Department of Pharmaceutical Engineering, School of Chemical Engineering, Wuhan University of Technology, Wuhan 430070, PR China.
Carbohydr Polym. 2013 Oct 15;98(1):36-42. doi: 10.1016/j.carbpol.2013.04.071. Epub 2013 May 14.
A series of melphalan-O-carboxymethyl chitosan (Mel-OCM-chitosan) conjugates with different spacers were prepared and structurally characterized. All conjugates showed satisfactory water-solubility (160-217 times of Mel solubility). In vitro drug release behaviors by both chemical and enzymatic hydrolysis were investigated. The prodrugs released Mel rapidly within papain and lysosomal enzymes of about 40-75%, while released only about 4-5% in buffer and plasma, which suggested that the conjugates have good plasma stability and the hydrolysis in both papain and lysosomes occurs mostly via enzymolysis. It was found that the spacers have important effect on the drug content, water solubility, drug release properties and cytotoxicity of Mel-OCM-chitosan conjugates. Cytotoxicity studies by MTT assay demonstrated that these conjugates had 52-70% of cytotoxicity against RPMI8226 cells in vitro as compared with free Mel, indicating the conjugates did not lose anti-cancer activity of Mel. Overall these studies indicated Mel-OCM-chitosan conjugates as potential prodrugs for cancer treatment.
一系列不同间隔臂的苯丙氨酸-O-羧甲基壳聚糖（Mel-OCM-壳聚糖）缀合物被制备并进行了结构表征。所有缀合物都表现出令人满意的水溶性（比 Mel 的溶解度高 160-217 倍）。通过化学和酶水解研究了体外药物释放行为。在木瓜蛋白酶和溶酶体酶中，前药迅速释放 Mel，约为 40-75%，而在缓冲液和血浆中仅释放约 4-5%，这表明缀合物具有良好的血浆稳定性，并且在木瓜蛋白酶和溶酶体中的水解主要通过酶解发生。研究发现，间隔臂对 Mel-OCM-壳聚糖缀合物的药物含量、水溶性、药物释放性质和细胞毒性有重要影响。MTT 法细胞毒性研究表明，与游离 Mel 相比，这些缀合物对 RPMI8226 细胞的体外细胞毒性为 52-70%，表明缀合物没有失去 Mel 的抗癌活性。综上所述，这些研究表明 Mel-OCM-壳聚糖缀合物作为癌症治疗的潜在前药。
