骨干可降解 HPMA 共聚物吉西他滨和铂缀合物对人卵巢癌细胞的联合细胞毒性。
Combination cytotoxicity of backbone degradable HPMA copolymer gemcitabine and platinum conjugates toward human ovarian carcinoma cells.
机构信息
Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT, USA; School of Medical Sciences, University of Phayao, Phayao, Thailand.
Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT, USA.
出版信息
Eur J Pharm Biopharm. 2014 May;87(1):187-96. doi: 10.1016/j.ejpb.2013.11.008. Epub 2013 Dec 4.
Abstract
Multiblock, backbone degradable HPMA copolymer-drug conjugates containing gemcitabine and DACH platinum (mP-GEM and mP-DACH Pt), respectively were synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization and subsequent chain extension by click chemistry. Using combination index analysis, the cytotoxicities of the two multiblock conjugates, as single agent and in combination, were evaluated in vitro in A2780 human ovarian cancer cells, with free drugs as controls. The greatest synergistic cytotoxic effect was observed when A2780 cells were sequentially exposed to mP-GEM for 24h and mP-DACH Pt for 48h. In addition, mechanistic studies support the rationale of the synergy between mP-GEM and mP-DACH Pt: mP-GEM pretreatment was able to enhance the platinum-DNA adduct accumulation and inhibit cell proliferation to a higher extent than single mP-DACH Pt treatment. These observations are useful for the development of combination macromolecular therapeutics for ovarian cancer based on the second-generation backbone degradable HPMA copolymers.
摘要
分别含有吉西他滨和 DACH 铂（mP-GEM 和 mP-DACH Pt）的多嵌段、主链可降解 HPMA 共聚物 - 药物偶联物通过可逆加成 - 断裂链转移（RAFT）聚合和随后的点击化学链延伸合成。使用组合指数分析，在 A2780 人卵巢癌细胞中，以游离药物作为对照，评估了两种多嵌段缀合物作为单一药物和联合使用的体外细胞毒性。当 A2780 细胞依次暴露于 mP-GEM 24 小时和 mP-DACH Pt 48 小时时，观察到最大的协同细胞毒性作用。此外，机制研究支持 mP-GEM 和 mP-DACH Pt 之间协同作用的原理：mP-GEM 预处理能够比单独的 mP-DACH Pt 处理更有效地增强铂-DNA 加合物的积累并抑制细胞增殖。这些观察结果对于基于第二代主链可降解 HPMA 共聚物的卵巢癌联合大分子治疗的开发是有用的。
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