides family; luteinizing hormone-releasing hormone receptors; and neurotensin receptors. Nanovectors of different sizes and shapes (micelles, liposomes, or hard nanoparticles loaded with doxorubicin or other cytotoxic drugs and externally functionalized with natural or synthetic peptides are able to target the overexpressed receptors and are described based on their formulation and in vitro and in vivo behaviors.Keywords: receptors binding peptides, drug delivery

    6. Cancer in silico drug discovery: a systems biology tool for identifying candidate drugs to target specific molecular tumor subtypes.

      Science.gov (United States)

      San Lucas, F Anthony; Fowler, Jerry; Chang, Kyle; Kopetz, Scott; Vilar, Eduardo; Scheet, Paul

      2014-12-01

      Large-scale cancer datasets such as The Cancer Genome Atlas (TCGA) allow researchers to profile tumors based on a wide range of clinical and molecular characteristics. Subsequently, TCGA-derived gene expression profiles can be analyzed with the Connectivity Map (CMap) to find candidate drugs to target tumors with specific clinical phenotypes or molecular characteristics. This represents a powerful computational approach for candidate drug identification, but due to the complexity of TCGA and technology differences between CMap and TCGA experiments, such analyses are challenging to conduct and reproduce. We present Cancer in silico Drug Discovery (CiDD; scheet.org/software), a computational drug discovery platform that addresses these challenges. CiDD integrates data from TCGA, CMap, and Cancer Cell Line Encyclopedia (CCLE) to perform computational drug discovery experiments, generating hypotheses for the following three general problems: (i) determining whether specific clinical phenotypes or molecular characteristics are associated with unique gene expression signatures; (ii) finding candidate drugs to repress these expression signatures; and (iii) identifying cell lines that resemble the tumors being studied for subsequent in vitro experiments. The primary input to CiDD is a clinical or molecular characteristic. The output is a biologically annotated list of candidate drugs and a list of cell lines for in vitro experimentation. We applied CiDD to identify candidate drugs to treat colorectal cancers harboring mutations in BRAF. CiDD identified EGFR and proteasome inhibitors, while proposing five cell lines for in vitro testing. CiDD facilitates phenotype-driven, systematic drug discovery based on clinical and molecular data from TCGA.

    7. Toward an increased understanding of the barriers to colonic drug absorption in humans: implications for early controlled release candidate assessment.

      Science.gov (United States)

      Tannergren, Christer; Bergendal, Anna; Lennernäs, Hans; Abrahamsson, Bertil

      2009-01-01

      The purpose of this study was to increase the understanding of in vivo colonic drug absorption in humans by summarizing and evaluating all regional in vivo human absorption data with focus on the interpretation of the colonic absorption data in relation to intestinal permeability and solubility. In addition, the usefulness of the Biopharmaceutics Classification System (BCS) in early assessment of the in vivo colonic absorption potential of controlled release drug candidates was investigated. Clinical regional absorption data (Cmax, Tmax, and AUC) of 42 drugs were collected from journal articles, abstracts, and internal reports, and the relative bioavailability in the colon (Frel(colon)) was obtained directly or calculated. Bioavailability, fraction dose absorbed, and information if the compounds were substrates for P-glycoprotein (P-gp) or cytochrome P450 3A (CYP3A) were also obtained. The BCS I drugs were well absorbed in the colon (Frel(colon) > 70%), although some drugs had lower values due to bacterial degradation in the colon. The low permeability drugs (BCS III/IV) had a lower degree of absorption in the colon (Frel(colon) colon), and atenolol and metoprolol may function as permeability markers for low and high colonic absorption, respectively. No obvious effect of P-gp on the colonic absorption of the drugs in this study was detected. There was insufficient data available to fully assess the impact of low solubility and slow dissolution rate. The estimated in vivo fractions dissolved of the only two compounds administered to the colon as both a solution and as solid particles were 55% and 92%, respectively. In conclusion, permeability and solubility are important barriers to colonic absorption in humans, and in vitro testing of these properties is recommended in early assessment of colonic absorption potential.

    8. The UDP-glucuronosyltransferases of the blood-brain barrier: their role in drug metabolism and detoxication

      Directory of Open Access Journals (Sweden)

      Mohamed eOuzzine

      2014-10-01

      Full Text Available UDP-glucuronosyltransferases (UGTs form a multigenic family of membrane-bound enzymes expressed in various tissues, including brain. They catalyze the formation of β-Dglucuronides from structurally unrelated substances (drugs, other xenobiotics, as well as endogenous compounds by the linkage of glucuronic acid from the high energy donor, UDP-αD-glucuronic acid. In brain, UGTs actively participate to the overall protection of the tissue against the intrusion of potentially harmful lipophilic substances that are metabolized as hydrophilic glucuronides. These metabolites are generally inactive, except for important pharmacologically glucuronides such as morphine-6-glucuronide. UGTs are mainly expressed in endothelial cells and astrocytes of the blood brain barrier. They are also associated to brain interfaces devoid of blood-brain barrier, such as circumventricular organ, pineal gland, pituitary gland and neuro-olfactory tissues. Beside their key-role as a detoxication barrier, UGTs play a role in the steady-state of endogenous compounds, like steroids or dopamine that participate to the function of the brain. UGT isoforms of family 1A, 2A, 2B and 3A are expressed in brain tissues to various levels and are known to present distinct but overlapping substrate specificity. The importance of these enzyme species with regard to the formation of toxic, pharmacologically or physiologically relevant glucuronides in the brain will be discussed.

    9. Identifying co-targets to fight drug resistance based on a random walk model

      Directory of Open Access Journals (Sweden)

      Chen Liang-Chun

      2012-01-01

      Full Text Available Abstract Background Drug resistance has now posed more severe and emergent threats to human health and infectious disease treatment. However, wet-lab approaches alone to counter drug resistance have so far still achieved limited success due to less knowledge about the underlying mechanisms of drug resistance. Our approach apply a heuristic search algorithm in order to extract active network under drug treatment and use a random walk model to identify potential co-targets for effective antibacterial drugs. Results We use interactome network of Mycobacterium tuberculosis and gene expression data which are treated with two kinds of antibiotic, Isoniazid and Ethionamide as our test data. Our analysis shows that the active drug-treated networks are associated with the trigger of fatty acid metabolism and synthesis and nicotinamide adenine dinucleotide (NADH-related processes and those results are consistent with the recent experimental findings. Efflux pumps processes appear to be the major mechanisms of resistance but SOS response is significantly up-regulation under Isoniazid treatment. We also successfully identify the potential co-targets with literature confirmed evidences which are related to the glycine-rich membrane, adenosine triphosphate energy and cell wall processes. Conclusions With gene expression and interactome data supported, our study points out possible pathways leading to the emergence of drug resistance under drug treatment. We develop a computational workflow for giving new insights to bacterial drug resistance which can be gained by a systematic and global analysis of the bacterial regulation network. Our study also discovers the potential co-targets with good properties in biological and graph theory aspects to overcome the problem of drug resistance.

    10. A green approach to dual-drug nanoformulations with targeting and synergistic effects for cancer therapy.

      Science.gov (United States)

      Wu, Shichao; Yang, Xiangrui; Lu, Yue; Fan, Zhongxiong; Li, Yang; Jiang, Yuan; Hou, Zhenqing

      2017-11-01

      Exploration of efficient dual-drug nanohybrids, particularly those with high drug loading, specific targeting property, and long-termed stability, is of highly importance in cancer therapy. A pH-driven coprecipitation was performed in the aqueous phase to obtain a dual-drug nanoformulation, composed of 10-hydroxycamptothecine (HCPT) nanoneedles integrated with an exterior thin layer of the methotrexate (MTX)-chitosan conjugate. The high stability of nanohybrids in water and the targeting property provided by the MTX ingredient function synergistically to the prolonged and sustained drug release property in tumor tissues and the increased cellular uptake. The cytotoxicity test illustrates that dual-drug nanoneedles possess the remarkable killing ability to HeLa cells with the combination index at 0.33 ± 0.07. After cellular internalization, the release of both drug ingredients results in an excellent anticancer activity in vivo with the minimized adverse side effects. Design of a green approach to the carrier-free, dual-drug nanoformulations enables to develop emerging drug delivery systems for cancer diagnosis and treatment.

