High-molecular-weight HPMA-based polymer drug carriers for delivery to tumor

Czech Academy of Sciences Publication Activity Database

Kostka, Libor; Etrych, Tomáš

2016-01-01

Roč. 65, Suppl. 2 (2016), S179-S190 ISSN 0862-8408 R&D Projects: GA MŠk(CZ) LO1507 Institutional support: RVO:61389013 Keywords : nanotherapeutics * pH responsive * HPMA copolymers Subject RIV: CD - Macromolecular Chemistry Impact factor: 1.461, year: 2016 http://www.biomed.cas.cz/physiolres/pdf/65%20Suppl%202/65_S179.pdf

HPMA copolymer-bound doxorubicin induces immunogenic tumor cell death.

Science.gov (United States)

Sirova, M; Kabesova, M; Kovar, L; Etrych, T; Strohalm, J; Ulbrich, K; Rihova, B

2013-01-01

Treatment of murine EL4 T cell lymphoma with N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer conjugates of doxorubicin (Dox) leads to complete tumor regression and to the development of therapy-dependent longlasting cancer resistance. This phenomenon occurs with two types of Dox conjugates tested, despite differences in the covalent linkage of Dox to the polymer carrier. Such a cancer resistance cannot fully express in conventional treatment with free Dox, due to substantial immunotoxicity of the treatment, which was not observed in the polymer conjugates. In this study, calreticulin (CRT) translocation and high mobility group box-1 protein (HMGB1) release was observed in EL4 cells treated with a conjugate releasing Dox by a pH-dependent manner. As a result, the treated tumor cells were engulfed by dendritic cells (DC) in vitro, and induced their expression of CD80, CD86, and MHC II maturation markers. Conjugates with Dox bound via an amide bond only increased translocation of HSPs to the membrane, which led to an elevated phagocytosis but was not sufficient to induce increase of the maturation markers on DCs in vitro. Both types of conjugates induced engulfment of the target tumor cells in vivo, that was more intense than that seen with free Dox. It means that the induction of anti-tumor immunity documented upon treatment of EL4 lymphoma with HPMA-bound Dox conjugates does not rely solely on CRT-mediated cell death, but involves multiple mechanisms.

Amphiphilic HPMA-LMA copolymers increase the transport of Rhodamine 123 across a BBB model without harming its barrier integrity.

Science.gov (United States)

Hemmelmann, Mirjam; Metz, Verena V; Koynov, Kaloian; Blank, Kerstin; Postina, Rolf; Zentel, Rudolf

2012-10-28

The successful non-invasive treatment of diseases associated with the central nervous system (CNS) is generally limited by poor brain permeability of various developed drugs. The blood-brain barrier (BBB) prevents the passage of therapeutics to their site of action. Polymeric drug delivery systems are promising solutions to effectively transport drugs into the brain. We recently showed that amphiphilic random copolymers based on the hydrophilic p(N-(2-hydroxypropyl)-methacrylamide), pHPMA, possessing randomly distributed hydrophobic p(laurylmethacrylate), pLMA, are able to mediate delivery of domperidone into the brain of mice in vivo. To gain further insight into structure-property relations, a library of carefully designed polymers based on p(HPMA) and p(LMA) was synthesized and tested applying an in vitro BBB model which consisted of human brain microvascular endothelial cells (HBMEC). Our model drug Rhodamine 123 (Rh123) exhibits, like domperidone, a low brain permeability since both substances are recognized by efflux transporters at the BBB. Transport studies investigating the impact of the polymer architecture in relation to the content of hydrophobic LMA revealed that random p(HPMA)-co-p(LMA) having 10mol% LMA is the most auspicious system. The copolymer significantly increased the permeability of Rh123 across the HBMEC monolayer whereas transcytosis of the polymer was very low. Further investigations on the mechanism of transport showed that integrity and barrier function of the BBB model were not harmed by the polymer. According to our results, p(HPMA)-co-p(LMA) copolymers are a promising delivery system for neurological therapeutics and their application might open alternative treatment strategies. Copyright © 2012 Elsevier B.V. All rights reserved.

Biodegradable star HPMA polymer-drug conjugates: biodegradability, distribution and anti-tumor efficacy

Czech Academy of Sciences Publication Activity Database

Etrych, Tomáš; Kovář, Lubomír; Strohalm, Jiří; Chytil, Petr; Říhová, Blanka; Ulbrich, Karel

2011-01-01

Roč. 154, č. 3 (2011), s. 241-248 ISSN 0168-3659 R&D Projects: GA AV ČR IAA400500806; GA AV ČR IAAX00500803; GA ČR GAP301/11/0325 Institutional research plan: CEZ:AV0Z40500505; CEZ:AV0Z50200510 Keywords : star polymer * HPMA copolymers * drug release Subject RIV: CD - Macromolecular Chemistry Impact factor: 5.732, year: 2011

Effective experimental tumor therapy with targeted polymer drug delivery systems based on HPMA copolymers.

Czech Academy of Sciences Publication Activity Database

Šírová, Milada; Horková, Veronika; Sivák, Ladislav; Etrych, Tomáš; Říhová, Blanka; Studenovský, Martin

SI (2016), s. 24-24 ISSN 0014-2980. [3rd Meeting of Middle – European Societies for Immunology and Allergology. 01.12.2016-03.12.2016, Budapest ] R&D Projects: GA ČR(CZ) GA14-12742S Institutional support: RVO:61388971 ; RVO:61389013 Keywords : Tumor therapy * polymer drug * HPMA copolymers Subject RIV: EE - Microbiology, Virology

Conjugated and Entrapped HPMA-PLA Nano-Polymeric Micelles Based Dual Delivery of First Line Anti TB Drugs: Improved and Safe Drug Delivery against Sensitive and Resistant Mycobacterium Tuberculosis.

Science.gov (United States)

Upadhyay, Seema; Khan, Iliyas; Gothwal, Avinash; Pachouri, Praveen K; Bhaskar, N; Gupta, Umesh D; Chauhan, Devendra S; Gupta, Umesh

2017-09-01

First line antiTB drugs have several physical and toxic manifestations which limit their applications. RIF is a hydrophobic drug and has low water solubility and INH is hepatotoxic. The main objective of the study was to synthesize, characterize HPMA-PLA co-polymeric micelles for the effective dual delivery of INH and RIF. HPMA-PLA co-polymer and HPMA-PLA-INH (HPI) conjugates were synthesized and characterized by FT-IR and 1 H-NMR spectroscopy. Later on RIF loaded HPMA-PLA-INH co-polymeric micelles (PMRI) were formulated and characterized for size, zeta potential and surface morphology (SEM, TEM) as well as critical micellar concentration. The safety was assessed through RBC's interaction study. The prepared PMRI were evaluated through MABA assay against sensitive and resistant strains of M. Tuberculosis. Size, zeta and entrapment efficiency for RIF loaded HPMA-PLA-INH polymeric micelles (PMRI) was 87.64 ± 1.98 nm, -19 ± 1.93 mV and 97.2 ± 1.56%, respectively. In vitro release followed controlled and sustained delivery pattern. Sustained release was also supported by release kinetics. Haemolytic toxicity of HPI and PMRI was 8.57 and 7.05% (p PLA polymeric micelles (PMRI) were more effective against sensitive and resistant M tuberculosis. The developed approach can lead to improved patient compliance and reduced dosing in future, offering improved treatment of tuberculosis.

HPMA copolymer-based polymer conjugates for the delivery and controlled release of retinoids

Czech Academy of Sciences Publication Activity Database

Lidický, Ondřej; Šírová, Milada; Etrych, Tomáš

2016-01-01

Roč. 65, Suppl. 2 (2016), S233-S241 ISSN 0862-8408 R&D Projects: GA MŠk(CZ) LQ1604 Institutional support: RVO:61389013 ; RVO:61388971 Keywords : polymer conjugate * retinoid * HPMA Subject RIV: EB - Genetics ; Molecular Biology; EA - Cell Biology (MBU-M) Impact factor: 1.461, year: 2016 http://www.biomed.cas.cz/physiolres/pdf/65%20Suppl%202/65_S233.pdf

Effect of radiotherapy and hyperthermia on the tumor accumulation of HPMA copolymer-based drug delivery systems

Czech Academy of Sciences Publication Activity Database

Lammers, T.; Peschke, P.; Kühnlein, R.; Šubr, Vladimír; Ulbrich, Karel; Debus, J.; Huber, P. E.; Hennink, W. E.; Storm, G.

2007-01-01

Roč. 117, č. 3 (2007), s. 333-341 ISSN 0168-3659 R&D Projects: GA ČR GA204/05/2255 Institutional research plan: CEZ:AV0Z40500505 Keywords : HPMA * drug delivery * tumor targeting Subject RIV: CD - Macromolecular Chemistry Impact factor: 4.756, year: 2007

Biodegradable micellar HPMA-based polymer-drug conjugates with betulinic acid for passive tumor targeting

Czech Academy of Sciences Publication Activity Database

Lomkova, Ekaterina A.; Chytil, Petr; Janoušková, Olga; Mueller, T.; Lucas, H.; Filippov, Sergey K.; Trhlíková, Olga; Aleshunin, P. A.; Skorik, Y. A.; Ulbrich, Karel; Etrych, Tomáš

2016-01-01

Roč. 17, č. 11 (2016), s. 3493-3507 ISSN 1525-7797 R&D Projects: GA MŠk(CZ) LO1507; GA MŠk(CZ) LQ1604; GA ČR(CZ) GA15-02986S Institutional support: RVO:61389013 Keywords : N-(2-hydroxypropyl)methacrylamide (HPMA) * polymeric micelles * drug delivery Subject RIV: CD - Macromolecular Chemistry Impact factor: 5.246, year: 2016

72/74As-labeling of HPMA based polymers for long-term in vivo PET imaging

DEFF Research Database (Denmark)

Herth, Matthias M; Barz, Matthias; Jahn, Markus

2010-01-01

In the context of molecular imaging, various polymers based on the clinically approved N-(2-hydroxypropyl)-methacrylamide (HPMA) have been radio-labeled using longer-living positron emitters 72As t1/2=26 h or 74As t1/2=17.8 d. This approach may lead to non-invasive determination of the long...

Traceless bioresponsive shielding of adenovirus hexon with HPMA copolymers maintains transduction capacity in vitro and in vivo

Czech Academy of Sciences Publication Activity Database

Prill, J.-M.; Šubr, Vladimír; Pasquarelli, N.; Engler, T.; Hoffmeister, A.; Kochanek, S.; Ulbrich, Karel; Kreppel, F.

2014-01-01

Roč. 9, č. 1 (2014), e82716_1-e82716_15 E-ISSN 1932-6203 Grant - others:AV ČR(CZ) AP0802 Program:Akademická prémie - Praemium Academiae Institutional support: RVO:61389013 Keywords : adenovirus * HPMA copolymers * bioresponsive shielding Subject RIV: CD - Macromolecular Chemistry Impact factor: 3.234, year: 2014

HPMA-based drug delivery system and its interactions of human serum albumin: SAXS, ITC, and NMR study

Czech Academy of Sciences Publication Activity Database

Filippov, Sergey K.; Kaberov, Leonid; Zhang, X.; Niebuur, B.-J.; Chytil, Petr; Etrych, Tomáš; Wieland, F.; Velychkivska, Nadiia; Starovoytova, Larisa; Svergun, D.; Papadakis, C.

2017-01-01

Roč. 254, 20 August (2017), s. 455 ISSN 0065-7727. [ACS National Meeting & Exposition /254./. 20.08.2017-24.08.2017, Washington] R&D Projects: GA ČR(CZ) GC15-10527J Institutional support: RVO:61389013 Keywords : HPMA * human serum albumin * SAXS Subject RIV: CF - Physical ; Theoretical Chemistry OBOR OECD: Physical chemistry

In Vitro and In Vivo Effect of HPMA Copolymer-bound Doxorubicin Targeted to Transferrin Receptor of B-cell Lymphoma 38C13

Czech Academy of Sciences Publication Activity Database

Kovář, Marek; Strohalm, Jiří; Ulbrich, Karel; Říhová, Blanka

2002-01-01

Roč. 10, č. 1 (2002), s. 23-30 ISSN 1061-186X Institutional research plan: CEZ:AV0Z5020903 Keywords : targeting * transferrin * hpma copolymer Subject RIV: EC - Immunology Impact factor: 2.045, year: 2002

Radioactive labeling of defined HPMA-based polymeric structures using [18F]FETos for in vivo imaging by positron emission tomography

DEFF Research Database (Denmark)

Herth, Matthias Manfred; Barz, Matthias; Moderegger, Dorothea

2009-01-01

and tyramine (3%) to form (18)F-labelable HPMA-polymer precursors. The labeling procedure of the phenolic tyramine moieties via the secondary labeling synthon 2-[(18)F]fluoroethyl-1-tosylate ([(18)F]FETos) provided radiochemical fluoroalkylation yields of ∼80% for block copolymers and >50% for random polymer...

Treatment with HPMA copolymer-based doxorubicin conjugate containing human immunoglobulin induces long-lasting systemic anti-tumour immunity in mice

Czech Academy of Sciences Publication Activity Database

Šírová, Milada; Strohalm, Jiří; Šubr, Vladimír; Plocová, Daniela; Rossmann, Pavel; Mrkvan, Tomáš; Ulbrich, Karel; Říhová, Blanka

2007-01-01

Roč. 56, - (2007), s. 35-47 ISSN 0340-7004 R&D Projects: GA MŠk 1M0505; GA ČR GA305/05/2268 Institutional research plan: CEZ:AV0Z50200510; CEZ:AV0Z40500505 Keywords : targered tumour therapy * hpma * human immunoglobulin Subject RIV: EE - Microbiology, Virology Impact factor: 3.728, year: 2007

Structural and chemical aspects of HPMA copolymers as drug carriers.

Science.gov (United States)

Ulbrich, Karel; Subr, Vladimír

2010-02-17

Synthetic strategies and chemical and structural aspects of the synthesis of HPMA copolymer conjugates with various drugs and other biologically active molecules are described and discussed in this chapter. The discussion is held from the viewpoint of design and structure of the polymer backbone and biodegradable spacer between a polymer and drug, structure and methods of attachment of the employed drugs to the carrier and structure and methods of conjugation with targeting moieties. Physicochemical properties of the water-soluble polymer-drug conjugates and polymer micelles including mechanisms of drug release are also discussed. Detailed description of biological behavior of the polymer-drug conjugates as well as application of the copolymers for surface modification and targeting of gene delivery vectors are not included, they are presented and discussed in separate chapters of this issue. Copyright 2009 Elsevier B.V. All rights reserved.

HPMA copolymer conjugate with pirarubicin: In vitro and ex vivo stability and drug release study

Czech Academy of Sciences Publication Activity Database

Islam, W.; Fang, J.; Etrych, Tomáš; Chytil, Petr; Ulbrich, Karel; Sakoguchi, A.; Kusakabe, K.; Maeda, H.

2018-01-01

Roč. 536, č. 1 (2018), s. 108-115 ISSN 0378-5173 R&D Projects: GA ČR(CZ) GA15-02986S; GA MŠk(CZ) LQ1604; GA MŠk(CZ) ED1.1.00/02.0109 Grant - others:AV ČR(CZ) JSPS-16-05 Program:Bilaterální spolupráce Institutional support: RVO:61389013 Keywords : EPR effect * HPMA copolymer * tumor-targeting Subject RIV: FR - Pharmacology ; Medidal Chemistry OBOR OECD: Pharmacology and pharmacy Impact factor: 3.649, year: 2016

Comparison between linear and star-like HPMA conjugated pirarubicin (THP) in pharmacokinetics and antitumor activity in tumor bearing mice

Czech Academy of Sciences Publication Activity Database

Nakamura, H.; Koziolová, Eva; Etrych, Tomáš; Chytil, Petr; Fang, J.; Ulbrich, Karel; Maeda, H.

2015-01-01

Roč. 90, February (2015), s. 90-96 ISSN 0939-6411 R&D Projects: GA ČR(CZ) GCP207/12/J030; GA ČR GPP207/11/P551; GA MŠk(CZ) ED1.1.00/02.0109 Institutional support: RVO:61389013 Keywords : HPMA polymer conjugate * pirarubicin (THP) * acid-cleavable linkage Subject RIV: CD - Macromolecular Chemistry Impact factor: 3.975, year: 2015

HPMA copolymer-conjugated pirarubicin in multimodal treatment of a patient with stage IV prostate cancer and extensive lung and bone metastases

Czech Academy of Sciences Publication Activity Database

Dozono, H.; Yanazume, S.; Nakamura, H.; Etrych, Tomáš; Chytil, Petr; Ulbrich, Karel; Fang, J.; Arimura, T.; Douchi, T.; Kobayashi, H.; Ikoma, M.; Maeda, H.

2016-01-01

Roč. 11, č. 1 (2016), s. 101-106 ISSN 1776-2596 R&D Projects: GA ČR(CZ) GCP207/12/J030; GA MŠk(CZ) EE2.3.30.0029 Institutional support: RVO:61389013 Keywords : HPMA copolymer * piraraubicin * multimodal treatment Subject RIV: CD - Macromolecular Chemistry Impact factor: 3.438, year: 2016

Synergistic effect of EMF-BEMER-type pulsed weak electromagnetic field and HPMA-bound doxorubicin on mouse EL4 T-cell lymphoma

Czech Academy of Sciences Publication Activity Database

Říhová, Blanka; Etrych, Tomáš; Šírová, Milada; Tomala, Jakub; Ulbrich, Karel; Kovář, Marek

2011-01-01

Roč. 19, č. 10 (2011), s. 890-899 ISSN 1061-186X R&D Projects: GA AV ČR IAA400200702 Institutional research plan: CEZ:AV0Z50200510; CEZ:AV0Z40500505 Keywords : EL4 T-cell lymphoma * athymic mice * DOX(HYD)-HPMA Subject RIV: EC - Immunology Impact factor: 2.696, year: 2011

The structure-dependent toxicity, pharmacokinetics and anti-tumour activity of HPMA copolymer conjugates in the treatment of solid tumours and leukaemia

Czech Academy of Sciences Publication Activity Database

Tomalová, Barbora; Šírová, Milada; Rossmann, Pavel; Pola, Robert; Strohalm, Jiří; Chytil, Petr; Černý, Viktor; Tomala, Jakub; Kabešová, Martina; Říhová, Blanka; Ulbrich, Karel; Etrych, Tomáš; Kovář, Marek

2016-01-01

Roč. 223, 10 February (2016), s. 1-10 ISSN 0168-3659 R&D Projects: GA ČR(CZ) GAP301/11/0325; GA MŠk(CZ) ED1.1.00/02.0109 Institutional support: RVO:61388971 ; RVO:61389013 Keywords : HPMA * Doxorubicin * Structure Subject RIV: EE - Microbiology, Virology; CD - Macromolecular Chemistry (UMCH-V) Impact factor: 7.786, year: 2016

1,3-Butadiene exposure and metabolism among Japanese American, Native Hawaiian, and White smokers.

Science.gov (United States)

Park, Sungshim Lani; Kotapati, Srikanth; Wilkens, Lynne R; Tiirikainen, Maarit; Murphy, Sharon E; Tretyakova, Natalia; Le Marchand, Loïc

2014-11-01

We hypothesize that the differences in lung cancer risk in Native Hawaiians, whites, and Japanese Americans may, in part, be due to variation in the metabolism of 1,3-butadiene, one of the most abundant carcinogens in cigarette smoke. We measured two biomarkers of 1,3-butadiene exposure, monohydroxybutyl mercapturic acid (MHBMA) and dihydroxybutyl mercapturic acid (DHBMA), in overnight urine samples among 584 Native Hawaiians, Japanese Americans, and white smokers in Hawaii. These values were normalized to creatinine levels. Ethnic-specific geometric means were compared adjusting for age at urine collection, sex, body mass index, and nicotine equivalents (a marker of total nicotine uptake). We found that mean urinary MHBMA differed by race/ethnicity (P = 0.0002). The values were highest in whites and lowest in Japanese Americans. This difference was only observed in individuals with the GSTT1-null genotype (P = 0.0001). No difference across race/ethnicity was found among those with at least one copy of the GSTT1 gene (P ≥ 0.72). Mean urinary DHBMA did not differ across racial/ethnic groups. The difference in urinary MHBMA excretion levels from cigarette smoking across three ethnic groups is, in part, explained by the GSTT1 genotype. Mean urinary MHBMA levels are higher in whites among GSTT1-null smokers. The overall higher excretion levels of MHBMA in whites and lower levels of MHBMA in Japanese Americans are consistent with the higher lung cancer risk in the former. However, the excretion levels of MHBMA in Native Hawaiians are not consistent with their disease risk and thus unlikely to explain their high risk of lung cancer. ©2014 American Association for Cancer Research.

HPMA copolymer conjugates of DOX and mitomycin C for combination therapy: physicochemical characterization, cytotoxic effects, combination index analysis, and anti-tumor efficacy

Czech Academy of Sciences Publication Activity Database

Kostková, Hana; Etrych, Tomáš; Říhová, Blanka; Kostka, Libor; Starovoytova, Larisa; Kovář, Marek; Ulbrich, Karel

2013-01-01

Roč. 13, č. 12 (2013), s. 1648-1660 ISSN 1616-5187 R&D Projects: GA ČR GAP301/11/0325; GA MŠk EE2.3.30.0029 Institutional support: RVO:61389013 ; RVO:61388971 Keywords : doxorubicin * HPMA copolymers * mitomycin C Subject RIV: CE - Biochemistry; FD - Oncology ; Hematology (MBU-M) Impact factor: 3.650, year: 2013

Synergistic effect of EMF-BEMER-type pulsed weak electromagnetic field and HPMA-bound doxorubicin on mouse EL4 T-cell lymphoma.

Science.gov (United States)

Říhová, Blanka; Etrych, Tomáš; Šírová, Milada; Tomala, Jakub; Ulbrich, Karel; Kovář, Marek

2011-12-01

We have investigated the effects of low-frequency pulsed electromagnetic field (LF-EMF) produced by BEMER device on experimental mouse T-cell lymphoma EL4 growing on conventional and/or athymic (nude) mice. Exposure to EMF-BEMER slowed down the growth of tumor mass and prolonged the survival of experimental animals. The effect was more pronounced in immuno-compromised nude mice compared to conventional ones. Acceleration of tumor growth was never observed. No measurable levels of Hsp 70 or increased levels of specific anti-EL4 antibodies were detected in the serum taken from experimental mice before and at different intervals during the experiment, i.e. before solid tumor appeared, at the time of its aggressive growth, and at the terminal stage of the disease. A significant synergizing antitumor effect was seen when EL4 tumor-bearing mice were simultaneously exposed to EMF-BEMER and treated with suboptimal dose of synthetic HPMA copolymer-based doxorubicin, DOX(HYD)-HPMA. Such a combination may be especially useful for heavily treated patients suffering from advanced tumor and requiring additional aggressive chemotherapy which, however, at that time could represent almost life-threatening way of medication.

Doxorubicin bound to a HPMA copolymer carrier through hydrazone bond is effective also in a cancer cell line with a limited content of lysosomes

Czech Academy of Sciences Publication Activity Database

Říhová, Blanka; Etrych, Tomáš; Pechar, Michal; Jelínková, Markéta; Šťastný, Marek; Hovorka, Ondřej; Kovář, Marek; Ulbrich, Karel

2001-01-01

Roč. 74, - (2001), s. 225-232 ISSN 0168-3659 R&D Projects: GA MZd NC5050; GA ČR GV307/96/K226 Institutional research plan: CEZ:AV0Z5020903 Keywords : HPMA copolymer carrier * proteolytically cleavable bond Subject RIV: EC - Immunology Impact factor: 2.626, year: 2001

Macromolecular HPMA-based nanoparticles with cholesterol for solid-tumor targeting: detailed study of the inner structure of a highly efficient drug delivery system

Czech Academy of Sciences Publication Activity Database

Filippov, Sergey K.; Chytil, Petr; Konarev, P. V.; Dyakonova, M.; Papadakis, C. M.; Zhigunov, Alexander; Pleštil, Josef; Štěpánek, Petr; Etrych, Tomáš; Ulbrich, Karel; Svergun, D. I.

