FRET-trackable biodegradable HPMA copolymer-epirubicin conjugates for ovarian carcinoma therapy

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• 作者：Jiyuan Yang^a ; Rui Zhang^a ; D. Christopher Radford^b ; Jind艡ich Kope膷ek^a ; ^b ; ^{jindrich.kopecek@utah.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：N-(2-hydroxypropyl)methacrylamide (HPMA) ; Epirubicin ; Ovarian carcinoma ; FRET
• 刊名：Journal of Controlled Release
• 出版年：2015
• 出版时间：28 November 2015
• 年：2015
• 卷：218
• 期：Complete
• 页码：36-44
• 全文大小：1281 K

文摘

To develop a biodegradable polymeric drug delivery system for the treatment of ovarian cancer with the capacity for non-invasive fate monitoring, we designed and synthesized N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-epirubicin (EPI) conjugates. The polymer backbone was labeled with acceptor fluorophore Cy5, while donor fluorophores (Cy3 or EPI) were attached to HPMA copolymer side chains via an enzyme-cleavable GFLG linker. This design allows elucidating separately the fate of the drug and of the polymer backbone using fluorescence resonance energy transfer (FRET). The degradable diblock conjugate (2P-EPI) was synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization using a bifunctional chain transfer agent (Peptide2CTA). The pharmacokinetics (PK) and therapeutic effect of 2P-EPI (Mw ~ 100 kDa) were determined in mice bearing human ovarian carcinoma A2780 xenografts. Compared to 1st generation conjugate (P-EPI, Mw < 50 kDa), 2P-EPI demonstrated remarkably improved PK such as fourfold terminal half-life (33.22 ± 3.18 h for 2P-EPI vs. 7.55 ± 3.18 h for P-EPI), which is primarily attributed to the increased molecular weight of the polymer carrier. Notably, complete tumor remission and long-term inhibition of tumorigenesis (100 days) were achieved in mice (n = 5) treated with 2P-EPI. Moreover, in vitro cell uptake and intracellular drug release were determined via FRET intensity changes. The results establish a solid foundation for future in vivo tracking of drug delivery and chain scission of polymeric conjugates by FRET imaging.