    11. Prediction of Effective Drug Combinations by Chemical Interaction, Protein Interaction and Target Enrichment of KEGG Pathways

      Directory of Open Access Journals (Sweden)

      Lei Chen

      2013-01-01

      Full Text Available Drug combinatorial therapy could be more effective in treating some complex diseases than single agents due to better efficacy and reduced side effects. Although some drug combinations are being used, their underlying molecular mechanisms are still poorly understood. Therefore, it is of great interest to deduce a novel drug combination by their molecular mechanisms in a robust and rigorous way. This paper attempts to predict effective drug combinations by a combined consideration of: (1 chemical interaction between drugs, (2 protein interactions between drugs’ targets, and (3 target enrichment of KEGG pathways. A benchmark dataset was constructed, consisting of 121 confirmed effective combinations and 605 random combinations. Each drug combination was represented by 465 features derived from the aforementioned three properties. Some feature selection techniques, including Minimum Redundancy Maximum Relevance and Incremental Feature Selection, were adopted to extract the key features. Random forest model was built with its performance evaluated by 5-fold cross-validation. As a result, 55 key features providing the best prediction result were selected. These important features may help to gain insights into the mechanisms of drug combinations, and the proposed prediction model could become a useful tool for screening possible drug combinations.

    12. ‘VIROSOMES’ A NOVEL STRATEGY FOR DELIVERY OF DRUGS AND TARGETING: AN OVERVIEW

      Directory of Open Access Journals (Sweden)

      M. Gowtham

      2012-10-01

      Full Text Available Over the years there has been a great revolution in drug delivery technologies. Virosomes drug delivery systems are an example of the various novel drug delivery systems available. A virosome is a drug or vaccine delivery mechanism consisting of unilamellar phospholipid bilayer vesicle incorporating virus derived proteins to allow the virosomes to fuse with target cells. Virosomes are not able to replicate but are pure fusion-active vesicle. These are reconstituted viral envelopes that can serve as vaccines and as vehicles for cellular delivery of macromolecules. The prospect of drug delivery and targeting using virosomes is an interesting field of research and development. Because virosomes are biocompatible, biodegradable, nontoxic, and non-autoimmunogenic, attempts have been made to use them as vaccines or adjuvants as well as delivery systems for drugs, nucleic acids, or genes for therapeutic purposes. The success of virosomal drug delivery depends on the methods used to prepare the encapsulated bioactive materials and incorporate them into the virosomes, as are characterization and formulation of the finished preparation. This article gives an insight of virosomes as a newer method of drug delivery. This article gives an insight of hydrogels and virosomes as a newer futuristic tool.

    13. Using an Old Drug to Target a New Drug Site: Application of Disulfiram to Target the Zn-Site in HCV NS5A Protein.

      Science.gov (United States)

      Lee, Yu-Ming; Duh, Yulander; Wang, Shih-Ting; Lai, Michael M C; Yuan, Hanna S; Lim, Carmay

      2016-03-23

      In viral proteins, labile Zn-sites, where Zn(2+) is crucial for maintaining the native protein structure but the Zn-bound cysteines are reactive, are promising drug targets. Here, we aim to (i) identify labile Zn-sites in viral proteins using guidelines established from our previous work and (ii) assess if clinically safe Zn-ejecting agents could eject Zn(2+) from the predicted target site and thus inhibit viral replication. As proof-of-concept, we identified a labile Zn-site in the hepatitis C virus (HCV) NS5A protein and showed that the antialcoholism drug, disulfiram, could inhibit HCV replication to a similar extent as the clinically used antiviral agent, ribavirin. The discovery of a novel viral target and a new role for disulfiram in inhibiting HCV replication will enhance the therapeutic armamentarium against HCV. The strategy presented can also be applied to identify labile sites in other bacterial or viral proteins that can be targeted by disulfiram or other clinically safe Zn-ejectors.

    14. Multi-target drug design approaches for multifactorial diseases: from neurodegenerative to cardiovascular applications.

      Science.gov (United States)

      Katselou, M G; Matralis, A N; Kourounakis, A P

      2014-01-01

      In multi-target drug design (MTD) medicinal chemistry aims to integrate multiple pharmacophores into a single drug molecule in order to make it active on several molecular biological mechanisms simultaneously. Given the fact that most diseases are multifactorial in nature, MTD is being pursued with increasing intensity, which has resulted in improved outcomes in disease models and several compounds have entered clinical trials. In a wide range of examples we illustrate how various functionalities have been combined within single structures and how this has affected their (pre)clinical outcome. This review describes the successful application of MTD for disorders such as neurodegenerative, cardiovascular, diabetes, metabolic and inflammatory diseases, especially focusing on the field of atherosclerosis where multi-target strategies are a promising alternative to the classical "one target-one drug" design approach.

    15. Progress and Challenges in Developing Aptamer-Functionalized Targeted Drug Delivery Systems

      Directory of Open Access Journals (Sweden)

      Feng Jiang

      2015-10-01

      Full Text Available Aptamers, which can be screened via systematic evolution of ligands by exponential enrichment (SELEX, are superior ligands for molecular recognition due to their high selectivity and affinity. The interest in the use of aptamers as ligands for targeted drug delivery has been increasing due to their unique advantages. Based on their different compositions and preparation methods, aptamer-functionalized targeted drug delivery systems can be divided into two main categories: aptamer-small molecule conjugated systems and aptamer-nanomaterial conjugated systems. In this review, we not only summarize recent progress in aptamer selection and the application of aptamers in these targeted drug delivery systems but also discuss the advantages, challenges and new perspectives associated with these delivery systems.

    16. Recent advances in lymphatic targeted drug deliver y system for tumor metastasis

      Institute of Scientific and Technical Information of China (English)

      Xiao-Yu Zhang; Wei-Yue Lu

      2014-01-01

      Te lymphatic system has an important defensive role in the human body. hTe metastasis of most tumors initially spreads through the surrounding lymphatic tissue and eventually forms lymphatic metastatic tumors;the tumor cells may even transfer to other organs to form other types of tumors. Clinically, lymphatic metastatic tumors develop rapidly. Given the limitations of surgical resection and the low effectiveness of radiotherapy and chemotherapy, the treatment of lymphatic metastatic tumors remains a great challenge. Lymph node metastasis may lead to the further spread of tumors and may be predictive of the endpoint event. Under these circumstances, novel and effective lymphatic targeted drug delivery systems have been explored to improve the speciifcity of anticancer drugs to tumor cells in lymph nodes. In this review, we summarize the principles of lymphatic targeted drug delivery and discuss recent advances in the development of lymphatic targeted carriers.

    17. Progress and Challenges in Developing Aptamer-Functionalized Targeted Drug Delivery Systems.

      Science.gov (United States)

      Jiang, Feng; Liu, Biao; Lu, Jun; Li, Fangfei; Li, Defang; Liang, Chao; Dang, Lei; Liu, Jin; He, Bing; Badshah, Shaikh Atik; Lu, Cheng; He, Xiaojuan; Guo, Baosheng; Zhang, Xiao-Bing; Tan, Weihong; Lu, Aiping; Zhang, Ge

      2015-01-01

      Aptamers, which can be screened via systematic evolution of ligands by exponential enrichment (SELEX), are superior ligands for molecular recognition due to their high selectivity and affinity. The interest in the use of aptamers as ligands for targeted drug delivery has been increasing due to their unique advantages. Based on their different compositions and preparation methods, aptamer-functionalized targeted drug delivery systems can be divided into two main categories: aptamer-small molecule conjugated systems and aptamer-nanomaterial conjugated systems. In this review, we not only summarize recent progress in aptamer selection and the application of aptamers in these targeted drug delivery systems but also discuss the advantages, challenges and new perspectives associated with these delivery systems.

    18. A targeted drug delivery system based on dopamine functionalized nano graphene oxide

      Science.gov (United States)

      Masoudipour, Elham; Kashanian, Soheila; Maleki, Nasim

      2017-01-01

      The cellular targeting property of a biocompatible drug delivery system can widely increase the therapeutic effect against various diseases. Here, we report a dopamine conjugated nano graphene oxide (DA-nGO) carrier for cellular delivery of the anticancer drug, Methotrexate (MTX) into DA receptor positive human breast adenocarcinoma cell line. The material was characterized using scanning electron microscopy, atomic force microscopy, Fourier transform infrared spectroscopy and UV-vis spectroscopy. Furthermore, the antineoplastic action of MTX loaded DA-nGO against DA receptor positive and negative cell lines were explored. The results presented in this article demonstrated that the application of DA functionalized GO as a targeting drug carrier can improve the drug delivery efficacy for DA receptor positive cancer cell lines and promise future designing of carrier conjugates based on it.