2012-01-01

Roč. 13, č. 8 (2012), s. 2594-2604 ISSN 1525-7797 R&D Projects: GA MŠk ME09059; GA AV ČR IAAX00500803; GA ČR GAP108/12/0640 Institutional research plan: CEZ:AV0Z40500505 Institutional support: RVO:61389013 Keywords : HPMA * cholesterol * SAXS Subject RIV: CD - Macromolecular Chemistry Impact factor: 5.371, year: 2012

Acid-labile pHPMA modification of four-arm oligoaminoamide pDNA polyplexes balances shielding and gene transfer activity in vitro and in vivo

Czech Academy of Sciences Publication Activity Database

Beckert, L.; Kostka, Libor; Kessel, E.; Krhac Levacic, A.; Kostková, Hana; Etrych, Tomáš; Lächelt, U.; Wagner, E.

2016-01-01

Roč. 105, August (2016), s. 85-96 ISSN 0939-6411 R&D Projects: GA MŠk(CZ) LO1507; GA MŠk(CZ) LQ1604; GA MŠk(CZ) ED1.1.00/02.0109 Institutional support: RVO:61389013 Keywords : pH-sensitive shielding * pHPMA * AzMMMan Subject RIV: CD - Macromolecular Chemistry Impact factor: 4.159, year: 2016

Synthesis and properties of star HPMA copolymer nanocarriers synthesised by RAFT polymerisation designed for selective anticancer drug delivery and imaging

Czech Academy of Sciences Publication Activity Database

Chytil, Petr; Koziolová, Eva; Janoušková, Olga; Kostka, Libor; Ulbrich, Karel; Etrych, Tomáš

2015-01-01

Roč. 15, č. 6 (2015), s. 839-850 ISSN 1616-5187 R&D Projects: GA ČR GPP207/11/P551; GA ČR(CZ) GCP207/12/J030; GA MŠk(CZ) EE2.3.30.0029; GA MŠk(CZ) ED1.1.00/02.0109 Institutional support: RVO:61389013 Keywords : drug delivery systems * HPMA copolymers * pH-controlled release Subject RIV: CD - Macromolecular Chemistry Impact factor: 3.680, year: 2015

Pronounced cellular uptake of pirarubicin versus that of other anthracyclines: comparison of HPMA copolymer conjugates of pirarubicin and doxorubicin

Czech Academy of Sciences Publication Activity Database

Nakamura, H.; Koziolová, Eva; Chytil, Petr; Tsukigawa, K.; Fang, J.; Haratake, M.; Ulbrich, Karel; Etrych, Tomáš; Maeda, H.

2016-01-01

Roč. 13, č. 12 (2016), s. 4106-4115 ISSN 1543-8384 R&D Projects: GA ČR(CZ) GA15-02986S; GA MŠk(CZ) LO1507; GA MŠk(CZ) ED1.1.00/02.0109 Grant - others:AV ČR,Japan Society for the Promotion of Science(CZ) JSPS-16-05 Program:Bilaterální spolupráce Institutional support: RVO:61389013 Keywords : HPMA polymer conjugate * pirarubicin (THP) * doxorubicin (DOX) Subject RIV: CD - Macromolecular Chemistry Impact factor: 4.440, year: 2016

Micelle-forming HPMA copolymer conjugates of ritonavir bound via a pH-sensitive spacer with improved cellular uptake designed for enhanced tumor accumulation

Czech Academy of Sciences Publication Activity Database

Koziolová, Eva; Machová, Daniela; Pola, Robert; Janoušková, Olga; Chytil, Petr; Laga, Richard; Filippov, Sergey K.; Šubr, Vladimír; Etrych, Tomáš; Pechar, Michal

2016-01-01

Roč. 4, č. 47 (2016), s. 7620-7629 ISSN 2050-750X R&D Projects: GA MŠk(CZ) LO1507; GA ČR(CZ) GAP301/12/1254; GA ČR(CZ) GA15-02986S; GA ČR(CZ) GA16-17207S Institutional support: RVO:61389013 Keywords : HPMA copolymer * tumor * micelle Subject RIV: CD - Macromolecular Chemistry Impact factor: 4.543, year: 2016

High throughput HPLC-ESI(-)-MS/MS methodology for mercapturic acid metabolites of 1,3-butadiene: Biomarkers of exposure and bioactivation.

Science.gov (United States)

Kotapati, Srikanth; Esades, Amanda; Matter, Brock; Le, Chap; Tretyakova, Natalia

2015-11-05

1,3-Butadiene (BD) is an important industrial and environmental carcinogen present in cigarette smoke, automobile exhaust, and urban air. The major urinary metabolites of BD in humans are 2-(N-acetyl-L-cystein-S-yl)-1-hydroxybut-3-ene/1-(N-acetyl-L-cystein-S-yl)-2-hydroxybut-3-ene (MHBMA), 4-(N-acetyl-L-cystein-S-yl)-1,2-dihydroxybutane (DHBMA), and 4-(N-acetyl-L-cystein-S-yl)-1,2,3-trihydroxybutyl mercapturic acid (THBMA), which are formed from the electrophilic metabolites of BD, 3,4-epoxy-1-butene (EB), hydroxymethyl vinyl ketone (HMVK), and 3,4-epoxy-1,2-diol (EBD), respectively. In the present work, a sensitive high-throughput HPLC-ESI(-)-MS/MS method was developed for simultaneous quantification of MHBMA and DHBMA in small volumes of human urine (200 μl). The method employs a 96 well Oasis HLB SPE enrichment step, followed by isotope dilution HPLC-ESI(-)-MS/MS analysis on a triple quadrupole mass spectrometer. The validated method was used to quantify MHBMA and DHBMA in urine of workers from a BD monomer and styrene-butadiene rubber production facility (40 controls and 32 occupationally exposed to BD). Urinary THBMA concentrations were also determined in the same samples. The concentrations of all three BD-mercapturic acids and the metabolic ratio (MHBMA/(MHBMA+DHBMA+THBMA)) were significantly higher in the occupationally exposed group as compared to controls and correlated with BD exposure, with each other, and with BD-hemoglobin biomarkers. This improved high throughput methodology for MHBMA and DHBMA will be useful for future epidemiological studies in smokers and occupationally exposed workers. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Genetic Determinants of 1,3-Butadiene Metabolism and Detoxification in Three Populations of Smokers with Different Risks of Lung Cancer.

Science.gov (United States)

Boldry, Emily J; Patel, Yesha M; Kotapati, Srikanth; Esades, Amanda; Park, Sungshim L; Tiirikainen, Maarit; Stram, Daniel O; Le Marchand, Loïc; Tretyakova, Natalia

2017-07-01

Background: 1,3-Butadiene (BD) is an important carcinogen in tobacco smoke that undergoes metabolic activation to DNA-reactive epoxides. These species can be detoxified via glutathione conjugation and excreted in urine as the corresponding N-acetylcysteine conjugates. We hypothesize that single nucleotide polymorphisms (SNPs) in BD-metabolizing genes may change the balance of BD bioactivation and detoxification in White, Japanese American, and African American smokers, potentially contributing to ethnic differences in lung cancer risk. Methods: We measured the levels of BD metabolites, 1- and 2-( N -acetyl-L-cysteine-S-yl)-1-hydroxybut-3-ene (MHBMA) and N -acetyl- S -(3,4-dihydroxybutyl)-L-cysteine (DHBMA), in urine samples from a total of 1,072 White, Japanese American, and African American smokers and adjusted these values for body mass index, age, batch, and total nicotine equivalents. We also conducted a genome-wide association study to identify genetic determinants of BD metabolism. Results: We found that mean urinary MHBMA concentrations differed significantly by ethnicity ( P = 4.0 × 10 -25 ). African Americans excreted the highest levels of MHBMA followed by Whites and Japanese Americans. MHBMA levels were affected by GSTT1 gene copy number ( P smokers. Impact: Our results show that the order of MHBMA levels among ethnic groups is consistent with their respective lung cancer risk and can be partially explained by GSTT1 genotype. Cancer Epidemiol Biomarkers Prev; 26(7); 1034-42. ©2017 AACR . ©2017 American Association for Cancer Research.

Influence of molar mass, dispersity, and type and location of hydrophobic side chain moieties on the critical micellar concentration and stability of amphiphilic HPMA-based polymer drug carriers

Czech Academy of Sciences Publication Activity Database

Filippov, Sergey K.; Vishnevetskaya, N. S.; Niebuur, B.-J.; Koziolová, Eva; Lomkova, Ekaterina A.; Chytil, Petr; Etrych, Tomáš; Papadakis, C. M.

2017-01-01

Roč. 295, č. 8 (2017), s. 1313-1325 ISSN 0303-402X R&D Projects: GA MZd(CZ) NV16-28600A; GA ČR(CZ) GC15-10527J Institutional support: RVO:61389013 Keywords : drug delivery * HPMA copolymers * fluorescence correlation spectroscopy Subject RIV: CD - Macromolecular Chemistry OBOR OECD: Polymer science Impact factor: 1.723, year: 2016

HPMA copolymer conjugates with reduced anti-CD20 antibody for cell-specific drug targeting. I. Synthesis and in vitro evaluation of binding efficacy and cytostatic activity

Czech Academy of Sciences Publication Activity Database

Etrych, Tomáš; Strohalm, Jiří; Kovář, Lubomír; Kabešová, Martina; Říhová, Blanka; Ulbrich, Karel

2009-01-01

Roč. 140, č. 1 (2009), s. 18-26 ISSN 0168-3659 R&D Projects: GA MŠk 1M0505; GA AV ČR IAAX00500803 Institutional research plan: CEZ:AV0Z40500505; CEZ:AV0Z50200510 Keywords : HPMA copolymers * drug delivery systems * doxorubicin * monoclonal anti-CD20 antibody * drug targeting Subject RIV: CD - Macromolecular Chemistry Impact factor: 5.949, year: 2009

The comparison of in vivo properties of water-soluble HPMA-based polymer conjugates with doxorubicin prepared by controlled RAFT or free radical polymerization

Czech Academy of Sciences Publication Activity Database

Chytil, Petr; Šírová, Milada; Koziolová, Eva; Ulbrich, Karel; Říhová, Blanka; Etrych, Tomáš

2015-01-01

Roč. 64, Suppl. 1 (2015), S41-S49 ISSN 0862-8408 R&D Projects: GA MŠk(CZ) EE2.3.30.0029; GA MŠk(CZ) ED1.1.00/02.0109 Institutional support: RVO:61389013 ; RVO:61388971 Keywords : HPMA copolymers * RAFT polymerization * drug delivery system Subject RIV: EB - Genetics ; Molecular Biology; CE - Biochemistry (MBU-M) Impact factor: 1.643, year: 2015 http://www.biomed.cas.cz/physiolres/pdf/64%20Suppl%201/64_S41.pdf

Dual fluorescent HPMA copolymers for passive tumor targeting with pH-sensitive drug release: synthesis and characterization of distribution and tumor accumulation in mice by noninvasive multispectral optical imaging

Czech Academy of Sciences Publication Activity Database

Hoffmann, S.; Vystrčilová, Lucie; Ulbrich, Karel; Etrych, Tomáš; Caysa, H.; Mueller, T.; Mäder, K.

2012-01-01

Roč. 13, č. 3 (2012), s. 652-663 ISSN 1525-7797 R&D Projects: GA AV ČR IAAX00500803; GA ČR GAP301/11/0325 Institutional research plan: CEZ:AV0Z40500505 Keywords : fluorescence dyes * star -like HPMA polymer carriers * diagnostics of tumors Subject RIV: EC - Immunology Impact factor: 5.371, year: 2012

The structure of polymer carriers controls the efficacy of the experimental combination treatment of tumors with HPMA copolymer conjugates carrying doxorubicin and docetaxel

Czech Academy of Sciences Publication Activity Database

Šírová, Milada; Strohalm, Jiří; Chytil, Petr; Lidický, Ondřej; Tomala, Jakub; Říhová, Blanka; Etrych, Tomáš

2017-01-01

Roč. 246, JAN 28 (2017), s. 1-11 ISSN 0168-3659 R&D Projects: GA ČR(CZ) GA14-12742S; GA ČR(CZ) GA15-02986S; GA MŠk(CZ) LQ1604; GA MŠk(CZ) ED1.1.00/02.0109; GA MZd(CZ) NV16-28600A; GA ČR(CZ) GAP301/12/1254 Institutional support: RVO:61388971 ; RVO:61389013 Keywords : Drug delivery * HPMA * Doxorubicin Subject RIV: EC - Immunology; CD - Macromolecular Chemistry (UMCH-V) OBOR OECD: Immunology; Polymer science (UMCH-V) Impact factor: 7.786, year: 2016

HPMA based macromolecular therapeutics: Internalization, intracellular pathway and cell death depend on the character of covalent bond between the drug and the peptidic spacer and also on spacer composition

Czech Academy of Sciences Publication Activity Database

Hovorka, Ondřej; Etrych, Tomáš; Šubr, Vladimír; Strohalm, Jiří; Ulbrich, Karel; Říhová, Blanka

2006-01-01

Roč. 14, č. 6 (2006), s. 391-403 ISSN 1061-186X R&D Projects: GA ČR GP305/04/P004; GA ČR GA305/05/2268; GA MŠk 1M0505 Institutional research plan: CEZ:AV0Z50200510; CEZ:AV0Z40500505 Keywords : hpma * intracellular transport * polymeric conjugates Subject RIV: EE - Microbiology, Virology Impact factor: 1.699, year: 2006

Studies on guanidinated N-3-aminopropyl methacrylamide-N-2-hydroxypropyl methacrylamide co-polymers as gene delivery carrier.

Science.gov (United States)

Qin, Zhu; Liu, Wei; Guo, Liang; Li, Xinsong

2012-01-01

Guanidinated N-3-aminopropyl methacrylamide (APMA)-N-2-hydroxypropyl methacrylamide (HPMA) co-polymers were prepared and evaluated to develop novel non-viral gene transfection carriers. The co-polymers were synthesized via radical co-polymerization of APMA and HPMA followed by total guanidination of amino groups, which employed guanidinated APMA (GPMA) for increasing cell-penetrating and HPMA as the positive shielding content. The molecular weight of guanidinated APMA-HPMA co-polymers (GPMA-HPMA) was determined by static light scattering. Furthermore, cytotoxicity and transfection experiments of GPMA-HPMA/pDNA complexes were conducted. A significant decrease of their parent cytotoxicity and an efficient transfection at relative low charge ratios were observed. The cellular distribution of most GPMA-HPMA/pDNA complexes was partially localized in the nucleus, as indicated by confocal laser scanning microscopy. The guanidination strategy employed may lead to non-viral gene delivery carriers that combine satisfactory transfection efficiency and cytotoxicity, which contribute to their cell-penetrating ability.

177Lu-labeled HPMA copolymers utilizing cathepsin B and S cleavable linkers: Synthesis, characterization and preliminary in vivo investigation in a pancreatic cancer model

International Nuclear Information System (INIS)

Ogbomo, Sunny M.; Shi, Wen; Wagh, Nilesh K.; Zhou, Zhengyuan; Brusnahan, Susan K.; Garrison, Jered C.

2013-01-01

Introduction: A major barrier to the advancement of therapeutic nanomedicines has been the non-target toxicity caused by the accumulation of the drug delivery systems in organs associated with the reticuloendothelial system, particularly the liver and spleen. Herein, we report the development of peptide based metabolically active linkers (MALs) that are enzymatically cleaved by cysteine cathepsin B and S, two proteases highly expressed in the liver and spleen. The overall goal of this approach is to utilize the MALs to lower the non-target retention and toxicity of radiolabeled drug delivery systems, thus resulting in higher diagnostic and radiotherapeutic efficacy. Methods: In this study three MALs (MAL0, MAL1 and MAL2) were investigated. MAL1 and MAL2 are composed of known substrates of cathepsin B and S, respectively, while MAL0 is a non-cleavable control. Both MAL1 and MAL2 were shown to undergo enzymatic cleavage with the appropriate cathepsin protease. Subsequent to conjugation to the HPMA copolymer and radiolabeling with 177 Lu, the peptide–polymer conjugates were renamed 177 Lu-metabolically active copolymers ( 177 Lu-MACs) with the corresponding designations: 177 Lu-MAC0, 177 Lu-MAC1 and 177 Lu-MAC2. Results: In vivo evaluation of the 177 Lu-MACs was performed in an HPAC human pancreatic cancer xenograft mouse model. 177 Lu-MAC1 and 177 Lu-MAC2 demonstrated 3.1 and 2.1 fold lower liver retention, respectively, compared to control ( 177 Lu-MAC0) at 72 h post-injection. With regard to spleen retention, 177 Lu-MAC1 and 177 Lu-MAC2 each exhibited a nearly fourfold lower retention, relative to control, at the 72 h time point. However, the tumor accumulation of the 177 Lu-MAC0 was two to three times greater than 177 Lu-MAC1 and 177 Lu-MAC2 at the same time point. The MAL approach demonstrated the capability of substantially reducing the non-target retention of the 177 Lu-labeled HPMA copolymers. Conclusions: While further studies are needed to optimize the

Direct Cytoplasmic Delivery and Nuclear Targeting Delivery of HPMA-MT Conjugates in a Microtubules Dependent Fashion.

Science.gov (United States)

Zhong, Jiaju; Zhu, Xi; Luo, Kui; Li, Lian; Tang, Manlin; Liu, Yanxi; Zhou, Zhou; Huang, Yuan

2016-09-06

As the hearts of tumor cells, the nucleus is the ultimate target of many chemotherapeutic agents and genes. However, nuclear drug delivery is always hampered by multiple intracellular obstacles, such as low efficiency of lysosome escape and insufficient nuclear trafficking. Herein, an N-(2-hydroxypropyl) methacrylamide (HPMA) polymer-based drug delivery system was designed, which could achieve direct cytoplasmic delivery by a nonendocytic pathway and transport into the nucleus in a microtubules dependent fashion. A special targeting peptide (MT), derived from an endogenic parathyroid hormone-related protein, was conjugated to the polymer backbone, which could accumulate into the nucleus a by microtubule-mediated pathway. The in vitro studies found that low temperature and NaN3 could not influence the cell internalization of the conjugates. Besides, no obvious overlay of the conjugates with lysosome demonstrated that the polymer conjugates could enter the tumor cell cytoplasm by a nonendocytic pathway, thus avoiding the drug degradation in the lysosome. Furthermore, after suppression of the microtubule dynamics with microtubule stabilizing docetaxel (DTX) and destabilizing nocodazole (Noc), the nuclear accumulation of polymeric conjugates was significantly inhibited. Living cells fluorescence recovery after photobleaching study found that the nuclear import rate of conjugates was 2-fold faster compared with the DTX and Noc treated groups. These results demonstrated that the conjugates transported into the nucleus in a microtubules dependent way. Therefore, in addition to direct cytoplasmic delivery, our peptide conjugated polymeric platform could simultaneously mediate nuclear drug accumulation, which may open a new path for further intracellular genes/peptides delivery.

Synthesis and Properties of Star HPMA Copolymer Nanocarriers Synthesised by RAFT Polymerisation Designed for Selective Anticancer Drug Delivery and Imaging.

Science.gov (United States)

Chytil, Petr; Koziolová, Eva; Janoušková, Olga; Kostka, Libor; Ulbrich, Karel; Etrych, Tomáš

2015-06-01

High-molecular-weight star polymer drug nanocarriers intended for the treatment and/or visualisation of solid tumours were synthesised, and their physico-chemical and preliminary in vitro biological properties were determined. The water-soluble star polymer carriers were prepared by the grafting of poly(amido amine) (PAMAM) dendrimers by hetero-telechelic N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers, synthesised by the controlled radical Reversible Addition Fragmentation chain Transfer (RAFT) polymerisation. The well-defined star copolymers with Mw values ranging from 2 · 10(5) to 6 · 10(5) showing a low dispersity (approximately 1.2) were prepared in a high yield. A model anticancer drug, doxorubicin, was bound to the star polymer through a hydrazone bond, enabling the pH-controlled drug release in the target tumour tissue. The activated polymer arm ends of the star copolymer carrier enable a one-point attachment for the targeting ligands and/or a labelling moiety. In this study, the model TAMRA fluorescent dye was used to prove the feasibility of the polymer carrier visualisation by optical imaging in vitro. The tailor-made structure of the star polymer carriers should facilitate the synthesis of targeted polymer-drug conjugates, even polymer theranostics, for simultaneous tumour drug delivery and imaging. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Preparation and properties of new cross-linked polyurethane acrylate electrolytes for lithium batteries

Energy Technology Data Exchange (ETDEWEB)

Santhosh, P.; Vasudevan, T.; Gopalan, A. [Department of Industrial Chemistry, Alagappa University, Karaikudi-630 003 (India); Lee, Kwang-Pill [Department of Chemistry Education, Kyungpook National University, Daegu 702-701 (Korea, Republic of)

2006-09-29

A cross-linked polyurethane acrylate (PUA) is synthesized by end-capping a hexamethylene diisocyanate, hexamethylene diisocyanate/poly(ethylene glycol)-based prepolymer with hydroxy butyl methacrylate (HBMA). Significant interactions of lithium ions with the soft and hard segments of the host polymer are observed for the PUA complexed with lithium perchlorate (LiClO{sub 4}) by means of differential scanning calorimetry (DSC), and Fourier transform infra-red (FT-IR) spectroscopy measurements. The DSC results indicate the formation of transient cross-links with the ether oxygen of the soft segment and mixing of soft and hard phases induced by the Li{sup +} ions. The results of FT-IR spectroscopy and thermogravimetric analysis measurements support the formation of different types of complexes by interaction of Li{sup +} ions with different coordination sites of PUA. No detectable interactions are found between Li{sup +} ions and groups in HBMA. In addition, PUA follows the Arrhenius relationship for ion transport. Predominant formation of contact ion-pairs of LiClO{sub 4} is observed through a.c. conductivity and DSC measurements. The lithium stripping-plating process is reversible and this implies better electrochemical stability over the working voltage range. Also, the PUA electrolyte shows better compatibility with lithium metal as inferred from impedance measurements and has a good cationic transference number that is suitable for the material to be used as a solid polymer electrolyte. Addition of HBMA into the PU matrix improves the tensile strength of the cross-linked PUA. Swelling measurements of PUA with plasticizer indicate better dimensional stability. A cell is constructed with PUA as the electrolyte and its performance is evaluated. (author)

HPMA-based block copolymers promote differential drug delivery kinetics for hydrophobic and amphiphilic molecules.

