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

0475079 - ÚMCH 2018 RIV NL eng J - Článek v odborném periodiku
Etrych, Tomáš - Tsukigawa, K. - Nakamura, H. - Chytil, Petr - Fang, J. - Ulbrich, Karel - Otagiri, M. - Maeda, H.
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. Roč. 106, 30 August (2017), s. 10-19. ISSN 0928-0987. E-ISSN 1879-0720
Grant CEP: GA ČR(CZ) GA15-02986S; GA MŠMT(CZ) LQ1604; GA MŠMT(CZ) ED1.1.00/02.0109
Grant ostatní: AV ČR,Japan Society for the Promotion of Science(CZ) JSPS-16-05
Program: Bilaterální spolupráce
Institucionální podpora: RVO:61389013
Klíčová slova: pirarubicin * PHPMA conjugate * tandem-diblock PHPMA conjugate
Obor OECD: Pharmacology and pharmacy
Impakt faktor: 3.466, rok: 2017

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.
Trvalý link: http://hdl.handle.net/11104/0272040