    19. Nanotechnology-based drug delivery treatments and specific targeting therapy for age-related macular degeneration.

      Science.gov (United States)

      Lin, Tai-Chi; Hung, Kuo-Hsuan; Peng, Chi-Hsien; Liu, Jorn-Hon; Woung, Lin-Chung; Tsai, Ching-Yao; Chen, Shih-Jen; Chen, Yan-Ting; Hsu, Chih-Chien

      2015-11-01

      Nanoparticles combined with cells, drugs, and specially designed genes provide improved therapeutic efficacy in studies and clinical setting, demonstrating a new era of treatment strategy, especially in retinal diseases. Nanotechnology-based drugs can provide an essential platform for sustaining, releasing and a specific targeting design to treat retinal diseases. Poly-lactic-co-glycolic acid is the most widely used biocompatible and biodegradable polymer approved by the Food and Drug Administration. Many studies have attempted to develop special devices for delivering small-molecule drugs, proteins, and other macromolecules consistently and slowly. In this article, we first review current progress in the treatment of age-related macular degeneration. Then, we discuss the function of vascular endothelial growth factor (VEGF) and the pharmacological effects of anti-VEGF-A antibodies and soluble or modified VEGF receptors. Lastly, we summarize the combination of antiangiogenic therapy and nanomedicines, and review current potential targeting therapy in age-related macular degeneration.

    20. Iontophoresis of minoxidil sulphate loaded microparticles, a strategy for follicular drug targeting?

      Science.gov (United States)

      Gelfuso, Guilherme M; Barros, M Angélica de Oliveira; Delgado-Charro, M Begoña; Guy, Richard H; Lopez, Renata F V

      2015-10-01

      The feasibility of targeting drugs to hair follicles by a combination of microencapsulation and iontophoresis has been evaluated. Minoxidil sulphate (MXS), which is used in the treatment of alopecia, was selected as a relevant drug with respect to follicular penetration. The skin permeation and disposition of MXS encapsulated in chitosan microparticles (MXS-MP) was evaluated in vitro after passive and iontophoretic delivery. Uptake of MXS was quantified at different exposure times in the stratum corneum (SC) and hair follicles. Microencapsulation resulted in increased (6-fold) drug accumulation in the hair follicles relative to delivery from a simple MXS solution. Application of iontophoresis enhanced follicular delivery for both the solution and the microparticle formulations. It appears, therefore, that microencapsulation and iontophoresis can act synergistically to enhance topical drug targeting to hair follicles.

    1. Enhanced Oral Delivery of Protein Drugs Using Zwitterion-Functionalized Nanoparticles to Overcome both the Diffusion and Absorption Barriers.

      Science.gov (United States)

      Shan, Wei; Zhu, Xi; Tao, Wei; Cui, Yi; Liu, Min; Wu, Lei; Li, Lian; Zheng, Yaxian; Huang, Yuan

      2016-09-28

      Oral delivery of protein drugs based on nanoparticulate delivery system requires permeation of the nanoparticles through the mucus layer and subsequent absorption via epithelial cells. However, overcoming these two barriers requires very different or even contradictory surface properties of the nanocarriers, which greatly limits the oral bioavailability of macromolecular drugs. Here we report a simple zwitterions-based nanoparticle (NP) delivery platform, which showed a great potency in simultaneously overcoming both the mucus and epithelium barriers. The dense and hydrophilic coating of zwitterions endows the NPs with excellent mucus penetrating ability. Moreover, the zwitterions-based NPs also possessed excellent affinity with epithelial cells, which significantly improved (4.5-fold) the cellular uptake of DLPC NPs, compared to PEGylated NPs. Our results also indicated that this affinity was due to the interaction between zwitterions and the cell surface transporter PEPT1. Moreover, the developed NPs loaded with insulin could induce a prominent hypoglycemic response in diabetic rats following oral administration. These results suggest that zwitterions-based NPs might provide a new perspective for oral delivery of protein therapeutics.

    2. Barriers to pharmacy-based syringe purchase among injection drug users in Tijuana, Mexico: a mixed methods study.

      Science.gov (United States)

      Pollini, Robin A; Lozada, Remedios; Gallardo, Manuel; Rosen, Perth; Vera, Alicia; Macias, Armando; Palinkas, Lawrence A; Strathdee, Steffanie A

      2010-06-01

      Injection drug users (IDUs) may be denied purchase of sterile syringes even where purchase without a prescription is legal. This study examined barriers to over-the-counter (OTC) syringe purchase among IDUs in Tijuana, Mexico. A quantitative survey and subsequent focus groups were used to quantify barriers to purchase, identify their correlates and provide in-depth exploration of syringe purchase experiences. Of 627 IDUs, 81% purchased a syringe in the past 6 months and 16% were refused or overcharged. Factors independently associated with refusal/overcharging were homelessness, receptive syringe sharing, >5 uses per syringe, and number of lifetime abscesses. Few pharmacies sold syringes to IDUs, who adapted by limiting purchase attempts to pharmacies known to sell syringes consistently. Failed purchases occurred when drug withdrawal required purchase at unusual times or locations, often following release from jail. IDUs reported syringe sharing, syringe reuse, and searching through unsecured medical waste for syringes in response to failed purchase attempts. Interventions to expand OTC syringe sales to IDUs, particularly near detention facilities, will facilitate safer injection practices.

    3. Pluronic F127 nanomicelles engineered with nuclear localized functionality for targeted drug delivery

      Energy Technology Data Exchange (ETDEWEB)

      Li, Yong-Yong; Li, Lan; Dong, Hai-Qing, E-mail: inano_donghq@tongji.edu.cn; Cai, Xiao-Jun; Ren, Tian-Bin, E-mail: rentianbin@yeah.net

      2013-07-01

      PKKKRKV (Pro-Lys-Lys-Lys-Arg-Lys-Val, PV7), a seven amino acid peptide, has emerged as one of the primary nuclear localization signals that can be targeted into cell nucleus via the nuclear import machinery. Taking advantage of chemical diversity and biological activities of this short peptide sequence, in this study, Pluronic F127 nanomicelles engineered with nuclear localized functionality were successfully developed for intracellular drug delivery. These nanomicelles with the size ∼ 100 nm were self-assembled from F127 polymer that was flanked with two PV7 sequences at its both terminal ends. Hydrophobic anticancer drug doxorubicin (DOX) with inherent fluorescence was chosen as the model drug, which was found to be efficiently encapsulated into nanomicelles with the encapsulation efficiency at 72.68%. In comparison with the non-functionalized namomicelles, the microscopic observation reveals that PV7 functionalized nanomicelles display a higher cellular uptake, especially into the nucleus of HepG2 cells, due to the nuclear localization signal effects. Both cytotoxicity and apoptosis studies show that the DOX-loaded nanomicelles were more potent than drug nanomicelles without nuclear targeting functionality. It was thus concluded that PV7 functionalized nanomicelles could be a potentially alternative vehicle for nuclear targeting drug delivery. - Highlights: ► A new nuclear targeted drug delivery system based on micelles is developed. ► This micellar system features a core-shell structure with the size peaked at 100 nm. ► PV7, a short peptide sequence, is adopted as a nuclear targeting ligand. ► PV7 functionalized drug loaded micelles are more potent in killing tumor cells.

    4. Identification of new drug targets and resistance mechanisms in Mycobacterium tuberculosis.

      Directory of Open Access Journals (Sweden)

      Thomas R Ioerger

      Full Text Available Identification of new drug targets is vital for the advancement of drug discovery against Mycobacterium tuberculosis, especially given the increase of resistance worldwide to first- and second-line drugs. Because traditional target-based screening has largely proven unsuccessful for antibiotic discovery, we have developed a scalable platform for target identification in M. tuberculosis that is based on whole-cell screening, coupled with whole-genome sequencing of resistant mutants and recombineering to confirm. The method yields targets paired with whole-cell active compounds, which can serve as novel scaffolds for drug development, molecular tools for validation, and/or as ligands for co-crystallization. It may also reveal other information about mechanisms of action, such as activation or efflux. Using this method, we identified resistance-linked genes for eight compounds with anti-tubercular activity. Four of the genes have previously been shown to be essential: AspS, aspartyl-tRNA synthetase, Pks13, a polyketide synthase involved in mycolic acid biosynthesis, MmpL3, a membrane transporter, and EccB3, a component of the ESX-3 type VII secretion system. AspS and Pks13 represent novel targets in protein translation and cell-wall biosynthesis. Both MmpL3 and EccB3 are involved in membrane transport. Pks13, AspS, and EccB3 represent novel candidates not targeted by existing TB drugs, and the availability of whole-cell active inhibitors greatly increases their potential for drug discovery.