Science.gov (United States)

Tomcin, Stephanie; Kelsch, Annette; Staff, Roland H; Landfester, Katharina; Zentel, Rudolf; Mailänder, Volker

2016-04-15

We describe a method how polymeric nanoparticles stabilized with (2-hydroxypropyl)methacrylamide (HPMA)-based block copolymers are used as drug delivery systems for a fast release of hydrophobic and a controlled release of an amphiphilic molecule. The versatile method of the miniemulsion solvent-evaporation technique was used to prepare polystyrene (PS) as well as poly-d/l-lactide (PDLLA) nanoparticles. Covalently bound or physically adsorbed fluorescent dyes labeled the particles' core and their block copolymer corona. Confocal laser scanning microscopy (CLSM) in combination with flow cytometry measurements were applied to demonstrate the burst release of a fluorescent hydrophobic drug model without the necessity of nanoparticle uptake. In addition, CLSM studies and quantitative calculations using the image processing program Volocity® show the intracellular detachment of the amphiphilic block copolymer from the particles' core after uptake. Our findings offer the possibility to combine the advantages of a fast release for hydrophobic and a controlled release for an amphiphilic molecule therefore pointing to the possibility to a 'multi-step and multi-site' targeting by one nanocarrier. We describe thoroughly how different components of a nanocarrier end up in cells. This enables different cargos of a nanocarrier having a consecutive release and delivery of distinct components. Most interestingly we demonstrate individual kinetics of distinct components of such a system: first the release of a fluorescent hydrophobic drug model at contact with the cell membrane without the necessity of nanoparticle uptake. Secondly, the intracellular detachment of the amphiphilic block copolymer from the particles' core after uptake occurs. This offers the possibility to combine the advantages of a fast release for a hydrophobic substance at the time of interaction of the nanoparticle with the cell surface and a controlled release for an amphiphilic molecule later on therefore

Determination of 3-hydroxypropylmercapturic acid in urine by three column-switching high-performance liquid chromatography with electrochemical detection using a diamond electrode.

Science.gov (United States)

Higashi, Kyohei; Shibasaki, Mana; Kuni, Kyoshiro; Uemura, Takeshi; Waragai, Masaaki; Uemura, Kenichi; Igarashi, Kazuei; Toida, Toshihiko

2017-09-29

A three column-switching high-performance liquid chromatography (HPLC) using an electrochemical detector (ECD) equipped with a diamond electrode was established to determine 3-hydroxypropylmercapturic acid (3-HPMA) in urine. An extracted urine sample was consecutively fractionated using a strong anion-exchange column (first column) and a C8 column (second column) via a switching valve before application on an Octa Decyl Silyl (ODS) column (third column), followed by ECD analysis. The% recovery of 3-HPMA standard throughout the three-column process and limit of detection (LOD) were 94±1% and 0.1pmol, respectively. A solid phase extraction step is required for the sensitive analysis of 3-HPMA in urine by column-switching HPLC-ECD despite a decreased% recovery (55%) of urine sample spiked with 100pmol of 3-HPMA. To test the utility of our column-switching HPLC-ECD method, 3-HPMA levels of 27 urine samples were determined, and the correlation between HPLC-ECD and LC-Electrospray ionization (ESI)-MS/MS method was examined. As a result, the median values of μmol 3-HPMA/g Creatinine (Cre) in urine obtained by column-switching HPLC-ECD and LC-MS/MS were 2.19±2.12μmol/g Cre and 2.13±3.38μmol/g Cre, respectively, and the calibration curve (y=1.5171x-1.007) exhibited good linearity within a defined range (r 2 =0.907). These results indicate that the combination of column-switching HPLC and ECD is a powerful tool for the specific, reliable detection of 3-HPMA in urine. Copyright © 2017 Elsevier B.V. All rights reserved.

High pressure phase behaviour of the binary mixture for the 2-hydroxyethyl methacrylate, 2-hydroxypropyl acrylate, and 2-hydroxypropyl methacrylate in supercritical carbon dioxide

International Nuclear Information System (INIS)

Byun, Hun-Soo; Choi, Min-Yong

2007-01-01

Experimental data of high pressure phase behaviour for binary mixtures of {carbon dioxide + 2-hydroxyethyl methacrylate (HEMA)}, {carbon dioxide + 2-hydroxypropyl acrylate (HPA)}, and {carbon dioxide + 2-hydroxypropyl methacrylate (HPMA)} were determined using a static type with the variable-volume cell at temperatures from (313.2 to 393.2) K and pressures up to 27.10 MPa. Among these binary experimental data, the bubble-point data were correlated with the Peng-Robinson equation of state using a van der Waals one-fluid mixing rule containing two interaction parameters (k ij and η ij ). The (carbon dioxide + HEMA), (carbon dioxide + HPA), and (carbon dioxide + HPMA) systems exhibit type-I phase behaviour. At constant pressure, the solubility of HEMA, HPA, and HPMA for the (Carbon dioxide + HEMA), (carbon dioxide + HPA), and (carbon dioxide + HPMA) systems increases as the temperature increases

Acrolein exposure is associated with increased cardiovascular disease risk.

Science.gov (United States)

DeJarnett, Natasha; Conklin, Daniel J; Riggs, Daniel W; Myers, John A; O'Toole, Timothy E; Hamzeh, Ihab; Wagner, Stephen; Chugh, Atul; Ramos, Kenneth S; Srivastava, Sanjay; Higdon, Deirdre; Tollerud, David J; DeFilippis, Andrew; Becher, Carrie; Wyatt, Brad; McCracken, James; Abplanalp, Wes; Rai, Shesh N; Ciszewski, Tiffany; Xie, Zhengzhi; Yeager, Ray; Prabhu, Sumanth D; Bhatnagar, Aruni

2014-08-06

Acrolein is a reactive aldehyde present in high amounts in coal, wood, paper, and tobacco smoke. It is also generated endogenously by lipid peroxidation and the oxidation of amino acids by myeloperoxidase. In animals, acrolein exposure is associated with the suppression of circulating progenitor cells and increases in thrombosis and atherogenesis. The purpose of this study was to determine whether acrolein exposure in humans is also associated with increased cardiovascular disease (CVD) risk. Acrolein exposure was assessed in 211 participants of the Louisville Healthy Heart Study with moderate to high (CVD) risk by measuring the urinary levels of the major acrolein metabolite-3-hydroxypropylmercapturic acid (3-HPMA). Generalized linear models were used to assess the association between acrolein exposure and parameters of CVD risk, and adjusted for potential demographic confounders. Urinary 3-HPMA levels were higher in smokers than nonsmokers and were positively correlated with urinary cotinine levels. Urinary 3-HPMA levels were inversely related to levels of both early (AC133(+)) and late (AC133(-)) circulating angiogenic cells. In smokers as well as nonsmokers, 3-HPMA levels were positively associated with both increased levels of platelet-leukocyte aggregates and the Framingham Risk Score. No association was observed between 3-HPMA and plasma fibrinogen. Levels of C-reactive protein were associated with 3-HPMA levels in nonsmokers only. Regardless of its source, acrolein exposure is associated with platelet activation and suppression of circulating angiogenic cell levels, as well as increased CVD risk. © 2014 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Mercapturic Acids Derived from the Toxicants Acrolein and Crotonaldehyde in the Urine of Cigarette Smokers from Five Ethnic Groups with Differing Risks for Lung Cancer.

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Sungshim L Park

Full Text Available The Multiethnic Cohort epidemiology study has clearly demonstrated that, compared to Whites and for the same number of cigarettes smoked, African Americans and Native Hawaiians have a higher risk for lung cancer whereas Latinos and Japanese Americans have a lower risk. Acrolein and crotonaldehyde are two important constituents of cigarette smoke which have well documented toxic effects and could play a role in lung cancer etiology. Their urinary metabolites 3-hydroxypropylmercapturic acid (3-HPMA and 3-hydroxy-1-methylpropylmercapturic acid (HMPMA, respectively, are validated biomarkers of acrolein and crotonaldehyde exposure. We quantified levels of 3-HPMA and HMPMA in the urine of more than 2200 smokers from these five ethnic groups, and also carried out a genome wide association study using blood samples from these subjects. After adjusting for age, sex, creatinine, and total nicotine equivalents, geometric mean levels of 3-HPMA and HMPMA were significantly different in the five groups (P < 0.0001. Native Hawaiians had the highest and Latinos the lowest geometric mean levels of both 3-HPMA and HMPMA. Levels of 3-HPMA and HMPMA were 3787 and 2759 pmol/ml urine, respectively, in Native Hawaiians and 1720 and 2210 pmol/ml urine in Latinos. These results suggest that acrolein and crotonaldehyde may be involved in lung cancer etiology, and that their divergent levels may partially explain the differing risks of Native Hawaiian and Latino smokers. No strong signals were associated with 3-HPMA in the genome wide association study, suggesting that formation of the glutathione conjugate of acrolein is mainly non-enzymatic, while the top significant association with HMPMA was located on chromosome 12 near the TBX3 gene, but its relationship to HMPMA excretion is not clear.

An inter-laboratory comparison of urinary 3-hydroxypropylmercapturic acid measurement demonstrates good reproducibility between laboratories

Directory of Open Access Journals (Sweden)

Bailey Brian

2011-10-01

Full Text Available Abstract Background Biomarkers have been used extensively in clinical studies to assess toxicant exposure in smokers and non-smokers and have recently been used in the evaluation of novel tobacco products. The urinary metabolite 3-HPMA, a metabolite of the major tobacco smoke toxicity contributor acrolein, is one example of a biomarker used to measure exposure to tobacco smoke. A number of laboratories have developed liquid chromatography with tandem mass spectrometry (LC-MS/MS based methods to measure urinary 3-HPMA; however, it is unclear to what extent the data obtained by these different laboratories are comparable. Findings This report describes an inter-laboratory comparison carried out to evaluate the comparability of 3-HPMA measurement between four laboratories. A common set of spiked and authentic smoker and non-smoker urine samples were used. Each laboratory used their in-house LC-MS/MS method and a common internal standard. A comparison of the repeatability ('r', reproducibility ('R', and coefficient of variation for 3-HPMA demonstrated that within-laboratory variation was consistently lower than between-laboratory variation. The average inter-laboratory coefficient of variation was 7% for fortified urine samples and 16.2% for authentic urine samples. Together, this represents an inter-laboratory variation of 12.2%. Conclusion The results from this first inter-laboratory comparison for the measurement of 3-HPMA in urine demonstrate a reasonably good consensus between laboratories. However, some consistent measurement biases were still observed between laboratories, suggesting that additional work may be required to further reduce the inter-laboratory coefficient of variation.

Synthesis and Characterization of TiO2 Modified with Polystyrene and Poly(3-chloro-2-hydroxypropyl Methacrylate as Adsorbents for the Solid Phase Extraction of Organophosphorus Pesticides

Directory of Open Access Journals (Sweden)

Enrique Alejo-Molina

2016-01-01

Full Text Available Novel hybrid TiO2 particles were developed and assessed as an adsorbent for solid phase extraction (SPE of organophosphorus pesticides (fensulfothion, parathion methyl, coumaphos, and diazinon from spiked water. The sol-gel method was used to synthesize TiO2 particles, which were coated with free-radical polystyrene (PS and poly(3-chloro-2-hydroxypropyl methacrylate (PClHPMA polymers. Particle structures were determined via Fourier transform infrared spectroscopy to confirm that the polymers were successfully anchored to the TiO2 particles. Thermogravimetric analysis was conducted to determine organic and inorganic matter in TiO2-PS and TiO2-PClHPMA particles showing results of 20 : 80 wt/wt% and 23 : 77 wt/wt%, respectively. SEM-EDS and X-ray diffraction test were conducted to determine the morphology and semielemental composition of the particles showing amorphous characteristics. By observing the contact angle, particles coated with PClHPMA were determined to be more hydrophilic than TiO2-PS particles. The pore size distributions obtained from the N2 adsorption-desorption isotherms were 0.150 and 0.168 cm3g−1. The specific surface area (BET was 239.9 m2g−1 for TiO2-PS and 225.7 m2g−1 for TiO2-PClHPMA. The synthesized particles showed relatively high yields of adsorption in SPE. The pesticide recoveries obtained by high performance liquid chromatography ranged from 6 to 26% for TiO2-PClHPMA and 44 to 92% for TiO2-PS.

Improved Tumor-Specific Drug Accumulation by Polymer Therapeutics with pH-Sensitive Drug Release Overcomes Chemotherapy Resistance.

Science.gov (United States)

Heinrich, Anne-Kathrin; Lucas, Henrike; Schindler, Lucie; Chytil, Petr; Etrych, Tomáš; Mäder, Karsten; Mueller, Thomas

2016-05-01

The success of chemotherapy is limited by poor selectivity of active drugs combined with occurrence of tumor resistance. New star-like structured N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-based drug delivery systems containing doxorubicin attached via a pH-sensitive hydrazone bond were designed and investigated for their ability to overcome chemotherapy resistance. These conjugates combine two strategies to achieve a high drug concentration selectively at the tumor site: (I) high accumulation by passive tumor targeting based on enhanced permeability and retention effect and (II) pH-sensitive site-specific drug release due to an acidic tumor microenvironment. Mice bearing doxorubicin-resistant xenograft tumors were treated with doxorubicin, PBS, poly HPMA (pHPMA) precursor or pHPMA-doxorubicin conjugate at different equivalent doses of 5 mg/kg bodyweight doxorubicin up to a 7-fold total dose using different treatment schedules. Intratumoral drug accumulation was analyzed by fluorescence imaging utilizing intrinsic fluorescence of doxorubicin. Free doxorubicin induced significant toxicity but hardly any tumor-inhibiting effects. Administering at least a 3-fold dose of pHPMA-doxorubicin conjugate was necessary to induce a transient response, whereas doses of about 5- to 6-fold induced strong regressions. Tumors completely disappeared in some cases. The onset of response was differential delayed depending on the tumor model, which could be ascribed to distinct characteristics of the microenvironment. Further fluorescence imaging-based analyses regarding underlying mechanisms of the delayed response revealed a related switch to a more supporting intratumoral microenvironment for effective drug release. In conclusion, the current study demonstrates that the concept of tumor site-restricted high-dose chemotherapy is able to overcome therapy resistance. Mol Cancer Ther; 15(5); 998-1007. ©2016 AACR. ©2016 American Association for Cancer Research.

Acrolein Exposure in U.S. Tobacco Smokers and Non-Tobacco Users: NHANES 2005-2006.

Science.gov (United States)

Alwis, K Udeni; deCastro, B Rey; Morrow, John C; Blount, Benjamin C

2015-12-01

Acrolein is a highly reactive α,β unsaturated aldehyde and respiratory irritant. Acrolein is formed during combustion (e.g., burning tobacco or biomass), during high-temperature cooking of foods, and in vivo as a product of oxidative stress and polyamine metabolism. No biomonitoring reference data have been reported to characterize acrolein exposure for the U.S. Our goals were to a) evaluate two acrolein metabolites in urine--N-acetyl-S-(3-hydroxypropyl)-L-cysteine (3HPMA) and N-acetyl-S-(2-carboxyethyl)-L-cysteine (CEMA)--as biomarkers of exposure to acrolein for the U.S. population by age, sex, race, and smoking status; and b) assess tobacco smoke as a predictor of acrolein exposure. We analyzed urine from National Health and Nutrition Examination Survey (NHANES 2005-2006) participants ≥ 12 years old (n = 2,866) for 3HPMA and CEMA using ultra-high-performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry (UPLC/ESI-MSMS). Sample-weighted linear regression models stratified for non-tobacco users versus tobacco smokers (as defined by serum cotinine and self-report) characterized the association of urinary 3HPMA and CEMA with tobacco smoke exposure, adjusting for urinary creatinine, sex, age, and race/ethnicity. 3HPMA and CEMA levels were higher among tobacco smokers (cigarettes, cigars, and pipe users) than among non-tobacco users. The median 3HPMA levels for tobacco smokers and non-tobacco users were 1,089 and 219 μg/g creatinine, respectively. Similarly, median CEMA levels were 203 μg/g creatinine for tobacco smokers and 78.8 μg/g creatinine for non-tobacco users. Regression analysis showed that serum cotinine was a significant positive predictor (p acrolein exposure in the U.S. population.

Spacer length impacts the efficacy of targeted docetaxel conjugates in prostate-specific membrane antigen expressing prostate cancer.

Science.gov (United States)

Peng, Zheng-Hong; Sima, Monika; Salama, Mohamed E; Kopečková, Pavla; Kopeček, Jindřich

2013-12-01

Combination of targeted delivery and controlled release is a powerful technique for cancer treatment. In this paper, we describe the design, synthesis, structure validation and biological properties of targeted and non-targeted N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-docetaxel conjugates. Docetaxel (DTX) was conjugated to HPMA copolymer via a tetrapeptide spacer (-GFLG-). 3-(1,3-dicarboxypropyl)-ureido]pentanedioic acid (DUPA) was used as the targeting moiety to actively deliver DTX for treatment of Prostate-Specific Membrane Antigen (PSMA) expressing prostate cancer. Short and long spacer DUPA monomers were prepared, and four HPMA copolymer--DTX conjugates (non-targeted, two targeted with short spacer of different molecular weight and targeted with long spacer) were prepared via Reversible Addition-Fragmentation Chain Transfer (RAFT) copolymerization. Following confirmation of PSMA expression on C4-2 cell line, the DTX conjugates' in vitro cytotoxicity was tested against C4-2 tumor cells and their anticancer efficacies were assessed in nude mice bearing s.c. human prostate adenocarcinoma C4-2 xenografts. The in vivo results show that the spacer length between targeting moieties and HPMA copolymer backbone can significantly affect the treatment efficacy of DTX conjugates against C4-2 tumor bearing nu/nu mice. Moreover, histological analysis indicated that the DUPA-targeted DTX conjugate with longer spacer had no toxicity in major organs of treated mice.

Aqueous dispersion polymerization: a new paradigm for in situ block copolymer self-assembly in concentrated solution.

Science.gov (United States)

Sugihara, Shinji; Blanazs, Adam; Armes, Steven P; Ryan, Anthony J; Lewis, Andrew L

2011-10-05

Reversible addition-fragmentation chain transfer polymerization has been utilized to polymerize 2-hydroxypropyl methacrylate (HPMA) using a water-soluble macromolecular chain transfer agent based on poly(2-(methacryloyloxy)ethylphosphorylcholine) (PMPC). A detailed phase diagram has been elucidated for this aqueous dispersion polymerization formulation that reliably predicts the precise block compositions associated with well-defined particle morphologies (i.e., pure phases). Unlike the ad hoc approaches described in the literature, this strategy enables the facile, efficient, and reproducible preparation of diblock copolymer spheres, worms, or vesicles directly in concentrated aqueous solution. Chain extension of the highly hydrated zwitterionic PMPC block with HPMA in water at 70 °C produces a hydrophobic poly(2-hydroxypropyl methacrylate) (PHPMA) block, which drives in situ self-assembly to form well-defined diblock copolymer spheres, worms, or vesicles. The final particle morphology obtained at full monomer conversion is dictated by (i) the target degree of polymerization of the PHPMA block and (ii) the total solids concentration at which the HPMA polymerization is conducted. Moreover, if the targeted diblock copolymer composition corresponds to vesicle phase space at full monomer conversion, the in situ particle morphology evolves from spheres to worms to vesicles during the in situ polymerization of HPMA. In the case of PMPC(25)-PHPMA(400) particles, this systematic approach allows the direct, reproducible, and highly efficient preparation of either block copolymer vesicles at up to 25% solids or well-defined worms at 16-25% solids in aqueous solution.

Mercapturic Acids Derived from the Toxicants Acrolein and Crotonaldehyde in the Urine of Cigarette Smokers from Five Ethnic Groups with Differing Risks for Lung Cancer.

Science.gov (United States)

Park, Sungshim L; Carmella, Steven G; Chen, Menglan; Patel, Yesha; Stram, Daniel O; Haiman, Christopher A; Le Marchand, Loic; Hecht, Stephen S

2015-01-01

The Multiethnic Cohort epidemiology study has clearly demonstrated that, compared to Whites and for the same number of cigarettes smoked, African Americans and Native Hawaiians have a higher risk for lung cancer whereas Latinos and Japanese Americans have a lower risk. Acrolein and crotonaldehyde are two important constituents of cigarette smoke which have well documented toxic effects and could play a role in lung cancer etiology. Their urinary metabolites 3-hydroxypropylmercapturic acid (3-HPMA) and 3-hydroxy-1-methylpropylmercapturic acid (HMPMA), respectively, are validated biomarkers of acrolein and crotonaldehyde exposure. We quantified levels of 3-HPMA and HMPMA in the urine of more than 2200 smokers from these five ethnic groups, and also carried out a genome wide association study using blood samples from these subjects. After adjusting for age, sex, creatinine, and total nicotine equivalents, geometric mean levels of 3-HPMA and HMPMA were significantly different in the five groups (P acrolein and crotonaldehyde may be involved in lung cancer etiology, and that their divergent levels may partially explain the differing risks of Native Hawaiian and Latino smokers. No strong signals were associated with 3-HPMA in the genome wide association study, suggesting that formation of the glutathione conjugate of acrolein is mainly non-enzymatic, while the top significant association with HMPMA was located on chromosome 12 near the TBX3 gene, but its relationship to HMPMA excretion is not clear.

Self-Assembling Diblock Copolymers of Poly[N-(2-hydroxypropyl)methacrylamide] and a β-Sheet Peptide

Science.gov (United States)

Radu, Larisa Cristina; Yang, Jiyuan

2015-01-01

The self-assembly of hybrid diblock copolymers composed of poly(HPMA) and β-sheet peptide P11 (CH3CO-QQRFQWQFEQQ-NH2) blocks was investigated. Copolymers were synthesized via thiol-maleimide coupling reaction, by conjugation of semitelechelic poly(HPMA)-SH with maleimide-modified β-sheet peptide. As expected, CD and CR binding studies showed that the peptide block imposed its β-sheet structural arrangement on the structure of diblock copolymers. TEM and AFM proved that peptide and these copolymers had the ability to self-assemble into fibrils. PMID:18855948

Evaluation of dementia by acrolein, amyloid-β and creatinine.

Science.gov (United States)

Igarashi, Kazuei; Yoshida, Madoka; Waragai, Masaaki; Kashiwagi, Keiko

2015-10-23

Plasma, urine and cerebrospinal fluid (CSF) were examined for biochemical markers of dementia. Protein-conjugated acrolein (PC-Acro) and the amyloid-β (Aβ)40/42 ratio in plasma can be used to detect mild cognitive impairment (MCI) and Alzheimer's disease (AD). In plasma, PC-Acro and the Aβ40/42 ratio in MCI and AD were significantly higher relative to non-demented subjects. Furthermore, urine acrolein metabolite, 3-hydroxypropyl mercapturic acid (3-HPMA)/creatinine (Cre) and amino acid-conjugated acrolein (AC-Acro)/Cre in AD were significantly lower than MCI. It was also shown that reduced urine 3-HPMA/Cre correlated with increased plasma Aβ40/42 ratio in dementia. The Aβ40/PC-Acro ratio in CSF, together with Aβ40 and Aβ40/42 ratio, was lower in AD than MCI. Increased plasma PC-Acro and Aβ40/42 ratio and decreased urine 3-HPMA/Cre correlated with cognitive ability (MMSE). These results indicate that the measurements of acrolein derivatives together with Aβ and Cre in biologic fluids is useful to estimate severity of dementia. Copyright © 2015 Elsevier B.V. All rights reserved.

Constructive Epistemic Modeling: A Hierarchical Bayesian Model Averaging Method

Science.gov (United States)

Tsai, F. T. C.; Elshall, A. S.

