A thermally responsive biopolymer conjugated to an acid-sensitive derivative of paclitaxel stabilizes microtubules, arrests cell cycle, and induces apoptosis
A thermally responsive biopolymer conjugated to an acid-sensitive derivative of paclitaxel stabilizes microtubules, arrests cell cycle, and induces apoptosis
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DOI：
10.1007/s10637-010-9560-x
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发表时间：
2012-02-01
影响因子：
3.4
通讯作者：
Raucher, Drazen
中科院分区：
文献类型：
--
作者：
Moktan, Shama;Ryppa, Claudia;Raucher, Drazen
水溶性差限制了紫杉醇作为抗癌药物的治疗指数。已经报道了紫杉醇的可溶性前药的合成，或药物与大分子载体的缀合，以增加其水溶性。由于异常的肿瘤血液和淋巴管系统，大分子药物载体具有将药物靶向肿瘤部位的额外优势。本研究描述了一种热响应性大分子载体，弹性蛋白样多肽（ELP），用于紫杉醇的递送。通过与紫杉醇的6-马来酰亚胺基己酰腙衍生物（一种酸敏感性紫杉醇前药）缀合，将紫杉醇与ELP结合，用于潜在的乳腺癌治疗。在肿瘤部位高于特定转变温度的聚焦热疗导致ELP聚集和积聚，从而增加药物货物的局部浓度。本文所述的紫杉醇前药带有酸敏感性接头，其在溶酶体/内体pH下可裂解，这允许药物的受控细胞内释放。在高温存在下，ELP递送的紫杉醇通过稳定微管结构、将细胞阻滞在G2/M期并以与常规紫杉醇类似的方式诱导细胞凋亡来抑制MCF-7细胞增殖。它还抑制紫杉醇抗性MCF-7细胞系的增殖。这些数据提供了使用ELP作为紫杉醇递送载体的体外概念验证。
Poor aqueous solubility limits the therapeutic index of paclitaxel as an anti-cancer drug. Synthesis of soluble prodrugs of paclitaxel, or conjugation of the drug to macromolecular carriers have been reported to increase its water-solubility. Macromolecular drug carriers have an added advantage of targeting the drug to the tumor site due to the abnormal tumor blood and lymphatic vasculature. This study describes a thermally responsive macromolecular carrier, elastin-like polypeptide (ELP) for the delivery of paclitaxel. Paclitaxel was bound to ELP by conjugation with the 6-maleimidocaproyl hydrazone derivative of paclitaxel, an acid-sensitive paclitaxel prodrug, for the potential treatment of breast cancer. Focused hyperthermia above a specific transition temperature at the site of a tumor causes ELP to aggregate and accumulate, thereby increasing the local concentration of the drug cargo. The paclitaxel prodrug described here bears an acid-sensitive linker that is cleavable at the lysosomal/endosomal pH, which allows a controlled intracellular release of the drug. The ELP-delivered paclitaxel in the presence of hyperthermia inhibits MCF-7 cell proliferation by stabilizing the microtubule structures, arresting the cells at the G2/M stage, and inducing apoptosis in a manner similar to conventional paclitaxel. It also inhibits proliferation of a paclitaxel resistant MCF-7 cell line. These data provide an in vitro proof of concept for the use of ELP as a delivery vehicle of paclitaxel.