    5. Studies in Multifunctional Drug Development: Preparation and Evaluation of 11beta-Substituted Estradiol-Drug Conjugates, Cell Membrane Targeting Imaging Agents, and Target Multifunctional Nanoparticles

      Science.gov (United States)

      Dao, KinhLuan Lenny D.

      Cancer is the second leading cause of death after cardiovascular disease in the United State. Despite extensive research in development of antitumor drugs, most of these therapeutic entities often possess nonspecific toxicity, thus they can only be used to treat tumors in higher doses or more frequently. Because of the cytotoxicity and severe side effects, the drug therapeutic window normally is limited. Beside the toxicity issue, antitumor drug are also not selectively taken up by tumor cells, thus the necessitating concentrations that would eradicate the tumor can often not be used. In addition, tumor cells tend to develop resistance against the anticancer drugs after prolonged treatment. Therefore, alleviating the systemic cytotoxicity and side effects, improving in tumor selectivity, high potency, and therapeutic efficacy are still major obstacles in the area of anticancer drug development. A more promising approach for developing a selective agent for cancer is to conjugate a potent therapeutic drug, or an imaging agent with a targeting group, such as antibody or a high binding-specificity small molecule, that selectively recognize the overexpressed antigens or proteins on tumor cells. My research combines several approaches to describe this strategy via using different targeting molecules to different diseases, as well as different potent cytotoxic drugs for different therapies. Three studies related to the preparation and biological evaluation of new therapeutic agents, such as estradiol-drug hybrids, cell membrane targeted molecular imaging agents, and multifunctional NPs will be discussed. The preliminary results of these studies indicated that our new reagents achieved their initial objectives and can be further improved for optimized synthesis and in vivo experiments. The first study describes the method in which we employed a modular assembly approach to synthesize a novel 11beta-substituted steroidal anti-estrogen. The key intermediate was synthesized

    6. Multidrug resistance in oncology and beyond : from imaging of drug efflux pumps to cellular drug targets

      NARCIS (Netherlands)

      Nagengast, Wouter B; Oude Munnink, Thijs H; Dijkers, Eli; Hospers, Geesiena; Brouwers, Adrienne H; Schröder, Carolien P; Lub-de Hooge, Marjolijn; de Vries, Elisabeth G E

      2010-01-01

      Resistance of tumor cells to several structurally unrelated classes of natural products, including anthracyclines, taxanes, and epipodophyllotoxines, is often referred as multidrug resistance (MDR). This is associated with ATP-binding cassette transporters, which function as drug efflux pumps such a

    7. Polymeric particulate technologies for oral drug delivery and targeting: A pathophysiological perspective

      DEFF Research Database (Denmark)

      Hunter, A. Christy; Elsom, Jacqueline; Wibroe, Peter Popp;

      2012-01-01

      to optimize drug targeting and bioavailability. Frequently the carrier systems used are either constructed from or contain polymeric materials. Examples of these nanocarriers include polymeric nanoparticles, solid lipid nanocarriers, self-nanoemulsifying drug delivery systems and nanocrystals......Publication year: 2012 Source:Maturitas, Volume 73, Issue 1 A. Christy Hunter, Jacqueline Elsom, Peter P. Wibroe, S. Moein Moghimi The oral route for delivery of pharmaceuticals is the most widely used and accepted. Nanoparticles and microparticles are increasingly being applied within this arena...

    8. Drug delivery strategies to enhance the permeability of the blood-brain barrier for treatment of glioma.

      Science.gov (United States)

      Zhang, Fang; Xu, Chun-Lei; Liu, Chun-Mei

      2015-01-01

      Gliomas are amongst the most insidious and destructive types of brain cancer and are associated with a poor prognosis, frequent recurrences, and extremely high lethality despite combination treatment of surgery, radiotherapy, and chemotherapy. The existence of the blood-brain barrier (BBB) restricts the delivery of therapeutic molecules into the brain and offers the clinical efficacy of many pharmaceuticals that have been demonstrated to be effective for other kinds of tumors. This challenge emphasizes the need to be able to deliver drugs effectively across the BBB to reach the brain parenchyma. Enhancement of the permeability of the BBB and being able to transport drugs across it has been shown to be a promising strategy to improve drug absorption and treatment efficacy. This review highlights the innovative technologies that have been introduced to enhance the permeability of the BBB and to obtain an optimal distribution and concentration of drugs in the brain to treat gliomas, such as nanotechniques, hyperthermia techniques, receptor-mediated transport, cell-penetrating peptides, and cell-mediated delivery.

    9. Malarial kinases: novel targets for in silico approaches to drug discovery.

      Science.gov (United States)

      Bullard, Kristen M; DeLisle, Robert Kirk; Keenan, Susan M

      2013-01-01

      Malaria, the disease caused by infection with protozoan parasites from the genus Plasmodium, claims the lives of nearly 1 million people annually. Developing nations, particularly in the African Region, bear the brunt of this malaria burden. Alarmingly, the most dangerous etiologic agent of malaria, Plasmodium falciparum, is becoming increasingly resistant to current first-line antimalarials. In light of the widespread devastation caused by malaria, the emergence of drug-resistant P. falciparum strains, and the projected decrease in funding for malaria eradication that may occur over the next decade, the identification of promising new targets for antimalarial drug design is imperative. P. falciparum kinases have been proposed as ideal drug targets for antimalarial drug design because they mediate critical cellular processes within the parasite and are, in many cases, structurally and mechanistically divergent when compared with kinases from humans. Identifying a molecule capable of inhibiting the activity of a target enzyme is generally an arduous and expensive process that can be greatly aided by utilizing in silico drug design techniques. Such methods have been extensively applied to human kinases, but as yet have not been fully exploited for the exploration and characterization of antimalarial kinase targets. This review focuses on in silico methods that have been used for the evaluation of potential antimalarials and the Plasmodium kinases that could be explored using these techniques.

    10. Drug Target Identification and Elucidation of Natural Inhibitors for Bordetella petrii: An In Silico Study

      Science.gov (United States)

      Ray, Manisha; Pattnaik, Animesh; Pradhan, Sukanta Kumar

      2016-01-01

      Environmental microbes like Bordetella petrii has been established as a causative agent for various infectious diseases in human. Again, development of drug resistance in B. petrii challenged to combat against the infection. Identification of potential drug target and proposing a novel lead compound against the pathogen has a great aid and value. In this study, bioinformatics tools and technology have been applied to suggest a potential drug target by screening the proteome information of B. petrii DSM 12804 (accession No. PRJNA28135) from genome database of National Centre for Biotechnology information. In this regards, the inhibitory effect of nine natural compounds like ajoene (Allium sativum), allicin (A. sativum), cinnamaldehyde (Cinnamomum cassia), curcumin (Curcuma longa), gallotannin (active component of green tea and red wine), isoorientin (Anthopterus wardii), isovitexin (A. wardii), neral (Melissa officinalis), and vitexin (A. wardii) have been acknowledged with anti-bacterial properties and hence tested against identified drug target of B. petrii by implicating computational approach. The in silico studies revealed the hypothesis that lpxD could be a potential drug target and with recommendation of a strong inhibitory effect of selected natural compounds against infection caused due to B. petrii, would be further validated through in vitro experiments. PMID:28154518

    11. The Validation of Nematode-Specific Acetylcholine-Gated Chloride Channels as Potential Anthelmintic Drug Targets.

      Science.gov (United States)

      Wever, Claudia M; Farrington, Danielle; Dent, Joseph A

      2015-01-01

      New compounds are needed to treat parasitic nematode infections in humans, livestock and plants. Small molecule anthelmintics are the primary means of nematode parasite control in animals; however, widespread resistance to the currently available drug classes means control will be impossible without the introduction of new compounds. Adverse environmental effects associated with nematocides used to control plant parasitic species are also motivating the search for safer, more effective compounds. Discovery of new anthelmintic drugs in particular has been a serious challenge due to the difficulty of obtaining and culturing target parasites for high-throughput screens and the lack of functional genomic techniques to validate potential drug targets in these pathogens. We present here a novel strategy for target validation that employs the free-living nematode Caenorhabditis elegans to demonstrate the value of new ligand-gated ion channels as targets for anthelmintic discovery. Many successful anthelmintics, including ivermectin, levamisole and monepantel, are agonists of pentameric ligand-gated ion channels, suggesting that the unexploited pentameric ion channels encoded in parasite genomes may be suitable drug targets. We validated five members of the nematode-specific family of acetylcholine-gated chloride channels as targets of agonists with anthelmintic properties by ectopically expressing an ivermectin-gated chloride channel, AVR-15, in tissues that endogenously express the acetylcholine-gated chloride channels and using the effects of ivermectin to predict the effects of an acetylcholine-gated chloride channel agonist. In principle, our strategy can be applied to validate any ion channel as a putative anti-parasitic drug target.