2014-12-01

Constructive epistemic modeling is the idea that our understanding of a natural system through a scientific model is a mental construct that continually develops through learning about and from the model. Using the hierarchical Bayesian model averaging (HBMA) method [1], this study shows that segregating different uncertain model components through a BMA tree of posterior model probabilities, model prediction, within-model variance, between-model variance and total model variance serves as a learning tool [2]. First, the BMA tree of posterior model probabilities permits the comparative evaluation of the candidate propositions of each uncertain model component. Second, systemic model dissection is imperative for understanding the individual contribution of each uncertain model component to the model prediction and variance. Third, the hierarchical representation of the between-model variance facilitates the prioritization of the contribution of each uncertain model component to the overall model uncertainty. We illustrate these concepts using the groundwater modeling of a siliciclastic aquifer-fault system. The sources of uncertainty considered are from geological architecture, formation dip, boundary conditions and model parameters. The study shows that the HBMA analysis helps in advancing knowledge about the model rather than forcing the model to fit a particularly understanding or merely averaging several candidate models. [1] Tsai, F. T.-C., and A. S. Elshall (2013), Hierarchical Bayesian model averaging for hydrostratigraphic modeling: Uncertainty segregation and comparative evaluation. Water Resources Research, 49, 5520-5536, doi:10.1002/wrcr.20428. [2] Elshall, A.S., and F. T.-C. Tsai (2014). Constructive epistemic modeling of groundwater flow with geological architecture and boundary condition uncertainty under Bayesian paradigm, Journal of Hydrology, 517, 105-119, doi: 10.1016/j.jhydrol.2014.05.027.

Development of Nanomedicines for Treatment of Posttraumatic Osteoarthritis

Science.gov (United States)

2016-03-01

expression and provided sustained inhibition of osteoclast formation. 15. SUBJECT TERMS nanomedicine, PTOA, DMM, osteoarthritis, prodrug, glucocorticoid ...KEYWORDS: Nanomedicine, PTOA, DMM, osteoarthritis, prodrug, glucocorticoid , dexamethasone, HPMA copolymer 3. ACCOMPLISHMENTS: What were the

Macromolecular nanotheranostics for multimodal anticancer therapy

Science.gov (United States)

Huis in't Veld, Ruben; Storm, Gert; Hennink, Wim E.; Kiessling, Fabian; Lammers, Twan

2011-10-01

Macromolecular carrier materials based on N-(2-hydroxypropyl)methacrylamide (HPMA) are prototypic and well-characterized drug delivery systems that have been extensively evaluated in the past two decades, both at the preclinical and at the clinical level. Using several different imaging agents and techniques, HPMA copolymers have been shown to circulate for prolonged periods of time, and to accumulate in tumors both effectively and selectively by means of the Enhanced Permeability and Retention (EPR) effect. Because of this, HPMA-based macromolecular nanotheranostics, i.e. formulations containing both drug and imaging agents within a single formulation, have been shown to be highly effective in inducing tumor growth inhibition in animal models. In patients, however, as essentially all other tumor-targeted nanomedicines, they are generally only able to improve the therapeutic index of the attached active agent by lowering its toxicity, and they fail to improve the efficacy of the intervention. Bearing this in mind, we have recently reasoned that because of their biocompatibility and their beneficial biodistribution, nanomedicine formulations might be highly suitable systems for combination therapies. In the present manuscript, we briefly summarize several exemplary efforts undertaken in this regard in our labs in the past couple of years, and we show that long-circulating and passively tumor-targeted macromolecular nanotheranostics can be used to improve the efficacy of radiochemotherapy and of chemotherapy combinations.

Acrolein Exposure in Hookah Smokers and Non-Smokers Exposed to Hookah Tobacco Secondhand Smoke: Implications for Regulating Hookah Tobacco Products.

Science.gov (United States)

Kassem, Nada O F; Kassem, Noura O; Liles, Sandy; Zarth, Adam T; Jackson, Sheila R; Daffa, Reem M; Chatfield, Dale A; Carmella, Steven G; Hecht, Stephen S; Hovell, Melbourne F

2018-03-06

Acrolein is a highly ciliatoxic agent, a toxic respiratory irritant, a cardiotoxicant, and a possible carcinogen present in tobacco smoke including hookah tobacco. 105 hookah smokers and 103 non-smokers attended exclusively hookah smoking social events at either a hookah lounge or private home, and provided urine samples the morning of and the morning after the event. Samples were analyzed for 3-hydroxypropylmercapturic acid (3-HPMA), a metabolite of acrolein. Geometric mean (GM) urinary 3-HPMA levels in hookah smokers and non-smokers exposed to secondhand smoke (SHS) increased significantly, 1.41 times, 95% CI = 1.15 to 1.74 and 1.39 times, 95% CI = 1.16 to 1.67, respectively, following a hookah social event. The highest increase (1.68 times, 95% CI = 1.15 to 2.45; p = 0.007) in 3-HPMA post a hookah social event was among daily hookah smokers (GM, from 1991 pmol/mg to 3348 pmol/mg). Pre-to-post event change in urinary 3-HPMA was significantly positively correlated with pre-to-post event change in urinary cotinine among hookah smokers at either location of hookah event, (ρ = 0.359, p = 0.001), and among non-smokers in hookah lounges (ρ = 0.369, p = 0.012). Hookah tobacco smoke is a source of acrolein exposure. Findings support regulating hookah tobacco products including reducing humectants and sugar additives, which are precursors of acrolein under certain pyrolysis conditions. We suggest posting health warning signs for indoor smoking in hookah lounges, and encouraging voluntary bans of smoking hookah tobacco in private homes. Our study is the first to quantify the increase in acrolein exposure in hookah smokers and non-smokers exposed to exclusively hookah tobacco SHS at hookah social events in homes or hookah lounges. Our findings provide additional support for regulating hookah tobacco product content, protecting non-smokers' health by posting health warning signs for indoor smoking in hookah lounges, and encouraging home bans on hookah tobacco smoking to

An intelligent biopolymer gel with pendant L-proline methyl ester

International Nuclear Information System (INIS)

Yoshida, Masaru; Safranj, A.; Omichi, Hideki; Katakai, Ryoichi.

1995-01-01

Linear poly(acryloyl-L-proline methyl ester, A-ProOMe), obtained by radiation-induced polymerization of its monomer in ethanol, exhibits a lower critical solution temperature (LCST) at 14degC. A-ProOMe was copolymerized with a minor amount of 2-hydroxypropyl methacrylate (HPMA) or 2-hydroxyethyl methacrylate (HEMA), to obtain intelligent biopolymer gels for application in drug delivery systems. The poly(A-ProOMe/HPMA) gel was characterized by an initial rapid shrinkage at the surface in the swollen state, as resulting in formation of a rigid membrane barrier devoid of micropores. This gel is called a surface regulated matrix. In the case of poly(A-ProOMe/HEMA), no such a barrier formed, instead, the whole matrix shrunk without the disappearance of micropores. This gel is called a matrix pumping gel. Testosterone (T) was incorporated into the poly(A-ProOMe/HPMA) gel, and it was found that the daily dose of T released in vivo from this formulation remained constant at approximately 30 μg/day throughout an experimental period of 54 weeks. On the other hand, 9-β-D-arabinofuranosyladenine (Ara-A) was incorporated into the poly(A-ProOMe/HEMA) gel to evaluate the pulsatile drug release when cycled at 10 and 37degC. The in vitro release rate of Ara-A was found to be 11 ng/h at 10degC and 33 ng/h at 37degC. (author)

Metabolic acidosis may be as protective as hypercapnic acidosis in an ex-vivo model of severe ventilator-induced lung injury: a pilot study.

Science.gov (United States)

Kapetanakis, Theodoros; Siempos, Ilias I; Metaxas, Eugenios I; Kopterides, Petros; Agrogiannis, George; Patsouris, Efstratios; Lazaris, Andreas C; Stravodimos, Konstantinos G; Roussos, Charis; Armaganidis, Apostolos

2011-04-13

There is mounting experimental evidence that hypercapnic acidosis protects against lung injury. However, it is unclear if acidosis per se rather than hypercapnia is responsible for this beneficial effect. Therefore, we sought to evaluate the effects of hypercapnic (respiratory) versus normocapnic (metabolic) acidosis in an ex vivo model of ventilator-induced lung injury (VILI). Sixty New Zealand white rabbit ventilated and perfused heart-lung preparations were used. Six study groups were evaluated. Respiratory acidosis (RA), metabolic acidosis (MA) and normocapnic-normoxic (Control - C) groups were randomized into high and low peak inspiratory pressures, respectively. Each preparation was ventilated for 1 hour according to a standardized ventilation protocol. Lung injury was evaluated by means of pulmonary edema formation (weight gain), changes in ultrafiltration coefficient, mean pulmonary artery pressure changes as well as histological alterations. HPC group gained significantly greater weight than HPMA, HPRA and all three LP groups (P = 0.024), while no difference was observed between HPMA and HPRA groups regarding weight gain. Neither group differ on ultrafiltration coefficient. HPMA group experienced greater increase in the mean pulmonary artery pressure at 20 min (P = 0.0276) and 40 min (P = 0.0012) compared with all other groups. Histology scores were significantly greater in HP vs. LP groups (p < 0.001). In our experimental VILI model both metabolic acidosis and hypercapnic acidosis attenuated VILI-induced pulmonary edema implying a mechanism other than possible synergistic effects of acidosis with CO2 for VILI attenuation.

Peptide–polymer ligands for a tandem WW-domain, an adaptive multivalent protein–protein interaction: lessons on the thermodynamic fitness of flexible ligands

Directory of Open Access Journals (Sweden)

Katharina Koschek

2015-05-01

Full Text Available Three polymers, poly(N-(2-hydroxypropylmethacrylamide (pHPMA, hyperbranched polyglycerol (hPG, and dextran were investigated as carriers for multivalent ligands targeting the adaptive tandem WW-domain of formin-binding protein (FBP21. Polymer carriers were conjugated with 3–9 copies of the proline-rich decapeptide GPPPRGPPPR-NH2 (P1. Binding of the obtained peptide–polymer conjugates to the tandem WW-domain was investigated employing isothermal titration calorimetry (ITC to determine the binding affinity, the enthalpic and entropic contributions to free binding energy, and the stoichiometry of binding for all peptide–polymer conjugates. Binding affinities of all multivalent ligands were in the µM range, strongly amplified compared to the monovalent ligand P1 with a KD > 1 mM. In addition, concise differences were observed, pHPMA and hPG carriers showed moderate affinity and bound 2.3–2.8 peptides per protein binding site resulting in the formation of aggregates. Dextran-based conjugates displayed affinities down to 1.2 µM, forming complexes with low stoichiometry, and no precipitation. Experimental results were compared with parameters obtained from molecular dynamics simulations in order to understand the observed differences between the three carrier materials. In summary, the more rigid and condensed peptide–polymer conjugates based on the dextran scaffold seem to be superior to induce multivalent binding and to increase affinity, while the more flexible and dendritic polymers, pHPMA and hPG are suitable to induce crosslinking upon binding.

Innovation in PDT based on EPR effect and non-laser based irradiation

Czech Academy of Sciences Publication Activity Database

Maeda, H.; Fang, J.; Nakamura, H.; Šubr, Vladimír; Ulbrich, Karel

2015-01-01

Roč. 8, č. 2 (2015), S-08 ISSN 1882-6490. [Annual Meeting of the Japanese Society for Molecular Imaging /10./. 20.05.2015-21.05.2015, Tokyo] Institutional support: RVO:61389013 Keywords : HPMA * polymer Subject RIV: CD - Macromolecular Chemistry

The Effect of Polymer Backbone Chemistry on the Induction of the Accelerated Blood Clearance in Polymer Modified Liposomes

KAUST Repository

Kierstead, Paul H.

2015-06-18

A variety of water-soluble polymers, when attached to a liposome, substantially increase liposome circulation half-life in animals. However, in certain conditions, liposomes modified with the most widely used polymer, polyethylene glycol (PEG), induce an IgM response resulting in an accelerated blood clearance (ABC) of the liposome upon the second injection. Modification of liposomes with other water-soluble polymers: HPMA (poly[N-(2-hydroxypropyl) methacrylamide]), PVP (poly(vinylpyrrolidone)), PMOX (poly(2-methyl-2-oxazoline)), PDMA (poly(N,N-dimethyl acrylamide)), and PAcM (poly(N-acryloyl morpholine)), increase circulation times of liposomes; but a precise comparison of their ability to promote long circulation or induce the ABC effect has not been reported. To obtain a more nuanced understanding of the role of polymer structure/MW to promote long circulation, we synthesized a library of polymer diacyl chain lipids with low polydispersity (1.04-1.09), similar polymer molecular weights (2.1-2.5 kDa) and incorporated them into 100 nm liposomes of a narrow polydispersity (0.25-1.3) composed of polymer-lipid/hydrogenated soy phosphatidylcholine/cholesterol/diD: 5.0/54.5/40/0.5. We confirm that HPMA, PVP, PMOX, PDMA and PAcM modified liposome have increased circulation times in rodents and that PVP, PDMA, PAcM do not induce the ABC effect. We demonstrate for the first time, that HPMA does not cause an ABC effect whereas PMOX induces a pronounced ABC effect in rats. We find that a single dose of liposomes coated with PEG and PMOX generate an IgM response in rats towards the respective polymer. Finally, in this homologous polymer series, we observe a positive correlation (R = 0.84 in rats, R = 0.92 in mice) between the circulation time of polymer-modified liposomes and polymer viscosity; PEG and PMOX, the polymers that can initiate an ABC response were the two most viscous polymers. Our findings suggest that that polymers that do not cause an ABC effect such as, HPMA

The effect of polymer backbone chemistry on the induction of the accelerated blood clearance in polymer modified liposomes.

Science.gov (United States)

Kierstead, Paul H; Okochi, Hideaki; Venditto, Vincent J; Chuong, Tracy C; Kivimae, Saul; Fréchet, Jean M J; Szoka, Francis C

2015-09-10

A variety of water-soluble polymers, when attached to a liposome, substantially increase liposome circulation half-life in animals. However, in certain conditions, liposomes modified with the most widely used polymer, polyethylene glycol (PEG), induce an IgM response resulting in an accelerated blood clearance (ABC) of the liposome upon the second injection. Modification of liposomes with other water-soluble polymers: HPMA (poly[N-(2-hydroxypropyl) methacrylamide]), PVP (poly(vinylpyrrolidone)), PMOX (poly(2-methyl-2-oxazoline)), PDMA (poly(N,N-dimethyl acrylamide)), and PAcM (poly(N-acryloyl morpholine)), increases circulation times of liposomes; but a precise comparison of their ability to promote long circulation or induce the ABC effect has not been reported. To obtain a more nuanced understanding of the role of polymer structure/MW to promote long circulation, we synthesized a library of polymer diacyl chain lipids with low polydispersity (1.04-1.09), similar polymer molecular weights (2.1-2.5kDa) and incorporated them into 100nm liposomes of a narrow polydispersity (0.25-1.3) composed of polymer-lipid/hydrogenated soy phosphatidylcholine/cholesterol/diD: 5.0/54.5/40/0.5. We confirm that HPMA, PVP, PMOX, PDMA and PAcM modified liposome have increased circulation times in rodents and that PVP, PDMA, and PAcM do not induce the ABC effect. We demonstrate for the first time, that HPMA does not cause an ABC effect whereas PMOX induces a pronounced ABC effect in rats. We find that a single dose of liposomes coated with PEG and PMOX generates an IgM response in rats towards the respective polymer. Finally, in this homologous polymer series, we observe a positive correlation (R=0.84 in rats, R=0.92 in mice) between the circulation time of polymer-modified liposomes and polymer viscosity; PEG and PMOX, the polymers that can initiate an ABC response were the two most viscous polymers. Our findings suggest that polymers that do not cause an ABC effect such as, HPMA or

Hydrolytically degradable polymer micelles for drug delivery: a SAXS/SANS kinetic study

Czech Academy of Sciences Publication Activity Database

Filippov, Sergey K.; Franklin, J. M.; Konarev, P. V.; Chytil, Petr; Etrych, Tomáš; Bogomolova, Anna; Dyakonova, M.; Papadakis, C. M.; Radulescu, A.; Ulbrich, Karel; Štěpánek, Petr; Svergun, D. I.

2013-01-01

Roč. 14, č. 11 (2013), s. 4061-4070 ISSN 1525-7797 R&D Projects: GA ČR GAP208/10/1600 Institutional support: RVO:61389013 Keywords : HPMA * micelles * drug release Subject RIV: CF - Physical ; Theoretical Chemistry Impact factor: 5.788, year: 2013

Metabolic acidosis may be as protective as hypercapnic acidosis in an ex-vivo model of severe ventilator-induced lung injury: a pilot study

Directory of Open Access Journals (Sweden)

Patsouris Efstratios

2011-04-01

Full Text Available Abstract Background There is mounting experimental evidence that hypercapnic acidosis protects against lung injury. However, it is unclear if acidosis per se rather than hypercapnia is responsible for this beneficial effect. Therefore, we sought to evaluate the effects of hypercapnic (respiratory versus normocapnic (metabolic acidosis in an ex vivo model of ventilator-induced lung injury (VILI. Methods Sixty New Zealand white rabbit ventilated and perfused heart-lung preparations were used. Six study groups were evaluated. Respiratory acidosis (RA, metabolic acidosis (MA and normocapnic-normoxic (Control - C groups were randomized into high and low peak inspiratory pressures, respectively. Each preparation was ventilated for 1 hour according to a standardized ventilation protocol. Lung injury was evaluated by means of pulmonary edema formation (weight gain, changes in ultrafiltration coefficient, mean pulmonary artery pressure changes as well as histological alterations. Results HPC group gained significantly greater weight than HPMA, HPRA and all three LP groups (P = 0.024, while no difference was observed between HPMA and HPRA groups regarding weight gain. Neither group differ on ultrafiltration coefficient. HPMA group experienced greater increase in the mean pulmonary artery pressure at 20 min (P = 0.0276 and 40 min (P = 0.0012 compared with all other groups. Histology scores were significantly greater in HP vs. LP groups (p Conclusions In our experimental VILI model both metabolic acidosis and hypercapnic acidosis attenuated VILI-induced pulmonary edema implying a mechanism other than possible synergistic effects of acidosis with CO2 for VILI attenuation.

Immunogenicity of coiled-coil based drug-free macromolecular therapeutics

Czech Academy of Sciences Publication Activity Database

Kverka, Miloslav; Hartley, J.M.; Chu, T.W.; Yang, J.; Heidchen, R.; Kopeček, J.

2014-01-01

Roč. 35, č. 2 (2014), s. 5886-5896 ISSN 1616-0177 R&D Projects: GA MŠk(CZ) EE2.3.30.0003 Grant - others:NIH(US) GM095606 Institutional support: RVO:61388971 Keywords : coiled-coil * enantiomers * HPMA copolymer Subject RIV: EC - Immunology

Long-circulating and passively tumor-targeted polymer-drug conjugates improve the efficacy and reduce the toxicity of radiochemotherapy

Czech Academy of Sciences Publication Activity Database

Lammers, T.; Šubr, Vladimír; Ulbrich, Karel; Peschke, P.; Huber, P. E.; Hennink, W. E.; Storm, G.; Kiessling, F.

2010-01-01

Roč. 12, č. 9 (2010), B413-B421 ISSN 1438-1656 R&D Projects: GA MŠk 1M0505 Institutional research plan: CEZ:AV0Z40500505 Keywords : HPMA copolymers * targeting * tumor targeting Subject RIV: EI - Biotechnology ; Bionics Impact factor: 1.746, year: 2010

Targeting adenovirus gene delivery to activated tumour-associated vasculature via endothelial selectins

Czech Academy of Sciences Publication Activity Database

Bachtarzi, H.; Stevenson, M.; Šubr, Vladimír; Ulbrich, Karel; Seymour, L. W.; Fisher, K. D.

2011-01-01

Roč. 150, č. 2 (2011), s. 196-203 ISSN 0168-3659 R&D Projects: GA MŠk 1M0505 Institutional research plan: CEZ:AV0Z40500505 Keywords : E-selectin * pHPMA * adenovirus Subject RIV: EI - Biotechnology ; Bionics Impact factor: 5.732, year: 2011

Cathepsin B-sensitive polymers for compartment-specific degradation and nucleic acid release.

Science.gov (United States)

Chu, David S H; Johnson, Russell N; Pun, Suzie H

2012-02-10

Degradable cationic polymers are desirable for in vivo nucleic acid delivery because they offer significantly decreased toxicity over non-degradable counterparts. Peptide linkers provide chemical stability and high specificity for particular endopeptidases but have not been extensively studied for nucleic acid delivery applications. In this work, enzymatically degradable peptide-HPMA copolymers were synthesized by RAFT polymerization of HPMA with methacrylamido-terminated peptide macromonomers, resulting in polymers with low polydispersity and near quantitative incorporation of peptides. Three peptide-HPMA copolymers were evaluated: (i) pHCathK(10), containing peptides composed of the linker phe-lys-phe-leu (FKFL), a substrate of the endosomal/lysosomal endopeptidase cathepsin B, connected to oligo-(L)-lysine for nucleic acid binding, (ii) pHCath(D)K(10), containing the FKFL linker with oligo-(D)-lysine, and (iii) pH(D)Cath(D)K(10), containing all (D) amino acids. Cathepsin B degraded copolymers pHCathK(10) and pHCath(D)K(10) within 1 h while no degradation of pH(D)Cath(D)K(10) was observed. Polyplexes formed with pHCathK(10) copolymers show DNA release by 4 h of treatment with cathepsin B; comparatively, polyplexes formed with pHCath(D)K(10) and pH(D)Cath(D)K(10) show no DNA release within 8 h. Transfection efficiency in HeLa and NIH/3T3 cells were comparable between the copolymers but pHCathK(10) was less toxic. This work demonstrates the successful application of peptide linkers for degradable cationic polymers and DNA release. Copyright © 2011 Elsevier B.V. All rights reserved.

Polymer brushes showing non-fouling in blood plasma challenge the currently accepted design of protein resistant surfaces

Czech Academy of Sciences Publication Activity Database

Rodriguez-Emmenegger, Cesar Adolfo; Brynda, Eduard; Riedel, Tomáš; Houska, Milan; Šubr, Vladimír; Bologna Alles, A.; Hasan, E.; Gautrot, J. E.; Huck, W. T. S.

2011-01-01

Roč. 32, č. 13 (2011), s. 952-957 ISSN 1022-1336 R&D Projects: GA AV ČR KAN200670701; GA AV ČR IAAX00500803 Institutional research plan: CEZ:AV0Z40500505 Keywords : biosensors * blood plasma * HPMA Subject RIV: CD - Macromolecular Chemistry Impact factor: 4.596, year: 2011

PCL-PEG graft copolymers with tunable amphiphilicity as efficient drug delivery systems

Czech Academy of Sciences Publication Activity Database

Al Samad, A.; Bethry, A.; Koziolová, Eva; Netopilík, Miloš; Etrych, Tomáš; Bakkour, Y.; Coudane, J.; El Omar, F.; Nottelet, B.

2016-01-01

Roč. 4, č. 37 (2016), s. 6228-6239 ISSN 2050-750X R&D Projects: GA MŠk(CZ) LO1507; GA ČR(CZ) GA15-02986S Institutional support: RVO:61389013 Keywords : HPMA copolymer * tumor * micelle Subject RIV: CD - Macromolecular Chemistry Impact factor: 4.543, year: 2016

Two step mechanisms of tumor selective delivery of N-(2-hydroxypropyl)methacrylamide copolymer conjugated with pirarubicin via an acid-cleavable linkage

Czech Academy of Sciences Publication Activity Database

Nakamura, H.; Etrych, Tomáš; Chytil, Petr; Ohkubo, M.; Fang, J.; Ulbrich, Karel; Maeda, H.

2014-01-01

Roč. 174, 28 January (2014), s. 81-87 ISSN 0168-3659 Grant - others:AV ČR(CZ) AP0802 Program:Akademická prémie - Praemium Academiae Institutional support: RVO:61389013 Keywords : HPMA polymer conjugate * pirarubicin (THP) * tumor selectivity Subject RIV: CD - Macromolecular Chemistry Impact factor: 7.705, year: 2014

Coating of adenovirus type 5 with polymers containing quaternary amines prevents binding to blood components

Czech Academy of Sciences Publication Activity Database

Šubr, Vladimír; Kostka, Libor; Selby-Milic, T.; Fisher, K.; Ulbrich, Karel; Seymour, W.; Carlisle, R. C.

