γ-聚谷氨酸-顺铂复合物的优化及稳定性研究  

Synthesis and Stability of Poly(γ-glutamic Acid )-Cisplatin PolymerDrug Conjugate

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作  者:张梦泽[1] 熊晔蓉[1,2] 刘凯双 谢佳蓉[1] 孙春萌[1] 蒋薇薇[3] 涂家生[1] 

机构地区:[1]中国药科大学药剂学教研室,江苏南京210009 [2]中国药科大学无机化学教研室,江苏南京211198 [3]国家知识产权局专利局专利审查协作江苏中心,江苏苏州215163

出  处:《药物生物技术》2015年第3期207-212,共6页Pharmaceutical Biotechnology

基  金:国家自然科学基金(No.81201182)

摘  要:采用较稳定的合成工艺,活化γ-聚谷氨酸(γ-PGA)表面基团,合成γ-聚谷氨酸-顺铂复合物(γ-PGACA-CDDP)后,对其含量测定的方法学和稳定性进行研究。并对PGA-CA-CDDP复合物进行了核磁表征。采用HPLC法对聚谷氨酸顺铂复合物中顺铂含量测定进行方法学验证,并选择多种容器研究高温、高湿、高热条件下复合物中的顺铂含量变化。结果:实验结果表明,新工艺合成的γ-PGA-CA-CDDP中顺铂的含量测定方法,可达到方法学要求。稳定性试验证明在高温高湿光照下,敞口放置难以稳定。在40℃下避光保存,较为稳定。所选用HPLC法可准确测定复合物中顺铂含量。稳定性试验结果表明,γ-PGA-CA-CDDP在高热及高湿条件下不稳定,应于低温干燥避光条件下贮存。Cisplatin,a widely used frontline chemotherapeutics for cancer therapy,possesses a high capability in killing cancer cells. However,severe side effects,especially hepatoxicity and nephrotoxicity,simultaneously coming with the great cancer-curing efficiency limited the application of cisplatin to a large extent. To overcome the obstacles,γ-PGA-CA-CDDP,as a novel cisplatin delivery system,was engineered which displayed a great anti-tumor efficiency without significant systemic toxicity. The aim of this study is to optimize the synthesis methods and to investigate the stability of the product at high temperature under high humidity and strong illumination. In current work,we used EDC / DMAP to activate the carboxyl groups in PGA which was subsequently reacted with citric acid( CA),followed by Cisplatin. The product,γ-PGA-CA-CDDP,was identified in structure by Nuclear Magnetic Resonance( NMR). High Performance Liquid Chromatography( HPLC) was employed for quantitative analysis of cisplatin in γ-PGA-CA-CDDP as well as the investigation of the content change of cisplatin in stability experiments. Moreover,several containers were selected for investigation of stability and evaluation of compatibility between γ-PGA-CA-CDDP and materials of containers. γ-PGA-CA-CDDP was successfully yielded based on the NMR results. Our data also exhibited that γ-PGA-CA-CDDP yielded by the optimized synthesis method possessed greater dissolution characteristics. Based on the results from stability study,it is suggested that γ-PGA-CA-CDDP should be stored in tightly closed containers in a dry and dark place at a temperature not exceeding 40 ℃. The findings in this work would push the application of γ-PGA-CA-CDDP as a chemotherapeutics forward.

关 键 词:Γ-聚谷氨酸 顺铂 稳定性研究 高温 高湿 强光 方法学研究 

分 类 号:Q503[生物学—生物化学]

 

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