School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, PR China.
Int J Pharm. 2010 May 31;391(1-2):55-64. doi: 10.1016/j.ijpharm.2010.02.016. Epub 2010 Feb 17.
Hydroxycamptothecin (HCPT) is valid to various malignant tumors, but its insoluble and unstable lactone ring in physiological environment have restricted the clinic application. This work was aimed to formulate HCPT-loaded poly(DL-lactic acid)-poly(ethylene glycol) (PELA) fibrous mats through blend electrospinning with 2-hydroxypropyl-beta-cyclodextrin (HPCD) to modulate the drug release and matrix degradation, and to enhance the structural integrity and cytotoxicity of the released HCPT. The entire drug fraction retained its active lactone form within electrospun fibers, and that was maintained over 85% during incubation for over 1 month. A biphasic release pattern was determined for HCPT-loaded electrospun fibers, which can be modulated by the addition of HPCD. HPCD served as solubilizer to maintain a large concentration gradient for HCPT between saturation and diffusion, and liberated HPCD created microstructure of ultrafine fibers, leading a faster release profile in the second phase. In vitro cytotoxicity test showed over 7 times higher inhibitory activity against cancer cells for HCPT-loaded electrospun fibers than free drug during 72h incubation. Higher apoptosis rates and the arrest of the cell cycle during the S and G(2)/M phases were detected through flow cytometry analysis. It indicated therapeutic potentials of HCPT-loaded electrospun fibers as implantable anti-cancer agents for local chemotherapy.
喜树碱（HCPT）对多种恶性肿瘤有效，但由于其在生理环境中不溶且内酯环不稳定，限制了其临床应用。本工作旨在通过共混静电纺丝用 2-羟丙基-β-环糊精（HPCD）制备负载 HCPT 的聚（DL-乳酸）-聚（乙二醇）（PELA）纤维毡，以调节药物释放和基质降解，并增强释放的 HCPT 的结构完整性和细胞毒性。所有药物部分在静电纺纤维中均保留其活性内酯形式，在孵育超过 1 个月的时间内，保留率超过 85%。负载 HCPT 的静电纺纤维表现出两相释放模式，可通过添加 HPCD 进行调节。HPCD 作为增溶剂，在 HCPT 的饱和相与扩散相之间维持较大的浓度梯度，释放出的 HPCD 形成超细纤维的微观结构，导致第二相的释放更快。体外细胞毒性试验表明，在 72h 孵育期间，负载 HCPT 的静电纺纤维对癌细胞的抑制活性比游离药物高 7 倍以上。通过流式细胞术分析检测到更高的细胞凋亡率和细胞周期在 S 和 G(2)/M 期的停滞。这表明负载 HCPT 的静电纺纤维作为局部化疗的植入式抗癌药物具有治疗潜力。