2009-01-01

Roč. 135, č. 2 (2009), s. 152-158 ISSN 0168-3659 R&D Projects: GA AV ČR KJB400500803 EU Projects: European Commission(XE) 512087 - GIANT Institutional research plan: CEZ:AV0Z40500505 Keywords : quaternary ammonium * HPMA * adenovirus Subject RIV: CD - Macromolecular Chemistry Impact factor: 5.949, year: 2009

Palliative therapy of advanced breast cancer with targeted polymer-bound drug

Czech Academy of Sciences Publication Activity Database

Říhová, Blanka; Strohalm, Jiří; Kubáčková, K.; Jelínková, Markéta; Rozprimová, L.; Šírová, Milada; Plocová, Daniela; Etrych, Tomáš; Mrkvan, Tomáš; Kovář, Marek; Ulbrich, Karel

2003-01-01

Roč. 12, č. 1 (2003), s. 375 ISSN 1107-3756. [World Congress on Advances in Oncology /8./. Crete, 16.10.2003-18.10.2003] Institutional research plan: CEZ:AV0Z4050913; CEZ:AV0Z5020903 Keywords : hpma * epr * lak Subject RIV: EE - Microbiology, Virology Impact factor: 1.940, year: 2003

Hydrolytically degradable polymer micelles for anticancer drug delivery to solid tumors

Czech Academy of Sciences Publication Activity Database

Chytil, Petr; Etrych, Tomáš; Kostka, Libor; Ulbrich, Karel

2012-01-01

Roč. 213, č. 8 (2012), s. 858-867 ISSN 1022-1352 R&D Projects: GA AV ČR IAAX00500803; GA ČR GAP301/11/0325 Institutional research plan: CEZ:AV0Z40500505 Keywords : HPMA copolymers * drug delivery systems * doxorubicin Subject RIV: EC - Immunology Impact factor: 2.386, year: 2012

G3-C12 Peptide Reverses Galectin-3 from Foe to Friend for Active Targeting Cancer Treatment.

Science.gov (United States)

Sun, Wei; Li, Lian; Yang, Qingqing; Shan, Wei; Zhang, Zhirong; Huang, Yuan

2015-11-02

Galectin-3 is overexpressed by numerous carcinomas and is a potential target for active tumor treatments. On the other hand, galectin-3 also plays a key role in cancer progression and prevents cells from undergoing apoptosis, thereby offsetting the benefits of active targeting drugs. However, the relative contribution of the protective antiapoptotic effects of galectin-3 and the proapoptotic effects of galectin-3-targeted therapies has remained yet unrevealed. Here, we show that a galectin-3-binding peptide G3-C12 could reverse galectin-3 from foe to friend for active targeting delivery system. Results showed G3-C12 modified N-(2-hydroxypropyl)methacrylamide copolymer doxorubicin conjugates (G3-C12-HPMA-Dox) could internalize into galectin-3 overexpressed PC-3 cells via a highly specific ligand-receptor pathway (2.2 times higher cellular internalization than HPMA-Dox). The internalized Dox stimulated the translocation of galectin-3 to the mitochondria to prevent from apoptosis. In turn, this caused G3-C12-HPMA-Dox to concentrate into the mitochondria after binding to galectin-3 intracellularly. Initially, mitochondrial galectin-3 weakened Dox-induced mitochondrial damage; however, as time progressed, G3-C12 active-mediation allowed increasing amounts of Dox to be delivered to the mitochondria, which eventually induced higher level of apoptosis than nontargeted copolymers. In addition, G3-C12 downregulates galectin-3 expression, 0.43 times lower than control cells, which could possibly be responsible for the suppressed cell migration. Thus, G3-C12 peptide exerts sequential targeting to both cell membrane and mitochondria via regulating galectin-3, and eventually reverses and overcomes the protective effects of galectin-3; therefore, it could be a promising agent for the treatment of galectin-3-overexpressing cancers.

Preparation and in vitro evaluation of polymer conjugates actively targeted using RGD-based peptides

Czech Academy of Sciences Publication Activity Database

Böhmová, Eliška; Pola, Robert; Pechar, Michal; Janoušková, Olga; Zuska, K.; Etrych, Tomáš

2017-01-01

Roč. 6, 4 (Suppl) (2017), s. 91 ISSN 2325-9604. [International Conference and Exhibition on Nanomedicine and Drug Delivery. 29.05.2017-31.05.2017, Osaka] R&D Projects: GA ČR(CZ) GA16-17207S Institutional support: RVO:61389013 Keywords : polymer drug carriers * HPMA * peptide tumor targeting Subject RIV: CD - Macromolecular Chemistry

Peptide-targeted polymer cancerostatics

Czech Academy of Sciences Publication Activity Database

Böhmová, Eliška; Pola, Robert

2016-01-01

Roč. 65, Suppl. 2 (2016), S153-S164 ISSN 0862-8408 R&D Projects: GA MŠk(CZ) LO1507 Institutional support: RVO:61389013 Keywords : HPMA copolymers * tumor targeting * peptides Subject RIV: CD - Macromolecular Chemistry Impact factor: 1.461, year: 2016 http://www.biomed.cas.cz/physiolres/pdf/65%20Suppl%202/65_S153.pdf

High-molecular-weight polymers containing biodegradable disulfide bonds: synthesis and in vitro verification of intracellular degradation

Czech Academy of Sciences Publication Activity Database

Etrych, Tomáš; Kovář, Lubomír; Šubr, Vladimír; Braunová, Alena; Pechar, Michal; Chytil, Petr; Říhová, Blanka; Ulbrich, Karel

2010-01-01

Roč. 25, č. 1 (2010), s. 5-26 ISSN 0883-9115 R&D Projects: GA AV ČR IAA400500806; GA AV ČR KAN200200651 Institutional research plan: CEZ:AV0Z40500505; CEZ:AV0Z50200510 Keywords : water-soluble polymers * reductive degradation * HPMA copolymers Subject RIV: CD - Macromolecular Chemistry Impact factor: 2.610, year: 2010

Radiosynoviorthesis of knees by means of 166Ho-holmium-boro-macroaggregates.

Science.gov (United States)

Kraft, Otakar; Kaspárek, Richard; Ullmann, Vojtech; Melichar, Frantisek; Kropácek, Martin; Mirzajevova, Marcela

2007-04-01

The aim of this study was to evaluate adverse and therapeutic effects of applicated holmium-boro-macroaggregates (HBMAs) in the radiosynoviorthesis (RSO) of knees in patients suffering from chronic synovitis. We started RSO of the knees by means of a new radiopharmaceutical (RF) HBMA in patients with gonarthrosis, rheumatoid arthritis, chronic synovitis, psoriatic arthritis, and gout arthropathy. Seventeen (17) intra-articular injections were performed in 15 patients who were receiving a mean activity of 972 MBq (range, 904-1057) of 166Ho-HBMA. Patient inclusion to the study followed a series of inclusion and exclusion criterions. The patients were hospitalized for 3 days. Side-effects were evaluated during their hospital stay and again after 6-8 weeks. Static scintigraphy of knee joints and measurements of blood radioactivity were performed. Therapeutic effects were evaluated after 6-8 weeks and at 6 months. In 2 hours and 2 days following the application, we proved, by means of knee and inguinal scintigraphy, only insignificant radiopharmaceutical leakage from the joint cavity to the inguinal lymph nodes in 4 patients. In the treated patients, no serious adverse effects occurred. Nine (9) patients were without complaints, 4 patients had slight knee exudation, and 2 patients had great exudation. Therapeutic effects were as follows: 2 patients were without pain, 9 were with lower pain, 3 were with the same pain, and 1 patient was with increased pain. Joint motion was improved in 7 patients, remained the same in 7 patients, and was impaired in 1 patient. Analgesics consumption was lower in 5 patients, the same in 9 patients, and greater in 1 patient. Knee exudation was absent in 2 patients, lower in 4 patients, the same in 6 patients, and greater in 3 patients. In 3 patients it was necessary to do surgical RSO. This RF can extend the range of clinically used radiopharmaceuticals for RSO and to supplement space between 90Y with high energy and 186Re with 169Er with

The pH-dependent and enzymatic release of cytarabine from hydrophilic polymer conjugates

Czech Academy of Sciences Publication Activity Database

Pola, Robert; Janoušková, Olga; Etrych, Tomáš

2016-01-01

Roč. 65, Suppl. 2 (2016), S225-S232 ISSN 0862-8408 R&D Projects: GA MŠk(CZ) LO1507 Institutional support: RVO:61389013 Keywords : HPMA copolymers * drug delivery system * nucleoside analogues Subject RIV: CD - Macromolecular Chemistry Impact factor: 1.461, year: 2016 http://www.biomed.cas.cz/physiolres/pdf/65%20Suppl%202/65_S225.pdf

Anti-lymphoma efficacy comparison of anti-Cd20 monoclonal antibody-targeted and non-targeted star-shaped polymer-prodrug conjugates

Czech Academy of Sciences Publication Activity Database

Lidický, Ondřej; Janoušková, Olga; Strohalm, Jiří; Alam, M.; Klener, P.; Etrych, Tomáš

2015-01-01

Roč. 20, č. 11 (2015), s. 19849-19864 ISSN 1420-3049 R&D Projects: GA MŠk(CZ) ED1.1.00/02.0109; GA ČR(CZ) GA15-02986S; GA MŠk(CZ) LO1507 Institutional support: RVO:61389013 Keywords : HPMA copolymers * drug delivery systems * doxorubicin Subject RIV: CD - Macromolecular Chemistry Impact factor: 2.465, year: 2015

Star polymer-drug conjugates with pH-controlled drug release and carrier degradation

Czech Academy of Sciences Publication Activity Database

Kostková, Hana; Schindler, Lucie; Kotrchová, Lenka; Kovář, Marek; Šírová, Milada; Kostka, Libor; Etrych, Tomáš

2017-01-01

Roč. 2017, 3 January (2017), s. 1-10, č. článku 8675435. ISSN 1687-4110 R&D Projects: GA MŠk(CZ) LQ1604 Institutional support: RVO:61389013 ; RVO:61388971 Keywords : star conjugate * HPMA copolymer * doxorubicin Subject RIV: CD - Macromolecular Chemistry; EE - Microbiology, Virology (MBU-M) OBOR OECD: Polymer science; Microbiology (MBU-M) Impact factor: 1.871, year: 2016

A Hybrid CPU/GPU Pattern-Matching Algorithm for Deep Packet Inspection.

Directory of Open Access Journals (Sweden)

Chun-Liang Lee

Full Text Available The large quantities of data now being transferred via high-speed networks have made deep packet inspection indispensable for security purposes. Scalable and low-cost signature-based network intrusion detection systems have been developed for deep packet inspection for various software platforms. Traditional approaches that only involve central processing units (CPUs are now considered inadequate in terms of inspection speed. Graphic processing units (GPUs have superior parallel processing power, but transmission bottlenecks can reduce optimal GPU efficiency. In this paper we describe our proposal for a hybrid CPU/GPU pattern-matching algorithm (HPMA that divides and distributes the packet-inspecting workload between a CPU and GPU. All packets are initially inspected by the CPU and filtered using a simple pre-filtering algorithm, and packets that might contain malicious content are sent to the GPU for further inspection. Test results indicate that in terms of random payload traffic, the matching speed of our proposed algorithm was 3.4 times and 2.7 times faster than those of the AC-CPU and AC-GPU algorithms, respectively. Further, HPMA achieved higher energy efficiency than the other tested algorithms.

Polymer conjugates of doxorubicin bound through an amide and hydrazone bond: impact of the carrier structure onto synergistic action in the treatment of solid tumours

Czech Academy of Sciences Publication Activity Database

Etrych, Tomáš; Šubr, Vladimír; Laga, Richard; Říhová, Blanka; Ulbrich, Karel

2014-01-01

Roč. 58, 16 July (2014), s. 1-12 ISSN 0928-0987 R&D Projects: GA ČR GAP301/11/0325; GA MŠk EE2.3.30.0029; GA MŠk(CZ) ED1.1.00/02.0109 Institutional support: RVO:61389013 ; RVO:61388971 Keywords : HPMA copolymer * synergistic effect * doxorubicin Subject RIV: CE - Biochemistry; FD - Oncology ; Hematology (MBU-M) Impact factor: 3.350, year: 2014

Complexation of anionic copolymers of acrylamide and N-(2-hydroxypropyl)methacrylamide with aminoglycoside antibiotics

Science.gov (United States)

Solovskii, M. V.; Tarabukina, E. B.; Amirova, A. I.; Zakharova, N. V.; Smirnova, M. Yu.; Gavrilova, I. I.

2014-03-01

The complexation of aminoglycoside antibiotics neomycin, gentamicin, kanamycin, and amikacin in the form of free bases with carboxyl- and sulfo-containing copolymers of acrylamide and N-(2-hydroxypropyl)methacrylamide (HPMA) in water and water-salt solutions is studied by means of viscometry, equilibrium dialysis, potentiometric titration, and molecular hydrodynamics. Factors influencing the stability of formed copolymer-antibiotic complexes and determinations of their toxicity are established.

Dual fluorescent N-(2-hydroxypropyl) methacrylamide-based conjugates for passive tumor targeting with reduction-sensitive drug release: proof of the concept, tumor accumulation, and biodistribution

Czech Academy of Sciences Publication Activity Database

Studenovský, Martin; Heinrich, A. K.; Lucas, H.; Mueller, T.; Mäder, K.; Etrych, Tomáš

2016-01-01

Roč. 31, č. 4 (2016), s. 348-360 ISSN 0883-9115 R&D Projects: GA ČR(CZ) GCP207/12/J030; GA ČR(CZ) GA14-12742S; GA MŠk(CZ) ED1.1.00/02.0109 Institutional support: RVO:61389013 Keywords : HPMA copolymers * reduction-responsive drug release * tumor accumulation Subject RIV: CD - Macromolecular Chemistry Impact factor: 1.310, year: 2016

High-molecular weight star conjugates containing docetaxel with high anti-tumor activity and low systemic toxicity in vivo

Czech Academy of Sciences Publication Activity Database

Etrych, Tomáš; Strohalm, Jiří; Šírová, Milada; Tomalová, Barbora; Rossmann, Pavel; Říhová, Blanka; Ulbrich, Karel; Kovář, Marek

2015-01-01

Roč. 6, č. 1 (2015), s. 160-170 ISSN 1759-9954 R&D Projects: GA ČR GAP301/11/0325; GA ČR GCP207/12/J030; GA MŠk(CZ) EE2.3.20.0055 Institutional support: RVO:61389013 ; RVO:61388971 Keywords : star polymer * HPMA copolymers * docetaxel Subject RIV: CD - Macromolecular Chemistry ; EC - Immunology (MBU-M) Impact factor: 5.687, year: 2015

Targeting angiogenesis-dependent calcified neoplasms using combined polymer therapeutics.

Directory of Open Access Journals (Sweden)

Ehud Segal

Full Text Available There is an immense clinical need for novel therapeutics for the treatment of angiogenesis-dependent calcified neoplasms such as osteosarcomas and bone metastases. We developed a new therapeutic strategy to target bone metastases and calcified neoplasms using combined polymer-bound angiogenesis inhibitors. Using an advanced "living polymerization" technique, the reversible addition-fragmentation chain transfer (RAFT, we conjugated the aminobisphosphonate alendronate (ALN, and the potent anti-angiogenic agent TNP-470 with N-(2-hydroxypropylmethacrylamide (HPMA copolymer through a Glycine-Glycine-Proline-Norleucine linker, cleaved by cathepsin K, a cysteine protease overexpressed at resorption sites in bone tissues. In this approach, dual targeting is achieved. Passive accumulation is possible due to the increase in molecular weight following polymer conjugation of the drugs, thus extravasating from the tumor leaky vessels and not from normal healthy vessels. Active targeting to the calcified tissues is achieved by ALN's affinity to bone mineral.The anti-angiogenic and antitumor potency of HPMA copolymer-ALN-TNP-470 conjugate was evaluated both in vitro and in vivo. We show that free and conjugated ALN-TNP-470 have synergistic anti-angiogenic and antitumor activity by inhibiting proliferation, migration and capillary-like tube formation of endothelial and human osteosarcoma cells in vitro. Evaluation of anti-angiogenic, antitumor activity and body distribution of HPMA copolymer-ALN-TNP-470 conjugate was performed on severe combined immunodeficiency (SCID male mice inoculated with mCherry-labeled MG-63-Ras human osteosarcoma and by modified Miles permeability assay. Our targeted bi-specific conjugate reduced VEGF-induced vascular hyperpermeability by 92% and remarkably inhibited osteosarcoma growth in mice by 96%.This is the first report to describe a new concept of a narrowly-dispersed combined polymer therapeutic designed to target both tumor and

HPMA conjugates and immunogenic cancer cell death

Czech Academy of Sciences Publication Activity Database

Kovář, Lubomír; Etrych, Tomáš; Kabešová, Martina; Strohalm, Jiří; Ulbrich, Karel; Říhová, Blanka

2009-01-01

Roč. 39, - (2009), s. 523-523 ISSN 0014-2980. [European Congress of Immunology /2./. 13.09.2009-16.09.2009, Berlin] Institutional research plan: CEZ:AV0Z50200510; CEZ:AV0Z40500505 Keywords : doxorubicin * tumor Subject RIV: EC - Immunology

A tumor-targeted polymer theranostics platform for positron emission tomography and fluorescence imaging

Czech Academy of Sciences Publication Activity Database

Koziolová, Eva; Goel, S.; Chytil, Petr; Janoušková, Olga; Barnhart, T. E.; Cai, W.; Etrych, Tomáš

2017-01-01

Roč. 9, č. 30 (2017), s. 10906-10918 ISSN 2040-3364 R&D Projects: GA ČR(CZ) GA15-02986S; GA MZd(CZ) NV16-28594A; GA MŠk(CZ) LO1507 Institutional support: RVO:61389013 Keywords : N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers * positron emission tomography ( PET ) * fluorescence imaging Subject RIV: CD - Macromolecular Chemistry OBOR OECD: Polymer science Impact factor: 7.367, year: 2016

iBodies: Modular Synthetic Antibody Mimetics Based on Hydrophilic Polymers Decorated with Functional Moieties

Czech Academy of Sciences Publication Activity Database

Šácha, Pavel; Knedlík, Tomáš; Schimer, Jiří; Tykvart, Jan; Parolek, Jan; Navrátil, Václav; Dvořáková, Petra; Sedlák, František; Ulbrich, Karel; Strohalm, Jiří; Majer, Pavel; Šubr, Vladimír; Konvalinka, Jan

2016-01-01

Roč. 55, č. 7 (2016), s. 2356-2360 ISSN 1433-7851 R&D Projects: GA ČR GBP208/12/G016; GA MŠk LO1302 Institutional support: RVO:61388963 ; RVO:61389013 Keywords : antibody mimetics * HPMA * molecular recognition * polymer conjugates * protein targeting Subject RIV: CE - Biochemistry; CD - Macromolecular Chemistry (UMCH-V) Impact factor: 11.994, year: 2016 http://onlinelibrary.wiley.com/doi/10.1002/anie.201508642/full

Polymer donors of nitric oxide improve the treatment of experimental solid tumours with nanosized polymer therapeutics

Czech Academy of Sciences Publication Activity Database

Šírová, Milada; Horková, Veronika; Etrych, Tomáš; Chytil, Petr; Říhová, Blanka; Studenovský, Martin

2017-01-01

Roč. 25, 9-10 (2017), s. 796-808 ISSN 1061-186X R&D Projects: GA ČR(CZ) GA14-12742S; GA MZd(CZ) NV16-28600A Institutional support: RVO:61388971 ; RVO:61389013 Keywords : Drug delivery * HPMA copolymers * enhanced EPR effect Subject RIV: EE - Microbiology, Virology; CD - Macromolecular Chemistry (UMCH-V) OBOR OECD: Microbiology; Polymer science (UMCH-V) Impact factor: 3.068, year: 2016

Improved tumor-specific drug accumulation by polymer therapeutics with pH-sensitive drug release overcomes chemotherapy resistance

Czech Academy of Sciences Publication Activity Database

Heinrich, A. K.; Lucas, H.; Schindler, Lucie; Chytil, Petr; Etrych, Tomáš; Mäder, K.; Mueller, T.

2016-01-01

Roč. 15, č. 5 (2016), s. 998-1007 ISSN 1535-7163 R&D Projects: GA MŠk(CZ) ED1.1.00/02.0109; GA ČR(CZ) GA15-02986S; GA ČR(CZ) GCP207/12/J030; GA ČR(CZ) GA14-12742S Institutional support: RVO:61389013 Keywords : HPMA copolymers * doxorubicin * pH-sensitivity Subject RIV: CD - Macromolecular Chemistry Impact factor: 5.764, year: 2016

Antitumor activity of IL-2/anti-IL-2 mAb immunocomplexes exerts synergism with that of N-(2-hydroxypropyl)methacrylamide copolymer-bound doxorubicin conjugate due to its low immunosuppressive activity

Czech Academy of Sciences Publication Activity Database

Tomala, Jakub; Chmelová, Helena; Strohalm, Jiří; Ulbrich, Karel; Šírová, Milada; Říhová, Blanka; Kovář, Marek

2011-01-01

Roč. 129, č. 8 (2011), s. 2002-2012 ISSN 0020-7136 R&D Projects: GA AV ČR IAA500200712; GA ČR GD310/08/H077; GA ČR GP301/07/P192; GA MŠk 1M0505 Institutional research plan: CEZ:AV0Z50200510; CEZ:AV0Z40500505 Keywords : IL-2 immunocomplexes * NK cells * HPMA copolymer-bound doxorubicin Subject RIV: EC - Immunology Impact factor: 5.444, year: 2011

Micellar and antibody-targeted polymer therapeutics

Czech Academy of Sciences Publication Activity Database

Etrych, Tomáš; Chytil, Petr; Kovář, Lubomír; Říhová, Blanka; Ulbrich, Karel

2010-01-01

Roč. 295, - (2010), s. 1-12 ISSN 1022-1360. [Prague Meetings on Macromolecules /73./ New Frontiers in Macromolecular Science: From Macromolecular Concepts of Living Matter to Polymers for Better Quality of Life. Prague, 05.07.2009-09.07.2009] R&D Projects: GA AV ČR IAA400500806; GA AV ČR IAAX00500803; GA MŠk 1M0505 Institutional research plan: CEZ:AV0Z40500505; CEZ:AV0Z50200510 Keywords : doxorubicin * drug delivery systems * HPMA copolymers Subject RIV: CD - Macromolecular Chemistry

Development of Non-Viral, Trophoblast-Specific Gene Delivery for Placental Therapy.

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Noura Abd Ellah

Full Text Available Low birth weight is associated with both short term problems and the fetal programming of adult onset diseases, including an increased risk of obesity, diabetes and cardiovascular disease. Placental insufficiency leading to intrauterine growth restriction (IUGR contributes to the prevalence of diseases with developmental origins. Currently there are no therapies for IUGR or placental insufficiency. To address this and move towards development of an in utero therapy, we employ a nanostructure delivery system complexed with the IGF-1 gene to treat the placenta. IGF-1 is a growth factor critical to achieving appropriate placental and fetal growth. Delivery of genes to a model of human trophoblast and mouse placenta was achieved using a diblock copolymer (pHPMA-b-pDMAEMA complexed to hIGF-1 plasmid DNA under the control of trophoblast-specific promoters (Cyp19a or PLAC1. Transfection efficiency of pEGFP-C1-containing nanocarriers in BeWo cells and non-trophoblast cells was visually assessed via fluorescence microscopy. In vivo transfection and functionality was assessed by direct placental-injection into a mouse model of IUGR. Complexes formed using pHPMA-b-pDMAEMA and CYP19a-923 or PLAC1-modified plasmids induce trophoblast-selective transgene expression in vitro, and placental injection of PLAC1-hIGF-1 produces measurable RNA expression and alleviates IUGR in our mouse model, consequently representing innovative building blocks towards human placental gene therapies.