    12. The Validation of Nematode-Specific Acetylcholine-Gated Chloride Channels as Potential Anthelmintic Drug Targets.

      Directory of Open Access Journals (Sweden)

      Claudia M Wever

      Full Text Available New compounds are needed to treat parasitic nematode infections in humans, livestock and plants. Small molecule anthelmintics are the primary means of nematode parasite control in animals; however, widespread resistance to the currently available drug classes means control will be impossible without the introduction of new compounds. Adverse environmental effects associated with nematocides used to control plant parasitic species are also motivating the search for safer, more effective compounds. Discovery of new anthelmintic drugs in particular has been a serious challenge due to the difficulty of obtaining and culturing target parasites for high-throughput screens and the lack of functional genomic techniques to validate potential drug targets in these pathogens. We present here a novel strategy for target validation that employs the free-living nematode Caenorhabditis elegans to demonstrate the value of new ligand-gated ion channels as targets for anthelmintic discovery. Many successful anthelmintics, including ivermectin, levamisole and monepantel, are agonists of pentameric ligand-gated ion channels, suggesting that the unexploited pentameric ion channels encoded in parasite genomes may be suitable drug targets. We validated five members of the nematode-specific family of acetylcholine-gated chloride channels as targets of agonists with anthelmintic properties by ectopically expressing an ivermectin-gated chloride channel, AVR-15, in tissues that endogenously express the acetylcholine-gated chloride channels and using the effects of ivermectin to predict the effects of an acetylcholine-gated chloride channel agonist. In principle, our strategy can be applied to validate any ion channel as a putative anti-parasitic drug target.

    13. The Validation of Nematode-Specific Acetylcholine-Gated Chloride Channels as Potential Anthelmintic Drug Targets

      Science.gov (United States)

      Wever, Claudia M.; Farrington, Danielle; Dent, Joseph A.

      2015-01-01

      New compounds are needed to treat parasitic nematode infections in humans, livestock and plants. Small molecule anthelmintics are the primary means of nematode parasite control in animals; however, widespread resistance to the currently available drug classes means control will be impossible without the introduction of new compounds. Adverse environmental effects associated with nematocides used to control plant parasitic species are also motivating the search for safer, more effective compounds. Discovery of new anthelmintic drugs in particular has been a serious challenge due to the difficulty of obtaining and culturing target parasites for high-throughput screens and the lack of functional genomic techniques to validate potential drug targets in these pathogens. We present here a novel strategy for target validation that employs the free-living nematode Caenorhabditis elegans to demonstrate the value of new ligand-gated ion channels as targets for anthelmintic discovery. Many successful anthelmintics, including ivermectin, levamisole and monepantel, are agonists of pentameric ligand-gated ion channels, suggesting that the unexploited pentameric ion channels encoded in parasite genomes may be suitable drug targets. We validated five members of the nematode-specific family of acetylcholine-gated chloride channels as targets of agonists with anthelmintic properties by ectopically expressing an ivermectin-gated chloride channel, AVR-15, in tissues that endogenously express the acetylcholine-gated chloride channels and using the effects of ivermectin to predict the effects of an acetylcholine-gated chloride channel agonist. In principle, our strategy can be applied to validate any ion channel as a putative anti-parasitic drug target. PMID:26393923

    14. Crowd sourcing a new paradigm for interactome driven drug target identification in Mycobacterium tuberculosis.

      Directory of Open Access Journals (Sweden)

      Rohit Vashisht

      Full Text Available A decade since the availability of Mycobacterium tuberculosis (Mtb genome sequence, no promising drug has seen the light of the day. This not only indicates the challenges in discovering new drugs but also suggests a gap in our current understanding of Mtb biology. We attempt to bridge this gap by carrying out extensive re-annotation and constructing a systems level protein interaction map of Mtb with an objective of finding novel drug target candidates. Towards this, we synergized crowd sourcing and social networking methods through an initiative 'Connect to Decode' (C2D to generate the first and largest manually curated interactome of Mtb termed 'interactome pathway' (IPW, encompassing a total of 1434 proteins connected through 2575 functional relationships. Interactions leading to gene regulation, signal transduction, metabolism, structural complex formation have been catalogued. In the process, we have functionally annotated 87% of the Mtb genome in context of gene products. We further combine IPW with STRING based network to report central proteins, which may be assessed as potential drug targets for development of drugs with least possible side effects. The fact that five of the 17 predicted drug targets are already experimentally validated either genetically or biochemically lends credence to our unique approach.

    15. An inflammation-targeting hydrogel for local drug delivery in inflammatory bowel disease.

      Science.gov (United States)

      Zhang, Sufeng; Ermann, Joerg; Succi, Marc D; Zhou, Allen; Hamilton, Matthew J; Cao, Bonnie; Korzenik, Joshua R; Glickman, Jonathan N; Vemula, Praveen K; Glimcher, Laurie H; Traverso, Giovanni; Langer, Robert; Karp, Jeffrey M

      2015-08-12

      There is a clinical need for new, more effective treatments for chronic and debilitating inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis. Targeting drugs selectively to the inflamed intestine may improve therapeutic outcomes and minimize systemic toxicity. We report the development of an inflammation-targeting hydrogel (IT-hydrogel) that acts as a drug delivery system to the inflamed colon. Hydrogel microfibers were generated from ascorbyl palmitate, an amphiphile that is generally recognized as safe (GRAS) by the U.S. Food and Drug Administration. IT-hydrogel microfibers loaded with the anti-inflammatory corticosteroid dexamethasone (Dex) were stable, released drug only upon enzymatic digestion, and demonstrated preferential adhesion to inflamed epithelial surfaces in vitro and in two mouse colitis models in vivo. Dex-loaded IT-hydrogel enemas, but not free Dex enemas, administered every other day to mice with colitis resulted in a significant reduction in inflammation and were associated with lower Dex peak serum concentrations and, thus, less systemic drug exposure. Ex vivo analysis of colon tissue samples from patients with ulcerative colitis demonstrated that IT-hydrogel microfibers adhered preferentially to mucosa from inflamed lesions compared with histologically normal sites. The IT-hydrogel drug delivery platform represents a promising approach for targeted enema-based therapies in patients with colonic IBD.

    16. P-glycoprotein alters blood–brain barrier penetration of antiepileptic drugs in rats with medically intractable epilepsy

      Directory of Open Access Journals (Sweden)

      Ma A

      2013-12-01

      Full Text Available Aimei Ma,1,* Cuicui Wang,2,3,* Yinghui Chen,2,3 Weien Yuan4 1Department of Neurology, The People's Hospital of Shanxi Province, Taiyuan, 2Department of Neurology, Jinshan Hospital, Fudan University, 3Department of Neurology, Shanghai Medical College, Shanghai, 4School of Pharmacy, Shanghai JiaoTong University, Shanghai, People's Republic of China *These authors contributed equally to this work Abstract: P-glycoprotein is one of the earliest known multidrug transporters and plays an important role in resistance to chemotherapeutic drugs. In this study, we detected levels of P-glycoprotein and its mRNA expression in a rat brain model of medically intractable epilepsy established by amygdala kindling and drug selection. We investigated whether inhibition of P-glycoprotein affects the concentration of antiepileptic drugs in cortical extracellular fluid. We found that levels of P-glycoprotein and its mRNA expression were upregulated in epileptic cerebral tissue compared with cerebral tissue from normal rats. The concentrations of two antiepileptic drugs, carbamazepine and phenytoin, were very low in the cortical extracellular fluid of rats with medically intractable epilepsy, and were restored after blockade of P-glycoprotein by verapamil. These results show that increased P-glycoprotein levels alter the ability of carbamazepine and phenytoin to penetrate the blood–brain barrier and reduce the concentrations of these agents in extracellular cortical fluid. High P-glycoprotein levels may be involved in resistance to antiepileptic drugs in medically intractable epilepsy. Keywords: P-glycoprotein, medically intractable epilepsy, antiepileptic drugs, amygdala kindling, verapamil

    17. Surface Modified Multifunctional and Stimuli Responsive Nanoparticles for Drug Targeting: Current Status and Uses

      Science.gov (United States)

      Siafaka, Panoraia I.; Üstündağ Okur, Neslihan; Karavas, Evangelos; Bikiaris, Dimitrios N.

