FRET-trackable biodegradable HPMA copolymer-epirubicin conjugates for ovarian carcinoma therapy.
FRET-trackable biodegradable HPMA copolymer-epirubicin conjugates for ovarian carcinoma therapy.
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DOI：
10.1016/j.jconrel.2015.09.045
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发表时间：
2015-11-28
期刊：
影响因子：
--
通讯作者：
Kopeček J
中科院分区：
文献类型：
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作者：
Yang J;Zhang R;Radford DC;Kopeček J
为了开发一种具有非侵入性命运监测能力的可生物降解的高分子药物递送系统用于治疗卵巢癌，我们设计并合成了N-（2-羟丙基）甲基丙烯酰胺（HPMA）共聚物-表阿霉素（EPI）缀合物。聚合物主链用受体荧光团Cy 5标记，而供体荧光团（Cy 3或EPI）通过酶可裂解的GFLG接头连接到HPMA共聚物侧链。这种设计允许使用荧光共振能量转移（FRET）分别阐明药物和聚合物骨架的命运。采用可逆加成-断裂链转移（RAFT）聚合法合成了可降解的二嵌段偶联物（2 P-EPI）。测定了2 P-EPI（分子量约100 kDa）在荷人卵巢癌A2780小鼠体内的药代动力学（PK）和治疗作用。与第一代缀合物（P-EPI，Mw<50 kDa）相比，2 P-EPI表现出显著改善的PK，例如四倍的终末半衰期（2 P-EPI为33.22±3.18 h，P-EPI为7.55±3.18 h），这主要归因于聚合物载体的分子量增加。值得注意的是，在用2 P-EPI治疗的小鼠（n=5）中实现了完全肿瘤缓解和肿瘤发生的长期抑制（100天）。此外，通过FRET强度变化确定体外细胞摄取和细胞内药物释放。这一结果为今后利用FRET成像技术在体内跟踪药物释放和聚合物偶联物断链奠定了坚实的基础。
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~100kDa) were determined in mice bearing human ovarian carcinoma A2780 xenografts. Compared to 1st generation conjugate (P-EPI, Mw<50kDa), 2P-EPI demonstrated remarkably improved PK such as four-fold 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.