HPMA Copolymer-Bound Doxorubicin Induces Immunogenic Tumor Cell Death

Czech Academy of Sciences Publication Activity Database

Šírová, Milada; Kabešová, Martina; Kovář, Lubomír; Etrych, Tomáš; Strohalm, Jiří; Ulbrich, Karel; Říhová, Blanka

2013-01-01

Roč. 20, č. 38 (2013), s. 4815-4826 ISSN 0929-8673 R&D Projects: GA ČR GAP301/12/1254 Institutional support: RVO:61388971 ; RVO:61389013 Keywords : Anti-tumor immune response * calreticulin * heat shock proteins Subject RIV: CE - Biochemistry Impact factor: 3.715, year: 2013

Glycan-decorated HPMA copolymers as high-affinity lectin ligands

Czech Academy of Sciences Publication Activity Database

Bojarová, Pavla; Chytil, Petr; Mikulová, Barbora; Bumba, Ladislav; Konefal, Rafal; Pelantová, Helena; Krejzová, Jana; Slámová, Kristýna; Petrásková, Lucie; Kotrchová, Lenka; Cvačka, Josef; Etrych, Tomáš; Křen, Vladimír

2017-01-01

Roč. 8, č. 17 (2017), s. 2647-2658 ISSN 1759-9954 R&D Projects: GA ČR GC15-02578J; GA MZd(CZ) NV16-28594A; GA MŠk(CZ) LD15085; GA MŠk(CZ) LM2015064; GA MŠk(CZ) LO1507 Institutional support: RVO:61388971 ; RVO:61389013 ; RVO:61388963 Keywords : BETA-N-ACETYLHEXOSAMINIDASE * WHEAT-GERM-AGGLUTININ * CLICK CHEMISTRY Subject RIV: CE - Biochemistry; CD - Macromolecular Chemistry (UMCH-V) OBOR OECD: Biochemistry and molecular biology; Polymer science (UMCH-V); Polymer science (UOCHB-X) Impact factor: 5.375, year: 2016

Synthesis of phosphate monomers and bonding to dentin: esterification methods and use of phosphorus pentoxide.

Science.gov (United States)

Ogliari, Fabrício Aulo; da Silva, Eduardo de Oliveira; Lima, Giana da Silveira; Madruga, Francine Cardozo; Henn, Sandrina; Bueno, Márcia; Ceschi, Marco Antônio; Petzhold, Cesar Liberato; Piva, Evandro

2008-03-01

The aim of this study was to synthesize an acidic monomer using an alternative synthetic pathway and to evaluate the influence of the acidic monomer concentration on the microtensile bond strength to dentin. The intermediary 5-hydroxypentyl methacrylate (HPMA) was synthesized through methacrylic acid esterification with 1,5-pentanediol, catalyzed by p-toluenesulfonic acid. To displace the reaction balance, the water generated by esterification was removed by three different methods: anhydrous sodium sulfate; molecular sieves or azeotropic distillation. In the next step, a phosphorus pentoxide (4.82 mmol) slurry was formed in cold acetone and 29 mmol of HPMA was slowly added by funnel addition. After the reaction ended, solvent was evaporated and the product was characterized by 1HNMR and FTIR. The phosphate monomer was introduced in a self-etch primer at concentrations of 0, 15, 30, 50, 70 and 100 wt%. Clearfil SE Bond was used as commercial reference. Microtensile bond strength to dentin was evaluated 24h after the bonding procedures, followed by fracture analysis (n=20). Data was submitted to ANOVA and Tukey's post hoc test. The highest yield was obtained (62%) when azeotropic distillation was used, while the reaction with molecular sieves was not feasible. The phosphoric moiety attachment to the monomer was successfully performed with a quantitative yield that reached around 100%. The acidic monomer concentration significantly affected the bond strength and the highest mean (55.1+/-12.8 MPa) was obtained when 50% of acidic monomer was used. The synthesis pathways described in the present study appear to be a viable alternative for developing phosphate monomers.

HPMA copolymer-drug conjugates with controlled tumor-specific drug release

Czech Academy of Sciences Publication Activity Database

Chytil, Petr; Koziolová, Eva; Etrych, Tomáš; Ulbrich, Karel

2018-01-01

Roč. 18, č. 1 (2018), s. 1-15, č. článku 1700209. ISSN 1616-5187 R&D Projects: GA ČR(CZ) GA15-02986S; GA ČR(CZ) GA17-13283S; GA ČR(CZ) GA17-08084S; GA MŠk(CZ) LO1507 Institutional support: RVO:61389013 Keywords : biodegradable spacer * controlled drug release * drug delivery systems Subject RIV: CD - Macromolecular Chemistry OBOR OECD: Polymer science Impact factor: 3.238, year: 2016

Structural and chemical aspects of HPMA copolymers as drug carriers

Czech Academy of Sciences Publication Activity Database

Ulbrich, Karel; Šubr, Vladimír

2010-01-01

Roč. 62, č. 17 (2010), s. 150-166 ISSN 0169-409X R&D Projects: GA AV ČR KAN200200651; GA AV ČR IAAX00500803 Institutional research plan: CEZ:AV0Z40500505 Keywords : drug-delivery systems * N-(2-hydroxypropyl)methacrylamide * polymer drug conjugates Subject RIV: CD - Macromolecular Chemistry Impact factor: 13.577, year: 2010

The same drug but a different mechanism of action: comparison of free doxorubicin with two different N-(2-hydroxypropyl)methacrylamide copolymer-bound doxorubicin conjugates in EL-4 cancer cell line.

Science.gov (United States)

Kovár, Lubomír; Strohalm, Jirí; Chytil, Petr; Mrkvan, Tomás; Kovár, Marek; Hovorka, Ondrej; Ulbrich, Karel; Ríhová, Blanka

2007-01-01

Doxorubicin is one of the most potent anti-tumor drugs with a broad spectrum of use. To reduce its toxic effect and improve its pharmacokinetics, we conjugated it to an HPMA copolymer carrier that enhances its passive accumulation within solid tumors via the EPR effect and decreases its cytotoxicity to normal, noncancer cells. In this study, we compared the antiproliferative, pro-survival, and death signals triggered in EL-4 cancer cells exposed to free doxorubicin and doxorubicin conjugated to a HPMA copolymer carrier via either enzymatically (PK1) or hydrolytically (HYD) degradable bonds. We have previously shown that the intracellular distribution of free doxorubicin, HYD, and PK1 is markedly different. Here, we demonstrated that these three agents greatly differ also in the antiproliferative effect and cell death signals they trigger. JNK phosphorylation sharply increased in cells treated with HYD, while treatment with free doxorubicin moderately decreased and treatment with PK1 even strongly decreased it. On the other hand, treatment with free doxorubicin greatly increased p38 phosphorylation, while PK1 and HYD increased it slightly. PK1 also significantly increased ERK phosphorylation, while both the free doxorubicin and HYD conjugate slightly decreased it. Long-term inhibition of JNK significantly increased both proliferation and viability of EL-4 cells treated with free doxorubicin, showing that the JNK signaling pathway could be critical for mediating cell death in EL-4 cells exposed to free doxorubicin. Both activation of caspase 3 and decreased binding activity of the p50 subunit of NFkappaB were observed in cells treated with free doxorubicin and HYD, while no such effects were seen in cells incubated with PK1. Analysis of the expression of genes involved in apoptosis and regulation of the cell cycle demonstrated that free doxorubicin and HYD have very similar mechanisms of action, while PK1 has very different characteristics.

Structural diversity of solid dispersions of acetylsalicylic acid as seen by solid-state NMR.

Science.gov (United States)

Policianova, Olivia; Brus, Jiri; Hruby, Martin; Urbanova, Martina; Zhigunov, Alexander; Kredatusova, Jana; Kobera, Libor

2014-02-03

Solid dispersions of active pharmaceutical ingredients are of increasing interest due to their versatile use. In the present study polyvinylpyrrolidone (PVP), poly[N-(2-hydroxypropyl)-metacrylamide] (pHPMA), poly(2-ethyl-2-oxazoline) (PEOx), and polyethylene glycol (PEG), each in three Mw, were used to demonstrate structural diversity of solid dispersions. Acetylsalicylic acid (ASA) was used as a model drug. Four distinct types of the solid dispersions of ASA were created using a freeze-drying method: (i) crystalline solid dispersions containing nanocrystalline ASA in a crystalline PEG matrix; (ii) amorphous glass suspensions with large ASA crystallites embedded in amorphous pHPMA; (iii) solid solutions with molecularly dispersed ASA in rigid amorphous PVP; and (iv) nanoheterogeneous solid solutions/suspensions containing nanosized ASA clusters dispersed in a semiflexible matrix of PEOx. The obtained structural data confirmed that the type of solid dispersion can be primarily controlled by the chemical constitutions of the applied polymers, while the molecular weight of the polymers had no detectable impact. The molecular structure of the prepared dispersions was characterized using solid-state NMR, wide-angle X-ray scattering (WAXS), and differential scanning calorimetry (DSC). By applying various (1)H-(13)C and (1)H-(1)H correlation experiments combined with T1((1)H) and T1ρ((1)H) relaxation data, the extent of the molecular mixing was determined over a wide range of distances, from intimate intermolecular contacts (0.1-0.5 nm) up to the phase-separated nanodomains reaching ca. 500 nm. Hydrogen-bond interactions between ASA and polymers were probed by the analysis of (13)C and (15)N CP/MAS NMR spectra combined with the measurements of (1)H-(15)N dipolar profiles. Overall potentialities and limitations of individual experimental techniques were thoroughly evaluated.

Chemical conjugation of cowpea mosaic viruses with reactive HPMA-based polymers

Czech Academy of Sciences Publication Activity Database

Laga, Richard; Koňák, Čestmír; Šubr, Vladimír; Ulbrich, Karel; Suthiwangcharoen, N.; Niu, Q.; Wang, Q.

2010-01-01

Roč. 21, č. 12 (2010), s. 1669-1685 ISSN 0920-5063 R&D Projects: GA AV ČR KJB400500803; GA ČR GA202/09/2078; GA AV ČR KAN200200651 Institutional research plan: CEZ:AV0Z40500505 Keywords : acylthiazolidine-2-thione reactive groups * bioconjugation * coating Subject RIV: CD - Macromolecular Chemistry Impact factor: 1.842, year: 2010

Electrical properties of poly(vinyl chloride) films stabilized with ter polymeric photo stabilizers containing UV-absorbing groups

International Nuclear Information System (INIS)

Eid, M.A.M.; Rabie, S.T.

2005-01-01

Some ter polymeric stabilizers based on polymerizable derivatives of 2,4-dihydroxybenzophenone and phenylsalicylate have been prepared and evaluated as photo stabilizers for rigid PVC. The prepared terpolymers which are namely, methylmethacrylate/2-hydroxyethylmethacrylate/4-methacryloxy- 2-hydroxybenzophenone (MMA/HEMA/HBMA), methylmethacrylate/ 2- Hydroxyethylmethacrylate/ 2-hydroxy-4-(3-methacrylo-xy-2- hydroxypropoxy) benzophenone (MMA/HEMA/PBMA) and methylmethacrylate / 2-Hydroxy-ethyl methacrylate / phenyl-5- methacryloxy methyl salicylate (MMA / HEMA / PMMS) were characterized and their structure were confirmed by GPC, FTIR and UV-VIS spectroscopy. The dielectric study was carried out over a frequency range from 100 Hz to 100 khz at room temperature(22 degree C). The results revealed that the stabilizing effect of these terpolymers depend on the type of stabilizer (terpolymer) and the content of UV absorber units in the terpolymer. The dielectric data for the investigated systems were found to be fitted by two absorption regions using Frohlich function. These regions ascribe the Maxwell.Wagner effect and the intramolecular motion involves the rotation of various segments of the side group as the main chain motion is restricted. The study led to a conclusion that MMA/HEMA/PBMA has the greatest stabilizing efficiency may be due to the relatively longer acrylic side chain in PBMA which makes the molecule more mobile and more flexible

Hydrogel based sensor arrays (2 × 2) with perforated piezoresistive diaphragms for metabolic monitoring (in vitro).

Science.gov (United States)

Orthner, M P; Lin, G; Avula, M; Buetefisch, S; Magda, J; Rieth, L W; Solzbacher, F

2010-03-19

This report details the first experimental results from novel hydrogel sensor array (2 × 2) which incorporates analyte diffusion pores into a piezoresistive diaphragm for the detection of hydrogel swelling pressures and hence chemical concentrations. The sensor assembly was comprised of three components, the active four sensors, HPMA/DMA/TEGDMA (hydroxypropyl methacrylate (HPMA), N,N-dimethylaminoethyl methacrylate (DMA) and crosslinker tetra-ethyleneglycol dimethacrylate (TEGDMA)) hydrogel, and backing plate. Each of the individual sensors of the array can be used with various hydrogels used to measure the presence of a number of stimuli including pH, ionic strength, and glucose concentrations. Ideally, in the future, these sensors will be used for continuous metabolic monitoring applications and implanted subcutaneously. In this paper and to properly characterize the sensor assembly, hydrogels sensitive to changes ionic strength were synthesized using hydroxypropyl methacrylate (HPMA), N,N-dimethylaminoethyl methacrylate (DMA) and crosslinker tetra-ethyleneglycol dimethacrylate (TEGDMA) and inserted into the sensor assembly. This hydrogel quickly and reversibly swells when placed environments of physiological buffer solutions (PBS) with ionic strengths ranging from 0.025 to 0.15 M, making it ideal for proof-of-concept testing and initial characterization. The assembly was wire bonded to a printed circuit board and coated with 3 ± 0.5 μm of Parylene-C using chemical vapor deposition (CVD) to protect the sensor and electrical connections during ionic strength wet testing. Two versions of sensors were fabricated for comparison, the first incorporated diffusion pores into the diaphragm, and the second used a solid diaphragm with perforated backing plate. This new design (perforated diaphragm) was shown to have slightly higher sensitivity than solid diaphragm sensors with separate diffuse backing plates when coupled with the hydrogel. The sensitivities for the 1 mm

聚吡咯-酰基吡唑啉酮复合膜修饰玻碳电极测定酚磺乙胺的研究%Electrochemical Behavior and Determination of Ethamsylate on Poly-pyrrole/HPMαFP Complex Film Coated Glassy Carbon Electrode

Institute of Scientific and Technical Information of China (English)

韩慧; 李锦州; 孙仁霞

2012-01-01

报道了一种新型聚吡咯-酰基吡唑啉酮复合膜修饰玻碳电极(Ppy/HPMαFP/GCE)对酚磺乙胺(ETH)电化学性质及其反应机理的研究.酚磺乙胺的电化学性质检测运用循环伏安法和脉冲伏安法.实验表明,与裸GCE和Ppy/GCE相比,Ppy/HPM α FP/GCE修饰电极对酚磺乙胺有良好的催化作用.聚吡咯与酰基吡唑啉酮产生了协同增效作用.在pH=5.5的磷酸盐(PBS)缓冲溶液中,该修饰电极测试ETH的CV曲线于0.35V和0.4V出现一对灵敏的氧化还原峰,峰电位差△Ep较裸玻碳电极降低510mV,比Ppy修饰电极降低100mV,峰电流显著增加.在最佳条件下,氧化峰电流与ETH浓度于2.0×10-6～1.0×10-4mol·L-1范围内呈现良好的线性关系,检出限为6.0×10-7mol·L-1.%In this paper, a novel voltammetric method using poly-pyrrole and acyl-pyrazolone composite film modified glassy carton electrode (Ppy /HPMaFP /CCE) was developed for studying the electrochemical behavior and reaction mechanism of ethamsylate. The electrochemical parameters of ethamsylate were investigated by cyclic voltammetry and differential pulse voltammetry. Compared to the bare GCE and Ppy /GCE, the Ppy/HP-MaFP /CCE showed an excellent electro-catalytical effect on the oxidation of ethamsylate with significant increase in the peak current. The above results indicated that a synergistic effect was existed between poly-pyrrole and HPMaFP. According to the experiment, In PBS buffer solution with a pH of 5.5, a pair of sensitive redox peaks with Epa=0.40V, Epc=0.35V(vs.SCE) was obtained on the PPyHPMaFP modified electrode. The difference of peak potentials(△ Ep) was 510mV which was lower than on bare glassy carbon electrode, and about 100mV lower than on Ppy modified electrode. Meanwhile, the peak current markedly increased. Under the optimum conditions, linear calibration curve was obtained in the concentration range of2.0×10-6 ～1.0×10-4 mol·L-1. The detection limit was 6.0×10-7 mol·L-1.

Neutral Polymeric Micelles for RNA Delivery

Science.gov (United States)

Lundy, Brittany B.; Convertine, Anthony; Miteva, Martina; Stayton, Patrick S.

2013-01-01

RNA interference (RNAi) drugs have significant therapeutic potential but delivery systems with appropriate efficacy and toxicity profiles are still needed. Here, we describe a neutral, ampholytic polymeric delivery system based on conjugatable diblock polymer micelles. The diblock copolymer contains a hydrophilic poly[N-(2-hydroxypropyl) methacrylamide-co-N-(2-(pyridin-2- yldisulfanyl)ethyl)methacrylamide) (poly[HPMA-co-PDSMA]) segment to promote aqueous stability and facilitate thiol-disulfide exchange reactions, and a second ampholytic block composed of propyl acrylic acid (PAA), dimethylaminoethyl methacrylate (DMAEMA), and butyl methacrylate (BMA). The poly[(HPMA-co-PDSMA)-b-(PAA-co-DMAEMA-co-BMA)] was synthesized using Reversible Addition-Fragmentation chain Transfer (RAFT) polymerization with an overall molecular weight of 22,000 g/mol and a PDI of 1.88. Dynamic light scattering and fluorescence measurements indicated that the diblock copolymers self-assemble under aqueous conditions to form polymeric micelles with a hydrodynamic radius and critical micelle concentration of 25 nm and 25 μg/mL respectively. Red blood cell hemolysis experiments show that the neutral hydrophilic micelles have potent membrane destabilizing activity at endosomal pH values. Thiolated siRNA targeting glyceraldehyde 3-phosphate dehydrogenase (GAPDH) was directly conjugated to the polymeric micelles via thiol exchange reactions with the pyridal disulfide groups present in the micelle corona. Maximum silencing activity in HeLa cells was observed at a 1:10 molar ratio of siRNA to polymer following a 48 h incubation period. Under these conditions 90 % mRNA knockdown and 65 % and protein knockdown of at 48 h was achieved with negligible toxicity. In contrast the polymeric micelles lacking a pH-responsive endosomalytic segment demonstrated negligible mRNA and protein knockdown under these conditions. The potent mRNA knockdown and excellent biocompatibility of the neutral siRNA conjugates

HPMA-based polymeric micelles for curcumin solubilization and inhibition of cancer cell growth

NARCIS (Netherlands)

Naksuriya, Ornchuma; Shi, Yang; Van Nostrum, Cornelus F.|info:eu-repo/dai/nl/134498690; Anuchapreeda, Songyot; Hennink, Wim E.|info:eu-repo/dai/nl/070880409; Okonogi, Siriporn

2015-01-01

Abstract Curcumin (CM) has been reported as a potential anticancer agent. However, its pharmaceutical applications as therapeutic agent are hampered because of its poor aqueous solubility. The present study explores the advantages of polymeric micelles composed of block copolymers of

Detection and cellular localisation of the synthetic soluble macromolecular drug carrier pHPMA

Czech Academy of Sciences Publication Activity Database

Kissel, M.; Peschke, P.; Šubr, Vladimír; Ulbrich, Karel; Strunz, A. M.; Kühnlein, R.; Debus, J.; Friedrich, E.

2002-01-01

Roč. 29, č. 8 (2002), s. 1055-1062 ISSN 1619-7070 R&D Projects: GA ČR GV307/96/K226 Institutional research plan: CEZ:AV0Z4050913 Keywords : EPR effect * Radiolabelled macromolecules * Pharmacokinetic Subject RIV: CD - Macromolecular Chemistry Impact factor: 3.568, year: 2002

Health risk evaluation in a population exposed to chemical releases from a petrochemical complex in Thailand.

Science.gov (United States)

Kampeerawipakorn, Ormrat; Navasumrit, Panida; Settachan, Daam; Promvijit, Jeerawan; Hunsonti, Potchanee; Parnlob, Varabhorn; Nakngam, Netnapa; Choonvisase, Suppachai; Chotikapukana, Passaornrawan; Chanchaeamsai, Samroeng; Ruchirawat, Mathuros

2017-01-01

Emissions from petrochemical industries may contain toxic and carcinogenic compounds that can pose health risk to human populations. The scenario may be worse in developing countries where management of such exposure-health problems is typically not well-implemented and the public may not be well-informed about such health risk. In Thailand, increasing incidences of respiratory diseases and cancers have been reported for the population around a major petrochemical complex, the Map Ta Phut Industrial Estate (MTPIE). This study aimed to systematically investigate an exposure-health risk among these populations. One-hundred and twelve healthy residents living nearby MTPIE and 50 controls located approximately 40km from MTPIE were recruited. Both external and internal exposure doses to benzene and 1,3-butadiene, known to be associated with the types of cancer that are of concern, were measured because they represent exposure to industrial and/or traffic-related emissions. Health risk was assessed using the biomarkers of early biological effects for cancer and inflammatory responses, as well as biomarkers of exposure for benzene and 1,3-butadiene. The exposure levels of benzene and 1,3-butadiene were similar for both the exposed and control groups. This was confirmed by a non-significant difference in the levels of specific urinary metabolites for benzene (trans,trans-muconic acid, t,t-MA) and 1,3-butadiene (monohydroxy-butyl mercapturic acid, MHBMA). Levels of 8-hydroxydeoxyguanosine (8-OHdG) and DNA strand breaks between the two groups were not statistically significantly different. However, functional biomarkers, interleukin-8 (IL-8) expression was significantly higher (pindustrial complex could be causing these functional abnormalities. Copyright © 2016 Elsevier Inc. All rights reserved.

