HPMA copolymer conjugate with pirarubicin: In vitro and ex vivo stability and drug release study
Language English Country Netherlands Media print-electronic
Document type Journal Article
PubMed
29133205
DOI
10.1016/j.ijpharm.2017.11.011
PII: S0378-5173(17)31055-4
Knihovny.cz E-resources
- Keywords
- Arginine, EPR effect, HPMA copolymer, Stability, Tumor environment responsive, Tumor-targeting,
- MeSH
- Arginine chemistry MeSH
- Doxorubicin analogs & derivatives chemistry MeSH
- Rabbits MeSH
- Rats MeSH
- Humans MeSH
- Methacrylates chemistry MeSH
- Mice MeSH
- Drug Carriers chemistry MeSH
- Pilot Projects MeSH
- Polymers chemistry MeSH
- Antineoplastic Agents chemistry MeSH
- Solubility drug effects MeSH
- Serum Albumin, Bovine chemistry MeSH
- Drug Liberation drug effects MeSH
- Animals MeSH
- Check Tag
- Rabbits MeSH
- Rats MeSH
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Arginine MeSH
- Doxorubicin MeSH
- hydroxypropyl methacrylate MeSH Browser
- Methacrylates MeSH
- Drug Carriers MeSH
- pirarubicin MeSH Browser
- Polymers MeSH
- Antineoplastic Agents MeSH
- Serum Albumin, Bovine MeSH
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.
Biodynamic Research Foundation Kenshin Bldg 3F Kuwamizu 1 chome 24 6 Chuo ku Kumamoto 862 0954 Japan
Department of Nanoscience School of Engineering Sojo University Kumamoto Japan
Faculty of Pharmaceutical Science Sojo University Kumamoto Japan
The Institute of Macromolecular Chemistry Czech Academy of Sciences Prague Czech Republic
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