      2016-01-01

      Nanocarriers, due to their unique features, are of increased interest among researchers working with pharmaceutical formulations. Polymeric nanoparticles and nanocapsules, involving non-toxic biodegradable polymers, liposomes, solid lipid nanoparticles, and inorganic–organic nanomaterials, are among the most used carriers for drugs for a broad spectrum of targeted diseases. In fact, oral, injectable, transdermal-dermal and ocular formulations mainly consist of the aforementioned nanomaterials demonstrating promising characteristics such as long circulation, specific targeting, high drug loading capacity, enhanced intracellular penetration, and so on. Over the last decade, huge advances in the development of novel, safer and less toxic nanocarriers with amended properties have been made. In addition, multifunctional nanocarriers combining chemical substances, vitamins and peptides via coupling chemistry, inorganic particles coated by biocompatible materials seem to play a key role considering that functionalization can enhance characteristics such as biocompatibility, targetability, environmental friendliness, and intracellular penetration while also have limited side effects. This review aims to summarize the “state of the art” of drug delivery carriers in nanosize, paying attention to their surface functionalization with ligands and other small or polymeric compounds so as to upgrade active and passive targeting, different release patterns as well as cell targeting and stimuli responsibility. Lastly, future aspects and potential uses of nanoparticulated drug systems are outlined. PMID:27589733

    18. Guidelines to PET measurements of the target occupancy in the brain for drug development

      Energy Technology Data Exchange (ETDEWEB)

      Takano, Akihiro; Varrone, Andrea; Gulyas, Balazs; Halldin, Christer [Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatric Research, Stockholm (Sweden); Salvadori, Piero [CNR Istituto di Fisiologia Clinica, Pisa (Italy); Gee, Antony [Kings College London, Department of Chemistry and Biology, Division of Imaging Sciences and Biomedical Engineering, London (United Kingdom); Windhorst, Albert; Lammertsma, Adriaan A. [VU University Medical Center, Department of Radiology and Nuclear Medicine, Amsterdam (Netherlands); Vercouillie, Johnny [Universite Francois Rabelais de Tours, UMR Inserm U930, Tours (France); Bormans, Guy [KU Leuven, Nuclear Medicine and Molecular Imaging, Department of Imaging and Pathology, Leuven (Belgium)

      2016-11-15

      This guideline summarizes the current view of the European Association of Nuclear Medicine Drug Development Committee. The purpose of this guideline is to guarantee a high standard of PET studies that are aimed at measuring target occupancy in the brain within the framework of development programs of drugs that act within the central nervous system (CNS drugs). This guideline is intended to present information specifically adapted to European practice. The information provided should be applied within the context of local conditions and regulations. (orig.)

    19. Methodologies and Application of New Target Identification, Drug Action Mechanism Investigation and New Molecular Entity Discovery

      Institute of Scientific and Technical Information of China (English)

      2011-01-01

      @@ The group, headed by Prof.JIANG Hualiang with the CAS Shanghai Institute of Materia Medica, has been centering on the basic research of pharmaceutical science, including identifying new targets, studying new drug action mechanisms and discovering new drug candidates.On the basis of new methodology development, an effective multi-disciplinary research platform for drug research and discovery has been established through the integration of different disciplines of computational chemistry, organic synthesis, molecular and cellular biology.A bunch of creative results have been achieved in these areas.

    20. DEVELOPMENT AND EVALUATION OF ENZYMATICALY TRIGGERED MULTIPARTICULATE COLON TARGETED DRUG DELIVERY SYSTEM

      Directory of Open Access Journals (Sweden)

      Mohapatra Santosh K

      2011-02-01

      Full Text Available The most critical challenge in oral colon specific drug delivery approach is to preserve the formulation during its passage through the stomach and about first six meters of the small intestine. Microbial enzyme-triggering mechanisms seem to be promising to provide more reliable colonic delivery .The objective of the present study was to develop biodegradable colon targeted multiparticulate system by using guar gum. In this study drug (Budesonide loaded pellets were coated with aqueous guar gum solution and subjected to In-vitro drug release studies simulating GIT with and without enzyme as well as coating properties were evaluated by SEM. In-vitro release studies indicates that drug release after 4.5 h lag time in presence of enzyme and lag time increase in absence of enzyme which indicated the enzyme triggered system for colonic release. This Multiparticulate system can be effectively used for colonic drug delivery for effective treatment of colonic diseases.

    1. [Economic Loss of Remaining Contents in Molecular Target Drug Preparation and the Simulation for Cost Saving].

      Science.gov (United States)

      Usami, Eiseki; Kimura, Michio; Fukuoka, Tomohiro; Okada, Kazutomo; Yoshimura, Tomoaki

      2016-06-01

      While preparing an anticancer drug, even if it is an expensive molecular target drug, the remainder is not divided and saved for use in other patients; instead, it is discarded, resulting in waste of medical resources. In this study, we examined the economic loss in terms of medical costs by calculating the discarded amounts of 12 commonly used molecular target drugs at Ogaki Municipal Hospital, Japan between January 2012 and December 2014. We found, on average, that drugs valued at ¥ 52,593,182 were discarded annually. In particular, the discarded amounts of relatively expensive drugs, such as bevacizumab, bortezomib, and rituximab, were valued at ¥ 16,646,300, ¥ 15,866,289, and ¥ 8,401,324, respectively. Among these, the average amount of waste per administration of bortezomib was particularly expensive, at a cost of ¥ 67,325. Bortezomib is a commonly used treatment, resulting in excessive cumulative discarded cost. In an effort to save cost, we should consider using small capacity standard injections. Development of a simulation that used the remaining drug contents from only 1 day showed that bevacizumab alone accounts for an average cost saving of ¥1 2,542,191(75.3%) per year. This study suggests that effectively utilizing the remaining drug contents would ensure efficient use of medical resources, thereby reducing economic losses.

    2. Doxorubicin loaded PVA coated iron oxide nanoparticles for targeted drug delivery

      Energy Technology Data Exchange (ETDEWEB)

      Kayal, S. [School of Materials Science and Engineering, Nanyang Technological University, Singapore 639798 (Singapore); Ramanujan, R.V., E-mail: ramanujan@ntu.edu.sg [School of Materials Science and Engineering, Nanyang Technological University, Singapore 639798 (Singapore)

      2010-04-06

      Magnetic drug targeting is a drug delivery system that can be used in locoregional cancer treatment. Coated magnetic particles, called carriers, are very useful for delivering chemotherapeutic drugs. Magnetic carriers were synthesized by coprecipitation of iron oxide followed by coating with polyvinyl alcohol (PVA). Characterization was carried out using X-ray diffraction, TEM, TGA, FTIR and VSM techniques. The magnetic core of the carriers was magnetite (Fe{sub 3}O{sub 4}), with average size of 10 nm. The room temperature VSM measurements showed that magnetic particles were superparamagnetic. The amount of PVA bound to the iron oxide nanoparticles were estimated by thermogravimetric analysis (TGA) and the attachment of PVA to the iron oxide nanoparticles was confirmed by FTIR analysis. Doxorubicin (DOX) drug loading and release profiles of PVA coated iron oxide nanoparticles showed that up to 45% of adsorbed drug was released in 80 h, the drug release followed the Fickian diffusion-controlled process. The binding of DOX to the PVA was confirmed by FTIR analysis. The present findings show that DOX loaded PVA coated iron oxide nanoparticles are promising for magnetically targeted drug delivery.