Influence of monomer on structure, processing and application characteristics of UV curable urethane acrylate composite coatings

International Nuclear Information System (INIS)

Grigale-Sorocina, Z; Kalnins, M; Gross, K A

2016-01-01

Increased interest in the esthetical natural nail coatings have encouraged more in-depth studies particularly of UV curable coatings: their formation, processing, structure, characteristics and removing. Typical requirement for nail coatings is good adhesion, but preferably for the short time of functioning (usual 2-4 weeks). This study investigated the impact of four different monomers (tertiobutyl cyclohexyl acrylate (TBCHA), ethylene glycol dimethacrylate (EGDMA), tetrahydrofurfuryl acrylate (THFA), hydroxypropyl methacrylate (HPMA)) to viscosity of uncured mixture and degree of conversion, mechanical properties, surface gloss, micro hardness and adhesion loss for cured films. Specific coating application requires comparatively high coating flexibility and stability of deformation characteristics. This can be achieved with composition containing 30% of monomer TBCHA, what shows ultimate elongation ε B = 0,23 - 0,24, modulus of elasticity E = 670-710 MPa and comparatively constant properties in 72 hours (ΔE = 1.3%, Δε B =6.0%). A composition with 40% of TBCHA shows the fastest coating destruction achieving adhesion loss within 3 min. (paper)

Study of the therapeutic benefit of cationic copolymer administration to vascular endothelium under mechanical stress

Science.gov (United States)

Giantsos-Adams, Kristina; Lopez-Quintero, Veronica; Kopeckova, Pavla; Kopecek, Jindrich; Tarbell, John M.; Dull, Randal

2015-01-01

Pulmonary edema and the associated increases in vascular permeability continue to represent a significant clinical problem in the intensive care setting, with no current treatment modality other than supportive care and mechanical ventilation. Therapeutic compound(s) capable of attenuating changes in vascular barrier function would represent a significant advance in critical care medicine. We have previously reported the development of HPMA-based copolymers, targeted to endothelial glycocalyx that are able to enhance barrier function. In this work, we report the refinement of copolymer design and extend our physiological studies todemonstrate that the polymers: 1) reduce both shear stress and pressure-mediated increase in hydraulic conductivity, 2) reduce nitric oxide production in response to elevated hydrostatic pressure and, 3) reduce the capillary filtration coefficient (Kfc) in an isolated perfused mouse lung model. These copolymers represent an important tool for use in mechanotransduction research and a novel strategy for developing clinically useful copolymers for the treatment of vascular permeability. PMID:20932573

Study on immobilized yeast cells with hydrophilic polymer carrier by radiation-induced copolymerization

International Nuclear Information System (INIS)

Li Zhengkui; Zhang Bosen

1993-01-01

Various kinds of monomers 2-hydroxyethyl methacrylate (HEMA), 2-hydroxyethyl acrylate (HEA), hydroxypropyl methacrylate (HPMA) and methoxy polyethylene glycol methylacrylate (M-23G) are copolymerized by radiation technique at low temperature (-78 degree C) and several kinds of copolymer carriers were obtained. Yeast cells are immobilized through adhesion and multiplication of yeast cells themselves on these carriers. The ethanol productivity of immobilized yeast cells with these carriers was related to the monomer composition and water content of copolymer carriers and the optimum monomer composition was 20%:10% in poly (HEA-M23G). In this case, the ethanol productivity of immobilized yeast cells was 26 mg/(ml · h), which was 4 times as high as that of free cells. Effect of adding crosslinking reagent (4G) in lower monomer composition of poly(HEA-M23G) on the ethanol productivity of immobilized cells was better than that in higher one in this work

The influence of a colonic microbiota on HPMA copolymer lectin conjugates binding in rodent intestine

Czech Academy of Sciences Publication Activity Database

Wróblewski, S.; Říhová, Blanka; Rossmann, Pavel; Hudcovic, Tomáš; Řeháková, Zuzana; Kopečková, P.; Kopeček, J.

2001-01-01

Roč. 9, č. 2 (2001), s. 85-94 ISSN 1061-186X R&D Projects: GA MPO PZ-Z2/24 Institutional research plan: CEZ:AV0Z5020903 Keywords : colonic microflora * germ-free * glycoproteins Subject RIV: EC - Immunology Impact factor: 2.186, year: 2001

HPMA-based polymer therapeutics improve the efficacy of surgery, of radiotherapy and of chemotherapy combinations

Czech Academy of Sciences Publication Activity Database

Lammers, T.; Šubr, Vladimír; Ulbrich, Karel; Peschke, P.; Huber, P. E.; Hennink, W. E.; Storm, G.; Kiessling, F.

2010-01-01

Roč. 5, č. 10 (2010), s. 1501-1523 ISSN 1743-5889 R&D Projects: GA MŠk 1M0505 Institutional research plan: CEZ:AV0Z40500505 Keywords : N-(2-hydroxypropyl)methacrylamide copolymers * nanomedicine * drug delivery Subject RIV: EI - Biotechnology ; Bionics Impact factor: 6.202, year: 2010

Proteolysis of truncated hemolysin A yields a stable dimerization interface

Energy Technology Data Exchange (ETDEWEB)

Novak, Walter R.P.; Bhattacharyya, Basudeb; Grilley, Daniel P.; Weaver, Todd M. (Wabash); (UW)

2017-02-21

Wild-type and variant forms of HpmA265 (truncated hemolysin A) fromProteus mirabilisreveal a right-handed, parallel β-helix capped and flanked by segments of antiparallel β-strands. The low-salt crystal structures form a dimeric structureviathe implementation of on-edge main-chain hydrogen bonds donated by residues 243–263 of adjacent monomers. Surprisingly, in the high-salt structures of two variants, Y134A and Q125A-Y134A, a new dimeric interface is formedviamain-chain hydrogen bonds donated by residues 203–215 of adjacent monomers, and a previously unobserved tetramer is formed. In addition, an eight-stranded antiparallel β-sheet is formed from the flap regions of crystallographically related monomers in the high-salt structures. This new interface is possible owing to additional proteolysis of these variants after Tyr240. The interface formed in the high-salt crystal forms of hemolysin A variants may mimic the on-edge β-strand positioning used in template-assisted hemolytic activity.

Macromolecular pHPMA-based nanoparticles with cholesterol for solid tumor targeting: behavior in HSA protein environment

Czech Academy of Sciences Publication Activity Database

Zhang, X.; Niebuur, B.-J.; Chytil, Petr; Etrych, Tomáš; Filippov, Sergey K.; Kikhney, A.; Wieland, D. C. F.; Svergun, D. I.; Papadakis, C. M.

2018-01-01

Roč. 19, č. 2 (2018), s. 470-480 ISSN 1525-7797 R&D Projects: GA ČR(CZ) GC15-10527J; GA MZd(CZ) NV16-28594A; GA MŠk(CZ) LO1507 Institutional support: RVO:61389013 Keywords : polymer carriers * N-(2-hydroxypropyl)methacrylamide * tumor targeting Subject RIV: CD - Macromolecular Chemistry OBOR OECD: Polymer science Impact factor: 5.246, year: 2016

HPMA-RGD Hydrogels Seeded with Mesenchymal Stem Cells Improve Functional Outcome in Chronic Spinal Cord Injury

Czech Academy of Sciences Publication Activity Database

Hejčl, Aleš; Šedý, Jiří; Kapcalová, Miroslava; Arboleda Toro, David; Amemori, Takashi; Lesný, Petr; Likavčanová, Katarína; Krumbholcová, Eva; Přádný, Martin; Michálek, Jiří; Burian, M.; Hájek, M.; Jendelová, Pavla; Syková, Eva

2010-01-01

Roč. 19, č. 10 (2010), s. 1535-1546 ISSN 1547-3287 R&D Projects: GA MŠk(CZ) LC554; GA AV ČR IAA500390902 Grant - others:GA ČR(CZ) GD309/08/H079; GA MZd(CZ) 1A8697; GA MŠk(CZ) 1M0538; EC FP6 project RESCUE(XE) LSHB-CT-2005-518233 Program:1M Institutional research plan: CEZ:AV0Z50390703; CEZ:AV0Z40500505 Keywords : magnetic-resonance tracking * spinal cord injury * stem cells Subject RIV: FH - Neurology Impact factor: 4.791, year: 2010

Combination chemotherapy using core-shell nanoparticles through the self-assembly of HPMA-based copolymers and degradable polyester

Czech Academy of Sciences Publication Activity Database

Jäger, Eliezer; Jäger, Alessandro; Chytil, Petr; Etrych, Tomáš; Říhová, Blanka; Giacomelli, F. C.; Štěpánek, Petr; Ulbrich, Karel

2013-01-01

Roč. 165, č. 2 (2013), s. 153-161 ISSN 0168-3659 R&D Projects: GA AV ČR IAAX00500803; GA ČR GA202/09/2078; GA ČR GPP207/11/P551 Institutional research plan: CEZ:AV0Z40500505; CEZ:AV0Z50200510 Institutional support: RVO:61389013 ; RVO:61388971 Keywords : combination therapy * polymeric core-shell nanoparticles * docetaxel Subject RIV: CD - Macromolecular Chemistry; EC - Immunology (MBU-M) Impact factor: 7.261, year: 2013

HPMA copolymer-doxorubicin conjugates: the effects of molecular weight and architecture on biodistribution and in vivo activity

Czech Academy of Sciences Publication Activity Database

Etrych, Tomáš; Šubr, Vladimír; Strohalm, Jiří; Šírová, Milada; Říhová, Blanka; Ulbrich, Karel

2012-01-01

Roč. 164, č. 3 (2012), s. 346-354 ISSN 0168-3659. [European Symposium on Controlled Drug Delivery /12./. Egmond aan Zee, 04.04.2012-06.04.2012] R&D Projects: GA AV ČR IAAX00500803; GA ČR GAP301/11/0325 Institutional research plan: CEZ:AV0Z40500505; CEZ:AV0Z50200510 Institutional support: RVO:61389013 ; RVO:61388971 Keywords : drug delivery * tumour accumulation * body distribution Subject RIV: CD - Macromolecular Chemistry; EC - Immunology (MBU-M) Impact factor: 7.633, year: 2012

Acute systemic accumulation of acrolein in mice by inhalation at a concentration similar to that in cigarette smoke.

Science.gov (United States)

Tully, Melissa; Zheng, Lingxing; Acosta, Glen; Tian, Ran; Shi, Riyi

2014-12-01

Cigarette smoke is an important environmental factor associated with a wide array of public health concerns. Acrolein, a component of tobacco smoke and a known toxin to various cell types, may be a key pathological factor mediating the adverse effects linked with tobacco smoke. Although acrolein is known to accumulate in the respiratory system after acute nasal exposure, it is not clear if it accumulates systemically, and less is known in the nervous system. The aim of this study was to assess the degree of acrolein accumulation in the circulation and in the spinal cord following acute acrolein inhalation in mice. Using a laboratory-fabricated inhalation chamber, we found elevated urinary 3-HPMA, an acrolein metabolite, and increased acrolein adducts in the spinal cord after weeks of nasal exposure to acrolein at a concentration similar to that in tobacco smoke. The data indicated that acrolein is absorbed into the circulatory system and some enters the nervous system. It is expected that these findings may facilitate further studies to probe the pathological role of acrolein in the nervous system resulting from smoke and other external sources.

Allergic contact dermatitis from sculptured acrylic nails: special presentation with an airborne pattern

Science.gov (United States)

Maio, Paula; Carvalho, Rodrigo; Amaro, Cristina; Santos, Raquel; Cardoso, Jorge

2012-01-01

Methylmethacrylate was first reported in 1941 as a cause of contact dermatitis. Since then, occupational contact allergies to acrylates in dentistry, orthopedic surgery, printing industry and industry have been reported, but few reports are found in the literature as a consequence of the contact with sculptured artificial acrylic nails which are increasingly popular. We describe here 3 patients with contact allergy to acrylates in artificial sculptured nails. Patch tests were performed with the Portuguese baseline series of contact allergens and an extended series of acrylates were applied. In particular, we tested three female patients with allergic contact dermatitis from sculptured acrylic nails. Two of these patients were both customers and also technical nail beauticians. Two patients developed periungual eczema; one presented only with face and eyelid dermatitis had no other lesions. The tests showed positive reaction to 2-hydroxyethylmethacrylate (2-HEMA) and 2-hydroxypropylmethacrylate (2-HPMA) in all the three patients. Our cases demonstrate the variety of clinical presentations of allergic contact dermatitis from acrylic sculptured nails. They show the need to warn patients of persistent and sometimes permanent side effects of these products. They also emphasize the importance of cosmetic ingredient labeling. PMID:25386316

Self-assembly of biodegradable copolyester and reactive HPMA-based polymers into nanoparticles as an alternative stealth drug delivery system

Czech Academy of Sciences Publication Activity Database

Jäger, Eliezer; Jäger, Alessandro; Etrych, Tomáš; Giacomelli, F. C.; Chytil, Petr; Jigounov, Alexander; Putaux, J.-L.; Říhová, Blanka; Ulbrich, Karel; Štěpánek, Petr

2012-01-01

Roč. 8, č. 37 (2012), s. 9563-9575 ISSN 1744-683X R&D Projects: GA AV ČR IAAX00500803; GA ČR GAP208/10/1600 Institutional research plan: CEZ:AV0Z40500505; CEZ:AV0Z50200510 Institutional support: RVO:61389013 ; RVO:61388971 Keywords : biodegradable nanoparticles * light scattering from polymer nanoparticles * doxorubicin drug release Subject RIV: CF - Physical ; Theoretical Chemistry; EC - Immunology (MBU-M) Impact factor: 3.909, year: 2012

Isotope Dilution nanoLC/ESI+-HRMS3 Quantitation of Urinary N7-(1-Hydroxy-3-buten-2-yl) Guanine Adducts in Humans and Their Use as Biomarkers of Exposure to 1,3-Butadiene.

Science.gov (United States)

Sangaraju, Dewakar; Boldry, Emily J; Patel, Yesha M; Walker, Vernon; Stepanov, Irina; Stram, Daniel; Hatsukami, Dorothy; Tretyakova, Natalia

2017-02-20

1,3-Butadiene (BD) is an important industrial and environmental chemical classified as a known human carcinogen. Occupational exposure to BD in the polymer and monomer industries is associated with an increased incidence of lymphoma. BD is present in automobile exhaust, cigarette smoke, and forest fires, raising concern about potential exposure of the general population to this carcinogen. Following inhalation exposure, BD is bioactivated to 3,4-epoxy-1-butene (EB). If not detoxified, EB is capable of modifying guanine and adenine bases of DNA to form nucleobase adducts, which interfere with accurate DNA replication and cause cancer-initiating mutations. We have developed a nanoLC/ESI + -HRMS 3 methodology for N7-(1-hydroxy-3-buten-2-yl) guanine (EB-GII) adducts in human urine (limit of detection: 0.25 fmol/mL urine; limit of quantitation: 1.0 fmol/mL urine). This new method was successfully used to quantify EB-GII in urine of F344 rats treated with 0-200 ppm of BD, occupationally exposed workers, and smokers belonging to two different ethnic groups. EB-GII amounts increased in a dose-dependent manner in urine of laboratory rats exposed to 0, 62.5, or 200 ppm of BD. Urinary EB-GII levels were significantly increased in workers occupationally exposed to 0.1-2.2 ppm of BD (1.25 ± 0.51 pg/mg of creatinine) as compared to administrative controls exposed to <0.01 ppm of BD (0.22 ± 0.08 and pg/mg of creatinine) (p = 0.0024), validating the use of EB-GII as a biomarker of human exposure to BD. EB-GII was also detected in smokers' urine with European American smokers excreting significantly higher amounts of EB-GII than African American smokers (0.48 ± 0.09 vs 0.12 ± 0.02 pg/mg of creatinine, p = 3.1 × 10 -7 ). Interestingly, small amounts of EB-GII were observed in animals and humans with no known exposure to BD, providing preliminary evidence for its endogenous formation. Urinary EB-GII adduct levels and urinary mercapturic acids of BD (MHBMA, DHBMA) were compared

A smart polymeric platform for multistage nucleus-targeted anticancer drug delivery.

Science.gov (United States)

Zhong, Jiaju; Li, Lian; Zhu, Xi; Guan, Shan; Yang, Qingqing; Zhou, Zhou; Zhang, Zhirong; Huang, Yuan

2015-10-01

Tumor cell nucleus-targeted delivery of antitumor agents is of great interest in cancer therapy, since the nucleus is one of the most frequent targets of drug action. Here we report a smart polymeric conjugate platform, which utilizes stimulus-responsive strategies to achieve multistage nuclear drug delivery upon systemic administration. The conjugates composed of a backbone based on N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer and detachable nucleus transport sub-units that sensitive to lysosomal enzyme. The sub-units possess a biforked structure with one end conjugated with the model drug, H1 peptide, and the other end conjugated with a novel pH-responsive targeting peptide (R8NLS) that combining the strength of cell penetrating peptide and nuclear localization sequence. The conjugates exhibited prolonged circulation time and excellent tumor homing ability. And the activation of R8NLS in acidic tumor microenvironment facilitated tissue penetration and cellular internalization. Once internalized into the cell, the sub-units were unleashed for nuclear transport through nuclear pore complex. The unique features resulted in 50-fold increase of nuclear drug accumulation relative to the original polymer-drug conjugates in vitro, and excellent in vivo nuclear drug delivery efficiency. Our report provides a strategy in systemic nuclear drug delivery by combining the microenvironment-responsive structure and detachable sub-units. Copyright © 2015 Elsevier Ltd. All rights reserved.

[Etiological and molecular characteristics of diarrhea caused Proteus mirabilis].

Science.gov (United States)

Shi, Xiaolu; Hu, Qinghua; Lin, Yiman; Qiu, Yaqun; Li, Yinghui; Jiang, Min; Chen, Qiongcheng

2014-06-01

To analyze the etiological characteristics, virulence genes and plasmids that carrying diarrhea-causing Proteus mirabilis and to assess their relationship with drug resistance and pathogenicity. Proteus mirabilis coming from six different sources (food poisoning, external environment and healthy people) were analyzed biochemically, on related susceptibility and pulsed-field gel electrophoresis (PFGE). Virulence genes were detected by PCR. Plasmids were extracted and sequenced after gel electrophoresis purification. The biochemical characteristics of Proteus mirabilis from different sources seemed basically the same, and each of them showed having common virulence genes, as ureC, rsmA, hpmA and zapA. However, the PFGE patterns and susceptibility of these strains were different, so as the plasmids that they carried. Plasmid that presented in the sequenced strain showed that the 2 683 bp length plasmid encodes qnrD gene was associated with the quinolone resistance. Etiological characteristics and molecular characteristics of Proteus mirabilis gathered from different sources, were analyzed. Results indicated that traditional biochemical analysis and common virulence gene identification might be able to distinguish the strains with different sources. However, PFGE and plasmids analysis could distinguish the sources of strains and to identify those plasmids that commonly carried by the drug-resistant strains. These findings also provided theoretical basis for further study on the nature of resistance and pathogenicity in Proteus mirabilis.

Interaction of spin-labeled HPMA-based nanoparticles with human blood plasma proteins - the introduction of protein-corona-free polymer nanomedicine

Czech Academy of Sciences Publication Activity Database

Klepac, Damir; Kostková, Hana; Petrova, Svetlana; Chytil, Petr; Etrych, Tomáš; Kereiche, S.; Raška, I.; Weitz, D. A.; Filippov, Sergey K.

2018-01-01

Roč. 10, č. 13 (2018), s. 6194-6204 ISSN 2040-3364 R&D Projects: GA MŠk(CZ) LH15213; GA ČR(CZ) GA17-07164S Institutional support: RVO:61389013 Keywords : EPR * nanoparticles * protein s Subject RIV: CD - Macromolecular Chemistry OBOR OECD: Polymer science Impact factor: 7.367, year: 2016

Overcoming multidrug resistance via simultaneous delivery of cytostatic drug and P-glycoprotein inhibitor to cancer cells by HPMA copolymer conjugate

Czech Academy of Sciences Publication Activity Database

Sivák, Ladislav; Šubr, Vladimír; Tomala, Jakub; Říhová, Blanka; Strohalm, Jiří; Etrych, Tomáš; Kovář, Marek

2017-01-01

Roč. 115, JAN 2017 (2017), s. 65-80 ISSN 0142-9612 R&D Projects: GA ČR(CZ) GAP301/12/1254; GA MŠk(CZ) LQ1604; GA MŠk(CZ) ED1.1.00/02.0109 Institutional support: RVO:61388971 ; RVO:61389013 Keywords : Multidrug resistance * P-glycoprotein * Doxorubicin Subject RIV: EE - Microbiology, Virology; CD - Macromolecular Chemistry (UMCH-V) OBOR OECD: Microbiology; Polymer sci ence (UMCH-V) Impact factor: 8.402, year: 2016

Overcoming multidrug resistance with inhibitor of ABC transporters bound to HPMA copolymer carrier as a potential therapeutic approach in cancer treatment

Czech Academy of Sciences Publication Activity Database

Sivák, Ladislav; Šubr, Vladimír; Ulbrich, Karel; Říhová, Blanka; Šírová, Milada; Kovář, Marek

SI (2016), s. 25-25 ISSN 0014-2980. [3rd Meeting of Middle – European Societies for Immunology and Allergology. 01.12.2016-03.12.2016, Budapest ] R&D Projects: GA ČR(CZ) GAP301/12/1254 Institutional support: RVO:61388971 ; RVO:61389013 Keywords : Cancer * chemotherapy * cytostatic drugs Subject RIV: EE - Microbiology, Virology

Micelles of zinc protoporphyrin conjugated to N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer for imaging and light-induced antitumor effects in vivo

Czech Academy of Sciences Publication Activity Database

Nakamura, H.; Liao, L.; Hitaka, Y.; Tsukigawa, K.; Šubr, Vladimír; Fang, J.; Ulbrich, Karel; Maeda, H.

2013-01-01

Roč. 165, č. 3 (2013), s. 191-198 ISSN 0168-3659 R&D Projects: GA AV ČR IAAX00500803 Institutional research plan: CEZ:AV0Z40500505 Institutional support: RVO:61389013 Keywords : fluorescence imaging * fluorescent nanoprobe * singlet oxygen Subject RIV: CD - Macromolecular Chemistry Impact factor: 7.261, year: 2013

Overcoming multidrug resistance in Dox-resistant neuroblastoma cell lines via treatment with HPMA copolymer conjugates containing anthracyclines and P-gp inhibitors

Czech Academy of Sciences Publication Activity Database

Koziolová, Eva; Janoušková, Olga; Cuchalová, Lucie; Hvězdová, Zuzana; Hraběta, J.; Eckschlager, T.; Sivák, Ladislav; Ulbrich, Karel; Etrych, Tomáš; Šubr, Vladimír

2016-01-01

Roč. 233, 10 July (2016), s. 136-146 ISSN 0168-3659 R&D Projects: GA ČR(CZ) GAP301/12/1254; GA MŠk(CZ) LO1507 Institutional support: RVO:61389013 ; RVO:61388971 Keywords : N-(2-hydroxypropyl)methacrylamide copolymers * multidrug resistance * P-glycoprotein inhibitors Subject RIV: CD - Macromolecular Chemistry ; FD - Oncology ; Hematology (MBU-M) Impact factor: 7.786, year: 2016

Characterizing EPR-mediated passive drug targeting using contrast-enhanced functional ultrasound imaging.

Science.gov (United States)

Theek, Benjamin; Gremse, Felix; Kunjachan, Sijumon; Fokong, Stanley; Pola, Robert; Pechar, Michal; Deckers, Roel; Storm, Gert; Ehling, Josef; Kiessling, Fabian; Lammers, Twan

2014-05-28

The Enhanced Permeability and Retention (EPR) effect is extensively used in drug delivery research. Taking into account that EPR is a highly variable phenomenon, we have here set out to evaluate if contrast-enhanced functional ultrasound (ceUS) imaging can be employed to characterize EPR-mediated passive drug targeting to tumors. Using standard fluorescence molecular tomography (FMT) and two different protocols for hybrid computed tomography-fluorescence molecular tomography (CT-FMT), the tumor accumulation of a ~10 nm-sized near-infrared-fluorophore-labeled polymeric drug carrier (pHPMA-Dy750) was evaluated in CT26 tumor-bearing mice. In the same set of animals, two different ceUS techniques (2D MIOT and 3D B-mode imaging) were employed to assess tumor vascularization. Subsequently, the degree of tumor vascularization was correlated with the degree of EPR-mediated drug targeting. Depending on the optical imaging protocol used, the tumor accumulation of the polymeric drug carrier ranged from 5 to 12% of the injected dose. The degree of tumor vascularization, determined using ceUS, varied from 4 to 11%. For both hybrid CT-FMT protocols, a good correlation between the degree of tumor vascularization and the degree of tumor accumulation was observed, within the case of reconstructed CT-FMT, correlation coefficients of ~0.8 and p-values of EPR, and potentially also to pre-select patients likely to respond to passively tumor-targeted nanomedicine treatments. Copyright © 2014 Elsevier B.V. All rights reserved.

