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

European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences
Tomáš EtrychHiroshi Maeda

Abstract

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 (39g/mol) (named LINEAR) and the disulfide-linked tandem-polymeric dimer of the poly(HPMA)-pirarubicin conjugate with an Mw above the renal threshold (93g/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 24h) 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 150days), without any apparent toxicity in an S180 tumor model. However, the LD50 value of LINEAR was slightly higher than that of DIBLOCK (50mg/kg vs 37.5mg/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.

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Nov 26, 2013·Journal of Controlled Release : Official Journal of the Controlled Release Society·Hideaki NakamuraHiroshi Maeda
Mar 19, 2014·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Tomáš EtrychKarel Ulbrich
Dec 3, 2014·European Journal of Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft Für Pharmazeutische Verfahrenstechnik E.V·Hideaki NakamuraHiroshi Maeda
Sep 28, 2015·Journal of Controlled Release : Official Journal of the Controlled Release Society·Jiyuan YangJindřich Kopeček

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Citations

Oct 2, 2020·Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan·Hideaki Nakamura
Feb 14, 2021·Journal of Personalized Medicine·Petr ChytilTomáš Etrych
Aug 11, 2021·Journal of Controlled Release : Official Journal of the Controlled Release Society·Enoch AppiahMamoru Haratake

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