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HPMA copolymer conjugate with pirarubicin: In vitro and ex vivo stability and drug release study
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SYSNO ASEP 0482175 Druh ASEP J - Článek v odborném periodiku Zařazení RIV J - Článek v odborném periodiku Poddruh J Článek ve WOS Název HPMA copolymer conjugate with pirarubicin: In vitro and ex vivo stability and drug release study Tvůrce(i) Islam, W. (JP)
Fang, J. (JP)
Etrych, Tomáš (UMCH-V) RID, ORCID
Chytil, Petr (UMCH-V) RID, ORCID
Ulbrich, Karel (UMCH-V) RID
Sakoguchi, A. (JP)
Kusakabe, K. (JP)
Maeda, H. (JP)Zdroj.dok. International Journal of Pharmaceutics. - : Elsevier - ISSN 0378-5173
Roč. 536, č. 1 (2018), s. 108-115Poč.str. 8 s. Jazyk dok. eng - angličtina Země vyd. GB - Velká Británie Klíč. slova EPR effect ; HPMA copolymer ; tumor-targeting Vědní obor RIV FR - Farmakologie a lékárnická chemie Obor OECD Pharmacology and pharmacy CEP GA15-02986S GA ČR - Grantová agentura ČR LQ1604 GA MŠMT - Ministerstvo školství, mládeže a tělovýchovy ED1.1.00/02.0109 GA MŠMT - Ministerstvo školství, mládeže a tělovýchovy Institucionální podpora UMCH-V - RVO:61389013 UT WOS 000424259100011 EID SCOPUS 85035026360 DOI 10.1016/j.ijpharm.2017.11.011 Anotace We have developed a tumor environment-responsive polymeric anticancer prodrug containing pirarubicin (THP) conjugated to N-(2-hydroxypropyl) methacrylamide copolymer (PHPMA), [P-THP], through a spacer containing pH-sensitive hydrazone bond, that showed remarkable therapeutic effect against various tumor models and in a human pilot study. Toward clinical development, here we report THP release profile from its HPMA copolymer conjugate, the conjugate stability, protein and cell-binding and solubility of P-THP. Size exclusion chromatography of P-THP (molecular weight 38 kDa) showed similar hydrodynamic volume as bovine serum albumin (BSA) in aqueous solution, with no apparent interactions with BSA, nor aggregation by itself. pH-responsive release of free THP was reconfirmed at pHs 6.5 and lower. The drug release was significantly affected by a type of used buffer. Phosphate buffer seems to facilitate faster hydrazone bond cleavage at pH 7.4 whereas higher stability was achieved in L-arginine solution which yielded only little cleavage and THP release, approx. 15% within 2 weeks at the same pH at 25 °C. Furthermore, ex vivo study using sera of different animal species showed very high stability of P-THP. Incubation with blood showed high stability of P-THP during circulation, without binding to blood cells. These findings revealed that L-arginine solution provides appropriate media for formulation of P-THP infusion solution as tumor-targeted polymeric anticancer drug based on EPR effect. Pracoviště Ústav makromolekulární chemie Kontakt Eva Čechová, cechova@imc.cas.cz ; Tel.: 296 809 358 Rok sběru 2019
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