Synthesis and Characterization of Super absorbent Hydrogels Based on Natural Polymers Using Ionizing Radiations

International Nuclear Information System (INIS)

Deghiedy, N.M.A.

2010-01-01

Radiation processing technology is a useful tool for modification of polymer material including grafting of monomer onto polymer. In this study, novel super absorbent hydrogels was prepared with biodegradable and eco-friendly properties by graft copolymerization of chitosan and different synthetic monomers (AAc, DEAEMA, HEMA, HPMA and HEA) using gamma irradiation to examine the potential use of these hydrogels in the controlled drug release systems. The different chitosan hydrogels were characterized using FTIR spectroscopy, scanning electron microscopy and thermal analysis techniques. The effects of the preparation conditions on the gelation process of the synthesized copolymer were investigated. The influence of variables such as feed concentration, irradiation dose, composition ratio, ph and temperature on the swelling of the prepared hydrogels was also examined. The water absorbency of these hydrogels in various ph and salt solutions was studied. The swelling kinetics of the prepared hydrogels and in vitro release dynamics of model drug (Chlortetracycline hydrochloride) from these hydrogels has been studied for the evaluation of swelling mechanism and drug release mechanism from the hydrogels. The adsorption and in vitro release profiles of Chlortetracycline HCl from the prepared gels were also estimated in different ph buffers. The amount of drug released from CS/ (AAc-DEAEMA) hydrogels was higher than that released from other modified CS/AAc hydrogels. This preliminary investigation of chitosan based hydrogels showed that they may be exploited to expand the utilization of these systems in drug delivery applications

Folic acid derivatives for PET imaging and therapy addressing folate receptor positive tumors

Energy Technology Data Exchange (ETDEWEB)

Schieferstein, Hanno

2013-07-01

conducted. The synthesis of the folate-boron clusters was straightforward. At first, a linker molecule based on maleic acid was synthesized, which was coupled to the boron cluster via Michael Addition of a thiol and alkene and subsequently coupled to the targeting moiety using CuAAC. The new conjugates of folate and boron clusters led to a significant increase of boron concentration in the cell of about 5-times compared to currently used and approved boron pharmaceuticals. Moreover, azido-folate derivatives were coupled to macromolecular carrier systems (pHPMA), which showed an enhanced and specific accumulation at target sites (up to 2.5-times) during in vivo experiments. A specific blockade could be observed up to 30% indicating an efficient targeting effect. A new kind of nanoparticles consisting of a PDLLA core and p((HPMA)-b-(LMA)) as surfactants were developed and successfully radiolabeled via {sup 18}F-click chemistry in good RCYs of 8±3%. The nanoparticles were obtained via the miniemulsion technique in combination with solvent evaporation. The {sup 18}F-labeled nanoparticles were applied to in vivo testing using a mouse model. PET imaging showed a ''mixed'' biodistribution of low molecular weight as well as high molecular weight systems, indicating a partial loss of the {sup 18}F-labeled surfactant. In conclusion, the presented work successfully utilized the FR-targeting concept in both, the diagnostic field (PET imaging) and for therapeutic approaches (BNCT, drug delivery systems). As a result, the high potential of FR-targeting in oncological applications has been shown and was confirmed by small animal PET imaging.

Folic acid derivatives for PET imaging and therapy addressing folate receptor positive tumors

International Nuclear Information System (INIS)

Schieferstein, Hanno

2013-01-01

the folate-boron clusters was straightforward. At first, a linker molecule based on maleic acid was synthesized, which was coupled to the boron cluster via Michael Addition of a thiol and alkene and subsequently coupled to the targeting moiety using CuAAC. The new conjugates of folate and boron clusters led to a significant increase of boron concentration in the cell of about 5-times compared to currently used and approved boron pharmaceuticals. Moreover, azido-folate derivatives were coupled to macromolecular carrier systems (pHPMA), which showed an enhanced and specific accumulation at target sites (up to 2.5-times) during in vivo experiments. A specific blockade could be observed up to 30% indicating an efficient targeting effect. A new kind of nanoparticles consisting of a PDLLA core and p((HPMA)-b-(LMA)) as surfactants were developed and successfully radiolabeled via 18 F-click chemistry in good RCYs of 8±3%. The nanoparticles were obtained via the miniemulsion technique in combination with solvent evaporation. The 18 F-labeled nanoparticles were applied to in vivo testing using a mouse model. PET imaging showed a ''mixed'' biodistribution of low molecular weight as well as high molecular weight systems, indicating a partial loss of the 18 F-labeled surfactant. In conclusion, the presented work successfully utilized the FR-targeting concept in both, the diagnostic field (PET imaging) and for therapeutic approaches (BNCT, drug delivery systems). As a result, the high potential of FR-targeting in oncological applications has been shown and was confirmed by small animal PET imaging.

Studies on the utility and mechanism of the V-79 cell metabolic cooperation assay for tumor promoters

International Nuclear Information System (INIS)

Hartman, T.G.

1985-01-01

Cigarette smoke condensate and its fractions were tested for activity in the V-79 Metabolic Cooperation Assay to determine the usefulness of the assay for analysis of a complex mixture and to compare the results obtained with previously conducted in vivo promoter assays. The whole condensate and several of its fractions were positive in the assay. In general, the Metabolic Cooperation Assay results were comparable to previously published results obtained on mouse skin. The effect of cell density, phorbol 12-myrystate-13-acetate (PMA) exposure time, concentration, pre-exposure and binding activity on the recovery of mutant V-79 Chinese hamster lung fibroblasts in the Metabolic Cooperation Assay was determined. A PMA exposure interval of only 1 minute resulted in maximum recovery of mutant cells. PMA began to inhibit metabolic cooperation at an exposure concentration of 0.1 ng/ml. Pre-exposure of cells to PMA increased the recovery of both post-PMA-treated and non-treated mutant cells in a dose-dependent manner. 3 H-PMA was rapidly bound to or taken up by the V-79 cells under assay conditions. The effect of calcium antagonists and representative compounds from several classes of anti-promoters including anti-inflammatory sterols, protease inhibitors, retinoids and cyclic nucleotides on metabolic determined. Each compound was tested for its effect on metabolic cooperation and also for its ability to reverse or modify the inhibitory properties of PMA on inter-cellular communication. Of all the compounds tested only cyclic adenosine monophosphate (cAMP) was able to antagonize the inhibitory effect of PMA

Comparison of the pharmacological and biological properties of HPMA copolymer-pirarubicin conjugates: A single-chain copolymer conjugate and its biodegradable tandem-diblock copolymer conjugate

Czech Academy of Sciences Publication Activity Database

Etrych, Tomáš; Tsukigawa, K.; Nakamura, H.; Chytil, Petr; Fang, J.; Ulbrich, Karel; Otagiri, M.; Maeda, H.

2017-01-01

Roč. 106, 30 August (2017), s. 10-19 ISSN 0928-0987 R&D Projects: GA ČR(CZ) GA15-02986S; GA MŠk(CZ) LQ1604; GA MŠk(CZ) ED1.1.00/02.0109 Grant - others:AV ČR,Japan Society for the Promotion of Science(CZ) JSPS-16-05 Program:Bilaterální spolupráce Institutional support: RVO:61389013 Keywords : pirarubicin * PHPMA conjugate * tandem-diblock PHPMA conjugate Subject RIV: FR - Pharmacology ; Medidal Chemistry OBOR OECD: Pharmacology and pharmacy Impact factor: 3.756, year: 2016

Mechanism of phorbol ester-mediated protein kinase C activation in EL4 thymoma cells

International Nuclear Information System (INIS)

Huang, F.L.; Arora, P.K.; Hanna, E.E.; Huang, K.P.

1987-01-01

Mouse thymoma EL4 cells respond to phorbol 12-myristate 13-acetate (PMA) in interleukin-2 secretion and growth inhibition. A rapid translocation of protein kinase C (PKC) from cytosol to the particulate fraction and followed by proteolytic degradation occur when EL4 cells are incubated with PMA. In the present study the translocated membrane-associated PKC (PP-PKC) was solubilized by buffer containing NP-40 and its behavior on column chromatography, molecular weight, and kinetic properties were compared to the cytosolic PKC (CS-PKC) from untreated cells. From DE-52 cellulose column, CS-PKC could be eluted by buffer containing 0.1 M KCl, whereas PP-PKC was eluted with buffer containing 0.25 M KCl and 0.2% NP-40. On gel filtration the partially purified PP-PKC from DE-52 was separated into two species: a high Mr species, which was a complex of 82KDa PKC, PMA, and lipid as evidenced by immunoblot analysis and labeling with [ 3 H]PMA and [ 3 H]myristic acid, and a 82KDa species, which was free of PMA and lipid. This 82KDa PP-PKC, though similar to the CS-PKC in molecular weight, is distinguishable from the CS-PKC in having lower Ka values for both Ca 2+ and PS and no longer requires diacylglycerol for maximum activation. These results indicate that upon PMA treatment of EL4 cells, the CS-PKC was modified through enhancing the kinase activity and affinity for membrane lipid. The modification results in the translocation and complexing of PKC with membrane lipid and PMA and subsequent degradation

Our first clinical experience with radiosynoviorthesis by means of (166)Ho-holmium-boro-macroaggregates.

Science.gov (United States)

Kraft, Otakar; Kasparek, R; Ullmann, V; Melichar, F; Kropacek, M; Mirzajevov, M

2005-01-01

In this paper, we evaluate the therapeutic and adverse effects of the application of 166-holmium-boro-macroaggregates (HMBA) in radiosynovectomy (RSO) of the knees. We assessed the efficacy and safety of (166)Ho-HBMA in a prospective clinical trial in patients suffering from chronic synovitis. An effective component of radiopharmaceutical (166)Ho-boro-macroaggregates is radionuclide (166)Ho which has both beta-emission and gamma-emission. The physical half-life time of 166 Ho is 26.8 hours. After application of the radiopharmaceutical into a joint cavity, the effect of beta-emission causes radiation necrosis of pathologically changed (inflamed) synovial membrane. From 15th April 2005, we have started RSO of knees by means of new radiopharmaceutical (166)Ho-boro-macroaggregates in patients with gonarthrosis, rheumatoid arthritis, chronic synovitis, psoriatic arthritis, gout arthropathy. Seventeen intra-articular injections were performed in fifteen patients receiving a mean activity of 972 MBq (range: 904-1,057 MBq) (166)Ho-HMBA. The patients were hospitalized for three days. Side effects were evaluated during hospital stay and after 6-8 weeks. Static scintigraphy of knee joints and measurements of blood radioactivity were performed. Therapeutic effects were evaluated after 6-8 weeks. In 2 hours and 2 days after application, we proved, by means of knee and inguinal scintigraphy, only insignificant radiopharmaceutical leakage from the joint cavity to the inguinal lymph nodes in four patients. In treated patients, no serious adverse effects occurred. Nine patients were without complaints; 4 patients had slight knee exsudation and 2 patients had great exsudation. Therapeutic effects after 6-8 weeks were as follows: 2 patients were without pain, 9 with lower pain, 3 with the same pain and 1 patient with increased pain. Joint motion was improved in 7 patients, remained the same in 7 patients and was impaired in 1 patient. Analgesics consumption was lower in 5 patients

Bio-inks for 3D printing of Cartilage Implants : Tailoring gelMA and polyHPMA-lac-PEG hydrogels for the fabrication of spatially organized constructs

NARCIS (Netherlands)

Mouser, V.H.M.

2017-01-01

A promising approach to treat cartilage defects is the implantation of stratified cell-laden hydrogel implants that mimic native cartilage. To fabricate such constructs, three-dimensional (3D) bioprinting techniques are promising, as they allow accurate deposition of (cell-laden) biomaterials, the

In-vitro investigations of a pH- and ionic-strength-responsive polyelectrolytic hydrogel using a piezoresistive microsensor

Science.gov (United States)

Schulz, Volker; Guenther, Margarita; Gerlach, Gerald; Magda, Jules J.; Tathireddy, Prashant; Rieth, Loren; Solzbacher, Florian

2010-01-01

Environmental responsive or smart hydrogels show a volume phase transition due to changes of external stimuli such as pH or ionic strength of an ambient solution. Thus, they are able to convert reversibly chemical energy into mechanical energy and therefore they are suitable as sensitive material for integration in biochemical microsensors and MEMS devices. In this work, micro-fabricated silicon pressure sensor chips with integrated piezoresistors were used as transducers for the conversion of mechanical work into an appropriate electrical output signal due to the deflection of a thin silicon bending plate. Within this work two different sensor designs have been studied. The biocompatible poly(hydroxypropyl methacrylate-N,N-dimethylaminoethyl methacrylate-tetra-ethyleneglycol dimethacrylate) (HPMA-DMA-TEGDMA) was used as an environmental sensitive element in piezoresistive biochemical sensors. This polyelectrolytic hydrogel shows a very sharp volume phase transition at pH values below about 7.4 which is in the range of the physiological pH. The sensor's characteristic response was measured in-vitro for changes in pH of PBS buffer solution at fixed ionic strength. The experimental data was applied to the Hill equation and the sensor sensitivity as a function of pH was calculated out of it. The time-dependent sensor response was measured for small changes in pH, whereas different time constants have been observed. The same sensor principal was used for sensing of ionic strength. The time-dependent electrical sensor signal of both sensors was measured for variations in ionic strength at fixed pH value using PBS buffer solution. Both sensor types showed an asymmetric swelling behavior between the swelling and the deswelling cycle as well as different time constants, which was attributed to the different nature of mechanical hydrogel-confinement inside the sensor. PMID:21152365

Our first clinical experience with radiosynoviorthesis by means of 166Ho-holmium-boro-macroaggregates

International Nuclear Information System (INIS)

Kraft, O.; Ullmann, V.; Kasparek, R.; Melichar, F.; Kropacek, M.; Mirzajevova, M.

2005-01-01

In this paper, we evaluate the therapeutic and adverse effects of the application of 166- holmium-boro-macroaggregates (HMBA) in radiosynovectomy (RSO) of the knees. We assessed the efficacy and safety of 166H o-HBMA in a prospective clinical trial in patients suffering from chronic synovitis. An effective component of radiopharmaceutical 166H o-boro-macroaggregates is radionuclide 166H o which has both b-emission and g-emission. The physical half-life time of 166H o is 26.8 hours. After application of the radiopharmaceutical into a joint cavity, the effect of b-emission causes radiation necrosis of pathologically changed (inflamed) synovial membrane. From 15 april 2005, we have started RSO of knees by means of new radiopharmaceutical 166H o-boro-macroaggregates in patients with gonarthrosis, rheumatoid arthritis, chronic synovitis, psoriatic arthritis, gout arthropathy. Seventeen intra-articular injections were performed in fifteen patients receiving a mean activity of 972 MBq (range: 904.1057 MBq) 166H o-HMBA. The patients were hospitalized for three days. Side effects were evaluated during hospital stay and after 6.8 weeks. Static scintigraphy of knee joints and measurements of blood radioactivity were performed. Therapeutic effects were evaluated after 6.8 weeks. In 2 hours and 2 days after application, we proved, by means of knee and inguinal scintigraphy, only insignificant radiopharmaceutical leakage from the joint cavity to the inguinal lymph nodes in four patients. In treated patients, no serious adverse effects occurred. Nine patients were without complaints; 4 patients had slight knee exudation and 2 patients had great exudation. Therapeutic effects after 6.8 weeks were as follows: 2 patients were without pain, 9 with lower pain, 3 with the same pain and 1 patient with increased pain. Joint motion was improved in 7 patients, remained the same in 7 patients and was impaired in 1 patient. Analgesics consumption was lower in 5 patients, the same in 9

Structural insight into the physical stability of amorphous Simvastatin dispersed in pHPMA: enhanced dynamics and local clustering as evidenced by solid-state NMR and Raman spectroscopy

Czech Academy of Sciences Publication Activity Database

Urbanová, Martina; Šturcová, Adriana; Kredatusová, Jana; Brus, Jiří

2015-01-01

Roč. 478, č. 2 (2015), s. 464-475 ISSN 0378-5173 R&D Projects: GA ČR(CZ) GA14-03636S; GA MŠk(CZ) LD14010 Grant - others:European Commission(XE) COST Action MP1202 HINT Institutional support: RVO:61389013 Keywords : solid dispersions * simvastatin * pharmaceuticals Subject RIV: CD - Macromolecular Chemistry Impact factor: 3.994, year: 2015

'Real-world' compensatory behaviour with low nicotine concentration e-liquid: subjective effects and nicotine, acrolein and formaldehyde exposure.

Science.gov (United States)

Dawkins, Lynne; Cox, Sharon; Goniewicz, Maciej; McRobbie, Hayden; Kimber, Catherine; Doig, Mira; Kośmider, Leon

2018-06-07

To compare the effects of i) high versus low nicotine concentration e-liquid, ii) fixed versus adjustable power and iii) the interaction between the two on: a) vaping behaviour, b) subjective effects, c) nicotine intake, and d) exposure to acrolein and formaldehyde in e-cigarette users vaping in their everyday setting. Counterbalanced, repeated measures with four conditions: i) low nicotine (6 mg/mL)/fixed power; ii) low nicotine/adjustable power; iii) high nicotine (18 mg/mL)/fixed power; iv) high nicotine/adjustable power. London and the South East, England. Twenty experienced e-cigarette users (recruited between September 2016 and February 2017) vaped ad libitum using an eVic Supreme™ with a 'Nautilus Aspire' tank over four weeks (one week per condition). Puffing patterns (daily puff number [PN], puff duration [PD], inter-puff interval [IPI]), mL of e-liquid consumed, changes to power (where permitted), and subjective effects (urge to vape, nicotine withdrawal symptoms) were measured in each condition. Nicotine intake was measured via salivary cotinine. 3-hydroxypropylmercapturic acid (3-HPMA), a metabolite of the toxicant acrolein, and formate, a metabolite of the carcinogen formaldehyde, were measured in urine. There was a significant nicotine concentration x power interaction for PD (p<0.01). PD was longer with low nicotine/fixed power compared with i) high nicotine/fixed power (p< 0.001 and ii) low nicotine/adjustable power (p< 0.01). PN and liquid consumed were higher in the low versus high nicotine condition (main effect of nicotine, p<0.05). Urge to vape and withdrawal symptoms were lower, and nicotine intake was higher, in the high nicotine condition (main effects of nicotine: p<0.01). Whilst acrolein levels did not differ, there was a significant nicotine x power interaction for formaldehyde (p<0.05). Use of a lower nicotine concentration e-liquid may be associated with compensatory behaviour (e.g., higher number and duration of puffs) and increases

Probing the structural dependence of carbon space lengths of poly(N-hydroxyalkyl acrylamide)-based brushes on antifouling performance.

Science.gov (United States)

Yang, Jintao; Zhang, Mingzhen; Chen, Hong; Chang, Yung; Chen, Zhan; Zheng, Jie

2014-08-11

Numerous biocompatible antifouling polymers have been developed for a wide variety of fundamental and practical applications in drug delivery, biosensors, marine coatings, and many other areas. Several antifouling mechanisms have been proposed, but the exact relationship among molecular structure, surface hydration property, and antifouling performance of antifouling polymers still remains elusive. Here this work strives to provide a better understanding of the structure-property relationship of poly(N-hydroxyalkyl acrylamide)-based materials. We have designed, synthesized, and characterized a series of polyHAAA brushes of various carbon spacer lengths (CSLs), that is, poly(N-hydroxymethyl acrylamide) (polyHMAA), poly(N-(2-hydroxyethyl)acrylamide) (polyHEAA), poly(N-(3-hydroxypropyl)acrylamide) (polyHPAA), and poly(N-(5-hydroxypentyl)acrylamide) (polyHPenAA), to study the structural dependence of CSLs on their antifouling performance. HMAA, HEAA, HPAA, and HPenAA monomers contained one, two, three, and five methylene groups between hydroxyl and amide groups, while the other groups in polymer backbones were the same as each other. The relation of such small structural differences of polymer brushes to their surface hydration and antifouling performance was studied by combined experimental and computational methods including surface plasmon resonance sensors, sum frequency generation (SFG) vibrational spectroscopy, cell adhesion assay, and molecular simulations. Antifouling results showed that all polyHAAA-based brushes were highly surface resistant to protein adsorption from single protein solutions, undiluted blood serum and plasma, as well as cell adhesion up to 7 days. In particular, polyHMAA and polyHEAA with the shorter CSLs exhibited higher surface hydration and better antifouling ability than polyHPMA and polyHPenAA. SFG and molecular simulations further revealed that the variation of CSLs changed the ratio of hydrophobicity/hydrophilicity of polymers

Synthesis and characterization of novel polyacid-stabilized latexes.

Science.gov (United States)

Yang, Pengcheng; Armes, S P

2012-09-18

A series of novel polyacid macromonomers based on 2-hydroxypropyl methacrylate (HPMA) were prepared by atom transfer radical polymerization (ATRP) via a two-step route. First, a range of well-defined PHPMA homopolymer precursors were synthesized by ATRP using a tertiary amine-functionalized initiator, 2-(dimethylamino)ethyl-2-bromoisobutyrylamide, and a CuCl/2, 2'-bipyridine (bpy) catalyst in alcoholic media at 50 °C. ATRP polymerizations were relatively slow and poorly controlled in pure isopropanol (IPA), especially when targeting higher degrees of polymerization (DP > 30). Improved control was achieved by addition of water: low polydispersity (M(w)/M(n) propyl methacrylate) (PSPMA) macromonomers by quaternizing the tertiary amine end-group with excess 4-vinylbenzyl chloride, followed by esterification of the pendent hydroxyl groups using excess succinic anhydride at 20 °C. These polyacid macromonomers were evaluated as reactive steric stabilizers for polystyrene latex synthesis under either aqueous emulsion polymerization or alcoholic dispersion polymerization conditions. Near-monodisperse polystyrene latexes were obtained via aqueous emulsion polymerization using 10 wt % PSPMA macromonomer (with respect to styrene monomer) with various initiators as evidenced by scanning electron microscopy, disk centrifuge photosedimentometry and light scattering studies. PSPMA macromomer concentrations as low as 1.0 wt % also produced near-monodisperse latexes, suggesting that these PSPMA macromonomers are highly effective stabilizers. Alcoholic dispersion polymerization of styrene conducted in various ethanol/water mixtures with 10 wt % PSPMA(50) macromonomer produced relatively large near-monodisperse latexes. Increasing the water content in such formulations led to smaller latexes, as expected. Control experiments conducted with 10 wt % PSPMA(50) homopolymer produced relatively large polydisperse latexes via emulsion polymerization and only macroscopic precipitates via

Antiproliferative effect of a lectin- and anti-Thy-1.2 antibody-targeted HPMA copolymer-bound doxorubicin on primary and metastatic human colorectal carcinoma and on human colorectal carcinoma transfected with the mouse Thy-1.2 gene

Czech Academy of Sciences Publication Activity Database

Říhová, Blanka; Jelínková, Markéta; Strohalm, Jiří; Šťastný, Marek; Hovorka, Ondřej; Plocová, Daniela; Kovář, Marek; Dráberová, Lubica; Ulbrich, Karel

2000-01-01

Roč. 11, č. 5 (2000), s. 664-673 ISSN 1043-1802 R&D Projects: GA ČR GV307/96/K226; GA MPO PZ-Z2/24/97; GA AV ČR KSK2039602 Institutional research plan: CEZ:A53/98:Z5-020-9ii Subject RIV: EC - Immunology Impact factor: 2.550, year: 2000