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Sequential combination therapy of ovarian cancer with degradable N -(2-hydroxypropyl)methacrylamide copolymer paclitaxel and gemcitabine conjugates

2014; National Academy of Sciences; Volume: 111; Issue: 33 Linguagem: Inglês

10.1073/pnas.1406233111

1091-6490

Rui Zhang, Jiyuan Yang, Monika Sima, Yan Zhou, Jindřich Kopeček,

Nanoplatforms for cancer theranostics

Significance In previous clinical testing, first-generation N -(2-hydroxypropyl)-methacrylamide (HPMA) copolymer-drug conjugates circumvented drug resistance and showed reduced side effects, although only minor improvement was seen in therapeutic efficacy. For effective clincial translation, second-generation high-molecular weight backbone-degradable HPMA copolymer carriers designed by our group sought to provide prolonged blood circulation and enhanced tumor accumulation to enable sufficient exposure of tumors to effective drug concentrations, and guarantee their biocompatibility by making polymer backbone degradable. The second-generation conjugates showed favorable pharmacokinetic profiles and controlled drug release, resulting in a dramatic improvement of therapeutic efficacy, as compared with first-generation conjugates and free drugs. For future industrial-scale manufacture, a new reversible addition-fragmentation chain transfer agent was developed that enables synthesis of conjugates in one step.