Enhanced efficacy against cervical carcinomas through polymeric micelles physically incorporating the proteasome inhibitor MG132.
Enhanced efficacy against cervical carcinomas through polymeric micelles physically incorporating the proteasome inhibitor MG132.
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DOI：
10.1111/cas.12926
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发表时间：
2016-06
期刊：
影响因子：
5.7
通讯作者：
Fujii T
中科院分区：
文献类型：
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作者：
Matsumoto Y;Miyamoto Y;Cabral H;Matsumoto Y;Nagasaka K;Nakagawa S;Yano T;Maeda D;Oda K;Kawana K;Nishiyama N;Kataoka K;Fujii T
复发或晚期宫颈癌的治疗仍然有限，需要新的治疗选择来改善患者的预后和生活质量。由于人乳头瘤病毒（human papilloma virus， HPV）感染在宫颈癌发生中起着至关重要的作用，HPV的E6和E7癌基因通过泛素蛋白酶体系统降解抑瘤蛋白，抑制泛素蛋白酶体系统似乎是抑制宫颈肿瘤生长的理想靶点。本研究重点研究了泛素蛋白酶体抑制剂MG132 （carbobenzoxy - Leu - Leu - Leu - leucinal）作为宫颈癌细胞的抗癌药物，并将其物理整合到胶束纳米药物中，以实现对实体肿瘤的选择性递送，并提高其体内疗效。这些负载MG132的聚合物胶束（MG132/m）在体内对HeLa和CaSki细胞的HPV阳性肿瘤，甚至对C33A细胞的HPV阴性肿瘤都有很强的肿瘤抑制作用。通过体重变化和组织病理学分析，MG132/m多次注射对小鼠无明显毒性。此外，MG132/m处理的肿瘤比游离MG132处理的肿瘤显示更高的肿瘤抑制蛋白、hScrib和p53水平以及细胞凋亡程度。MG132/m的这种增强功效归因于其在血液中的循环时间延长，这使得它们能够逐渐外渗和渗透到肿瘤组织中，这是通过活体显微镜确定的。这些结果支持将MG132结合到聚合物胶束中作为一种安全有效的治疗宫颈肿瘤的策略。
Treatment of recurrent or advanced cervical cancer is still limited, and new therapeutic choices are needed for improving prognosis and quality of life of patients. Because human papilloma virus (HPV) infection is critical in cervical carcinogenesis, with the E6 and E7 oncogenes of HPV degrading tumor suppressor proteins through the ubiquitin proteasome system, the inhibition of the ubiquitin proteasome system appears to be an ideal target to suppress the growth of cervical tumors. Herein, we focused on the ubiquitin proteasome inhibitor MG132 (carbobenzoxy‐Leu‐Leu‐leucinal) as an anticancer agent against cervical cancer cells, and physically incorporated it into micellar nanomedicines for achieving selective delivery to solid tumors and improving its in vivo efficacy. These MG132‐loaded polymeric micelles (MG132/m) showed strong tumor inhibitory in vivo effect against HPV‐positive tumors from HeLa and CaSki cells, and even in HPV‐negative tumors from C33A cells. Repeated injection of MG132/m showed no significant toxicity to mice under analysis by weight change or histopathology. Moreover, the tumors treated with MG132/m showed higher levels of tumor suppressing proteins, hScrib and p53, as well as apoptotic degree, than tumors treated with free MG132. This enhanced efficacy of MG132/m was attributed to their prolonged circulation in the bloodstream, which allowed their gradual extravasation and penetration within the tumor tissue, as determined by intravital microscopy. These results support the use of MG132 incorporated into polymeric micelles as a safe and effective therapeutic strategy against cervical tumors.