School of Biological Science and Technology, University of Jinan, Jinan, Shandong Province, P. R. China.
Pharmaceutical research laboratory, Shenyang Research Institute of Chemical Industry Co., Ltd, Shenyang, Liaoning Province, P. R. China.
J Biomed Mater Res B Appl Biomater. 2020 Nov;108(8):3345-3355. doi: 10.1002/jbm.b.34670. Epub 2020 Jun 24.
Doxorubicin shows good anticancer activity, but poor pharmacokinetic property and high organ toxicity restrict its clinical application. The synthesized phenylboronic acid-modified F127-chitosan conjugate was used to prepare doxorubicin-loaded micelles through dialysis method. The physicochemical properties of the doxorubicin-loaded micelles were characterized. These micelles were further evaluated for in vitro release/cytotoxicity, in vivo activity/biosafety, and pharmacokinetic studies. in vitro release experiment demonstrated that the release of doxorubicin from drug-loaded micelles was pH-dependent. in vitro cytotoxic study showed that the introduction of phenylboronic acid resulted in lower IC against B16 cells than that in non-modified F127-chitosan micelles group, and the doxorubicin-loaded micelles displayed lower in vitro activity against B16, A549, and HT-29 cells than free doxorubicin did. However, in vivo experiments confirmed that the doxorubicin-loaded micelles were safe for mouse main organs, obviously improved pharmacokinetic parameters of doxorubicin in rat and achieved comparable inhibition of tumor growth with no animal death in B16-bearing mice models throughout the experiment when compared with free doxorubicin. The phenylboronic acid-sialic acid interaction and pH-sensitive drug release might play important roles in increased tumor targeting and therapeutic effect of the doxorubicin-loaded micelles.
多柔比星具有良好的抗癌活性，但药代动力学性质差，器官毒性高，限制了其临床应用。本研究通过透析法制备了苯硼酸修饰的 F127-壳聚糖缀合物载多柔比星胶束。对载多柔比星胶束的理化性质进行了表征。进一步评价了载药胶束的体外释放/细胞毒性、体内活性/生物安全性和药代动力学研究。体外释放实验表明，载药胶束中多柔比星的释放具有 pH 依赖性。体外细胞毒性研究表明，苯硼酸的引入导致 B16 细胞的 IC 值低于非修饰的 F127-壳聚糖胶束组，载多柔比星胶束对 B16、A549 和 HT-29 细胞的体外活性低于游离多柔比星。然而，体内实验证实，载多柔比星胶束对小鼠主要器官安全，明显改善了多柔比星在大鼠体内的药代动力学参数，并在 B16 荷瘤小鼠模型中达到了与游离多柔比星相当的肿瘤生长抑制作用，整个实验过程中无动物死亡。苯硼酸-唾液酸相互作用和 pH 敏感的药物释放可能在增加肿瘤靶向和载多柔比星胶束的治疗效果方面发挥重要作用。