    3. Layered Double Hydroxide Modified by PEGylated Hyaluronic Acid as a Hybrid Nanocarrier for Targeted Drug Delivery

      Institute of Scientific and Technical Information of China (English)

      董岸杰; 李雪; 王伟伟; 韩尚聪; 刘鉴锋; 刘金剑; 赵军强; 许舒欣; 邓联东

      2016-01-01

      In recent years, organic-inorganic hybrid nanocarriers are explored for effective drug delivery and pref-erable disease treatments. In this study, using 5-fluorouracil(5-FU)as electronegative model drug, a new type of organic-inorganic hybrid drug delivery system(LDH/HA-PEG/5-FU)was conceived and manufactured by the ad-sorption of PEGylated hyaluronic acid(HA-PEG)on the surface of layered double hydroxide(LDH, prepared via hydrothermal method)and the intercalation of 5-FU in the interlamination of LDH via ion exchange strategy. The drug loading amount of LDH/HA-PEG/5-FU achieved as high as 34.2%. LDH, LDH/5-FU and LDH/HA-PEG/5-FU were characterized by FT-IR, XRD, TGA, laser particle size analyzer and SEM. With the benefit of pH-degradable feature of LDH and enzyme-degradable feature of HA, LDH/HA-PEG/5-FU showed pH-degradable and enzyme-degradable capacity inin vitro drug release. Moreover, the drug carrier LDH/HA-PEG contained biocom-patible PEG and tumor-targeted HA, resulting in lower cytotoxicity and better endocytosis compared with LDHin vitro. It was suggested that the organic-inorganic hybrid drug delivery system, which was endowed with the proper-ties of controlled release, low toxicity and tumor-targeting delivery for ameliorative cancer therapy, was advisable and might be applied further to fulfill other treatments.

    4. Identification of New Drug Targets in Multi-Drug Resistant Bacterial Infections

      Science.gov (United States)

      2013-10-01

      containing a misfolded or aggregated form of CS using ion exchange and then verified using gel filtration chromatography. Importantly, once these two CS...obtaining a high-resolution X-ray crystal structure useful for antibacterial drug design efforts. Based upon this progress, we expect to obtain this...chromatographic steps was developed. A gel filtration step again demonstrates multiple peaks, suggesting that we are still fighting aggregation

    5. A dual functional fluorescent probe for glioma imaging mediated by blood-brain barrier penetration and glioma cell targeting.

      Science.gov (United States)

      Ma, Hongwei; Gao, Zhiyong; Yu, Panfeng; Shen, Shun; Liu, Yongmei; Xu, Bainan

      2014-06-20

      Glioma is a huge threat for human being because it was hard to be completely removed owing to both the infiltrating growth of glioma cells and integrity of blood brain barrier. Thus effectively imaging the glioma cells may pave a way for surgical removing of glioma. In this study, a fluorescent probe, Cy3, was anchored onto the terminal of AS1411, a glioma cell targeting aptamer, and then TGN, a BBB targeting peptide, was conjugated with Cy3-AS1411 through a PEG linker. The production, named AsT, was characterized by gel electrophoresis, (1)H NMR and FTIR. In vitro cellular uptake and glioma spheroid uptake demonstrated the AsT could not only be uptaken by both glioma and endothelial cells, but also penetrate through endothelial cell monolayer and uptake by glioma spheroids. In vivo, AsT could effectively target to glioma with high intensity. In conclusion, AsT could be used as an effective glioma imaging probe.

    6. Fluorescence assays for monitoring RNA-ligand interactions and riboswitch-targeted drug discovery screening.

      Science.gov (United States)

      Liu, J; Zeng, C; Zhou, S; Means, J A; Hines, J V

      2015-01-01

      Riboswitches and other noncoding regulatory RNA are intriguing targets for the development of therapeutic agents. A significant challenge in the drug discovery process, however, is the identification of potent compounds that bind the target RNA specifically and disrupt its function. Essential to this process is an effectively designed cascade of screening assays. A screening cascade for identifying compounds that target the T box riboswitch antiterminator element is described. In the primary assays, moderate to higher throughput screening of compound libraries is achieved by combining the sensitivity of fluorescence techniques with functionally relevant assays. Active compounds are then validated and the binding to target RNA further characterized in secondary assays. The cascade of assays monitor ligand-induced changes in the steady-state fluorescence of an attached dye or internally incorporated 2-aminopurine; the fluorescence anisotropy of an RNA complex; and, the thermal denaturation fluorescence profile of a fluorophore-quencher labeled RNA. While the assays described have been developed for T box riboswitch-targeted drug discovery, the fluorescence methods and screening cascade design principles can be applied to drug discovery efforts targeted toward other medicinally relevant noncoding RNA.

    7. Depth-targeted transvascular drug delivery by using annular-shaped photomechanical waves

      Science.gov (United States)

      Akiyama, Takuya; Sato, Shunichi; Ashida, Hiroshi; Terakawa, Mitsuhiro

      2011-02-01

      Laser-based drug delivery is attractive for the targeting capability due to high spatial controllability of laser energy. Recently, we found that photomechanical waves (PMWs) can transiently increase the permeability of blood vessels in skin, muscle and brain of rats. In this study, we examined the use of annular-shaped PMWs to increase pressure at target depths due to superposition effect of pressure waves. This can increase the permeability of blood vessels located in the specific depth regions, enabling depth-targeted transvascular drug delivery. Annular PMWs were produced by irradiating a laser-absorbing material with annular-shaped pulsed laser beams that were produced by using an axicon lens. We first examined propagation and pressure characteristics of annular PMWs in tissue phantoms and confirmed an increased pressure at a target depth, which can be controlled by changing laser parameters. We injected Evans blue (EB) into a rat tail vein, and annular PMWs (inner diameter, 3 mm; outer diameter, 5 mm) were applied from the myofascial surface of the anterior tibialis muscle. After perfusion fixation, we observed fluorescence originating from EB in the tissue. We observed intense fluorescence at a target depth region of around 5 mm. These results demonstrate the capability of annular PMWs for depth-targeted transvascular drug delivery.

    8. Near-infrared fluorescence heptamethine carbocyanine dyes mediate imaging and targeted drug delivery for human brain tumor

      Science.gov (United States)

      Wu, Jason Boyang; Shi, Changhong; Chu, Gina Chia-Yi; Xu, Qijin; Zhang, Yi; Li, Qinlong; Yu, John S.; Zhau, Haiyen E.; Chung, Leland W.K.

      2016-01-01

      Brain tumors and brain metastases are among the deadliest malignancies of all human cancers, largely due to the cellular blood-brain and blood-tumor barriers that limit the delivery of imaging and therapeutic agents from the systemic circulation to tumors. Thus, improved strategies for brain tumor visualization and targeted treatment are critically needed. Here we identified and synthesized a group of near-infrared fluorescence (NIRF) heptamethine carbocyanine dyes and derivative NIRF dye-drug conjugates for effective imaging and therapeutic targeting of brain tumors of either primary or metastatic origin in mice, which is mechanistically mediated by tumor hypoxia and organic aniontransporting polypeptide genes. We also demonstrate that these dyes, when conjugated to chemotherapeutic agents such as gemcitabine, significantly restricted the growth of both intracranial glioma xenografts and prostate tumor brain metastases and prolonged survival in mice. These results show promise in the application of NIRF dyes as novel theranostic agents for the detection and treatment of brain tumors. PMID:26197410

    9. Near-infrared fluorescence heptamethine carbocyanine dyes mediate imaging and targeted drug delivery for human brain tumor.

      Science.gov (United States)

      Wu, Jason Boyang; Shi, Changhong; Chu, Gina Chia-Yi; Xu, Qijin; Zhang, Yi; Li, Qinlong; Yu, John S; Zhau, Haiyen E; Chung, Leland W K

      2015-10-01

      Brain tumors and brain metastases are among the deadliest malignancies of all human cancers, largely due to the cellular blood-brain and blood-tumor barriers that limit the delivery of imaging and therapeutic agents from the systemic circulation to tumors. Thus, improved strategies for brain tumor visualization and targeted treatment are critically needed. Here we identified and synthesized a group of near-infrared fluorescence (NIRF) heptamethine carbocyanine dyes and derivative NIRF dye-drug conjugates for effective imaging and therapeutic targeting of brain tumors of either primary or metastatic origin in mice, which is mechanistically mediated by tumor hypoxia and organic anion-transporting polypeptide genes. We also demonstrate that these dyes, when conjugated to chemotherapeutic agents such as gemcitabine, significantly restricted the growth of both intracranial glioma xenografts and prostate tumor brain metastases and prolonged survival in mice. These results show promise in the application of NIRF dyes as novel theranostic agents for the detection and treatment of brain tumors.

