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Comparison of the pharmacological and biological properties of HPMA copolymer-pirarubicin conjugates: A single-chain copolymer conjugate and its biodegradable tandem-diblock copolymer conjugate
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SYSNO ASEP 0475079 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Comparison of the pharmacological and biological properties of HPMA copolymer-pirarubicin conjugates: A single-chain copolymer conjugate and its biodegradable tandem-diblock copolymer conjugate Author(s) Etrych, Tomáš (UMCH-V) RID, ORCID
Tsukigawa, K. (JP)
Nakamura, H. (JP)
Chytil, Petr (UMCH-V) RID, ORCID
Fang, J. (JP)
Ulbrich, Karel (UMCH-V) RID
Otagiri, M. (JP)
Maeda, H. (JP)Source Title European Journal of Pharmaceutical Sciences. - : Elsevier - ISSN 0928-0987
Roč. 106, 30 August (2017), s. 10-19Number of pages 10 s. Language eng - English Country NL - Netherlands Keywords pirarubicin ; PHPMA conjugate ; tandem-diblock PHPMA conjugate Subject RIV FR - Pharmacology ; Medidal Chemistry OECD category Pharmacology and pharmacy R&D Projects GA15-02986S GA ČR - Czech Science Foundation (CSF) LQ1604 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) ED1.1.00/02.0109 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Institutional support UMCH-V - RVO:61389013 UT WOS 000406988600002 EID SCOPUS 85019559040 DOI 10.1016/j.ejps.2017.05.031 Annotation In this study, we compared the enhanced permeability and retention (EPR) effect, toxicity, and therapeutic effect of the conjugate of the linear polymer poly(N-(2-hydroxypropyl)methacrylamide) (HPMA) with pirarubicin with an Mw below the renal threshold (39 g/mol) (named LINEAR) and the disulfide-linked tandem-polymeric dimer of the poly(HPMA)-pirarubicin conjugate with an Mw above the renal threshold (93 g/mol) (named DIBLOCK). The DIBLOCK conjugate, which was susceptible to reductive degradation, showed both a better EPR effect (tumor delivery) (2.5 times greater at 24 h) and a prolonged plasma half-life. In addition, DIBLOCK had a better antitumor effect, as judged by percent survival, than did LINEAR (80% vs 65% at 150 days), without any apparent toxicity in an S180 tumor model. However, the LD50 value of LINEAR was slightly higher than that of DIBLOCK (50 mg/kg vs 37.5 mg/kg, respectively). DIBLOCK required a longer time than LINEAR to reach maximum accumulation in the tumor. DIBLOCK also showed a greater time-dependent increase in the concentration in the tumor compared with the plasma concentration. Workplace Institute of Macromolecular Chemistry Contact Eva Čechová, cechova@imc.cas.cz ; Tel.: 296 809 358 Year of Publishing 2018
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