Number of the records: 1
HPMA copolymer conjugate with pirarubicin: In vitro and ex vivo stability and drug release study
- 1.
SYSNO ASEP 0482175 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title HPMA copolymer conjugate with pirarubicin: In vitro and ex vivo stability and drug release study Author(s) 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)Source Title International Journal of Pharmaceutics. - : Elsevier - ISSN 0378-5173
Roč. 536, č. 1 (2018), s. 108-115Number of pages 8 s. Language eng - English Country GB - United Kingdom Keywords EPR effect ; HPMA copolymer ; tumor-targeting 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 000424259100011 EID SCOPUS 85035026360 DOI 10.1016/j.ijpharm.2017.11.011 Annotation 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. Workplace Institute of Macromolecular Chemistry Contact Eva Čechová, cechova@imc.cas.cz ; Tel.: 296 809 358 Year of Publishing 2019
Number of the records: 1