    10. Identification of attractive drug targets in neglected-disease pathogens using an in silico approach.

      Directory of Open Access Journals (Sweden)

      Gregory J Crowther

      Full Text Available BACKGROUND: The increased sequencing of pathogen genomes and the subsequent availability of genome-scale functional datasets are expected to guide the experimental work necessary for target-based drug discovery. However, a major bottleneck in this has been the difficulty of capturing and integrating relevant information in an easily accessible format for identifying and prioritizing potential targets. The open-access resource TDRtargets.org facilitates drug target prioritization for major tropical disease pathogens such as the mycobacteria Mycobacterium leprae and Mycobacterium tuberculosis; the kinetoplastid protozoans Leishmania major, Trypanosoma brucei, and Trypanosoma cruzi; the apicomplexan protozoans Plasmodium falciparum, Plasmodium vivax, and Toxoplasma gondii; and the helminths Brugia malayi and Schistosoma mansoni. METHODOLOGY/PRINCIPAL FINDINGS: Here we present strategies to prioritize pathogen proteins based on whether their properties meet criteria considered desirable in a drug target. These criteria are based upon both sequence-derived information (e.g., molecular mass and functional data on expression, essentiality, phenotypes, metabolic pathways, assayability, and druggability. This approach also highlights the fact that data for many relevant criteria are lacking in less-studied pathogens (e.g., helminths, and we demonstrate how this can be partially overcome by mapping data from homologous genes in well-studied organisms. We also show how individual users can easily upload external datasets and integrate them with existing data in TDRtargets.org to generate highly customized ranked lists of potential targets. CONCLUSIONS/SIGNIFICANCE: Using the datasets and the tools available in TDRtargets.org, we have generated illustrative lists of potential drug targets in seven tropical disease pathogens. While these lists are broadly consistent with the research community's current interest in certain specific proteins, and suggest

    11. Near- and sub-barrier fusion of 20O incident ions with 12C target nuclei

      Energy Technology Data Exchange (ETDEWEB)

      Rudolph, M. J. [Indiana University; Gosser, Z. Q. [Indiana University; Brown, K [Indiana University; De Souza, R. T. [Indiana University; Chbihi, A. [GANIL, CEA, Caen, France & CNRS, IN2P3, Caen, France; Jacquot, B. [GANIL, CEA, Caen, France & CNRS, IN2P3, Caen, France; Famiano, M. [Western Michigan University; Liang, J Felix [ORNL; Shapira, Dan [ORNL; Mercier, D. [Centre de Calcul du CNRS, France

      2012-01-01

      Evaporation residues resulting from fusion of {sup 20}O incident ions with {sup 12}C target nuclei have been measured for the first time. The cross-section associated with compound nuclei that de-excite via emission of charged particles is extracted. The resulting excitation function is compared with the predictions of a standard fusion model followed by statistical decay code. A significant underprediction of the measured cross-section by the fusion-evaporation model raises the question of whether the fusion cross-section is larger for the neutron-rich projectile or the statistical de-excitation is incorrectly predicted.

    12. SELF-BLM: Prediction of drug-target interactions via self-training SVM

      Science.gov (United States)

      Keum, Jongsoo; Nam, Hojung

      2017-01-01

      Predicting drug-target interactions is important for the development of novel drugs and the repositioning of drugs. To predict such interactions, there are a number of methods based on drug and target protein similarity. Although these methods, such as the bipartite local model (BLM), show promise, they often categorize unknown interactions as negative interaction. Therefore, these methods are not ideal for finding potential drug-target interactions that have not yet been validated as positive interactions. Thus, here we propose a method that integrates machine learning techniques, such as self-training support vector machine (SVM) and BLM, to develop a self-training bipartite local model (SELF-BLM) that facilitates the identification of potential interactions. The method first categorizes unlabeled interactions and negative interactions among unknown interactions using a clustering method. Then, using the BLM method and self-training SVM, the unlabeled interactions are self-trained and final local classification models are constructed. When applied to four classes of proteins that include enzymes, G-protein coupled receptors (GPCRs), ion channels, and nuclear receptors, SELF-BLM showed the best performance for predicting not only known interactions but also potential interactions in three protein classes compare to other related studies. The implemented software and supporting data are available at https://github.com/GIST-CSBL/SELF-BLM. PMID:28192537

    13. Pluronic F127 nanomicelles engineered with nuclear localized functionality for targeted drug delivery.

      Science.gov (United States)

      Li, Yong-Yong; Li, Lan; Dong, Hai-Qing; Cai, Xiao-Jun; Ren, Tian-Bin

      2013-07-01

      PKKKRKV (Pro-Lys-Lys-Lys-Arg-Lys-Val, PV7), a seven amino acid peptide, has emerged as one of the primary nuclear localization signals that can be targeted into cell nucleus via the nuclear import machinery. Taking advantage of chemical diversity and biological activities of this short peptide sequence, in this study, Pluronic F127 nanomicelles engineered with nuclear localized functionality were successfully developed for intracellular drug delivery. These nanomicelles with the size ~100 nm were self-assembled from F127 polymer that was flanked with two PV7 sequences at its both terminal ends. Hydrophobic anticancer drug doxorubicin (DOX) with inherent fluorescence was chosen as the model drug, which was found to be efficiently encapsulated into nanomicelles with the encapsulation efficiency at 72.68%. In comparison with the non-functionalized namomicelles, the microscopic observation reveals that PV7 functionalized nanomicelles display a higher cellular uptake, especially into the nucleus of HepG2 cells, due to the nuclear localization signal effects. Both cytotoxicity and apoptosis studies show that the DOX-loaded nanomicelles were more potent than drug nanomicelles without nuclear targeting functionality. It was thus concluded that PV7 functionalized nanomicelles could be a potentially alternative vehicle for nuclear targeting drug delivery.

    14. Transdermal Drug Delivery Mediated by Microneedle Arrays: Innovations and Barriers to Success.

      Science.gov (United States)

      Caffarel-Salvador, Ester; Donnelly, Ryan F

      2016-01-01

      Microneedles (MN) offer a simple, minimally invasive and reduced pain alternative to hypodermic needles for drug delivery, including vaccines. Previous studies investigating the use of MN have highlighted the benefit of this technology to facilitate dermal and transdermal drug delivery. Going forward towards commercialization, it is important to consider the perceptions and acceptability that MN technology will have once available in the market. This review collects the opinions and expectations of different population groups such as children, parents, paediatricians and the general public on various MN systems. In addition, the low pain perception scores, based on a visual analog scale for MN application, should also lead to a greater acceptability of this technology as a means of transdermal drug delivery. This review also highlights the potential challenges associated with the different types of MN together with issues of sterility and biocompatibility which will be important future factors to consider.

    15. Network-based approaches for drug response prediction and targeted therapy development in cancer.

      Science.gov (United States)

      Dorel, Mathurin; Barillot, Emmanuel; Zinovyev, Andrei; Kuperstein, Inna

      2015-08-21

      Signaling pathways implicated in cancer create a complex network with numerous regulatory loops and redundant pathways. This complexity explains frequent failure of one-drug-one-target paradigm of treatment, resulting in drug resistance in patients. To overcome the robustness of cell signaling network, cancer treatment should be extended to a combination therapy approach. Integrating and analyzing patient high-throughput data together with the information about biological signaling machinery may help deciphering molecular patterns specific to each patient and finding the best combinations of candidates for therapeutic targeting. We review state of the art in the field of targeted cancer medicine from the computational systems biology perspective. We summarize major signaling network resources and describe their characteristics with respect to applicability for drug response prediction and intervention targets suggestion. Thus discuss methods for prediction of drug sensitivity and intervention combinations using signaling networks together with high-throughput data. Gradual integration of these approaches into clinical routine will improve prediction of response to standard treatments and adjustment of intervention schemes.

    16. Pathways Targeted by Antidiabetes Drugs Are Enriched for Multiple Genes Associated With Type 2 Diabetes Risk