Chu Bingyang, Qu Ying, Huang Yixing, Zhang Lan, Chen Xiaoxin, Long Chaofeng, He Yunqi, Ou Caiwen, Qian Zhiyong
Department of Orthopaedic Surgery, Second Affiliated Hospital of Wenzhou Medical University, 109 Xueyuan Road, Wenzhou 325027, PR China; R&D Center of New Product, Guangdong Zhongsheng Pharmaceutical Co.,Ltd., Dongguan 523325,PR China; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, PR China.
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, PR China.
Int J Pharm. 2016 Mar 16;500(1-2):345-59. doi: 10.1016/j.ijpharm.2016.01.030. Epub 2016 Jan 18.
In this study, PEG-derivatized octacosanol copolymer was successfully developed to improve the anti-tumor activity and eliminate toxicity of the commercial formulation of paclitaxel (PTX). MPEG2K-C28, the conjugation of monomethoxy Poly(ethylene glycol) 2000 and octacosanol, was readily soluble in aqueous solution and self-assembled to form micelles with small sizes (< 20 nm) that are efficient in encapsulating PTX with a drug loading of 9.38 ± 0.18% and an encapsulation efficiency of 93.90 ± 2.12%. Meanwhile, octacosanol is very safe for humans and amazingly exhibits antitumor activity through inhibition activity of matrix metalloproteinases (MMPs) and translocation of the transcription factor (nuclear factor-kappa B, NF-κB) to the nucleus, which may be able to promote synergistic effects with PTX. A sustained and slower in vitro release behavior was observed in the (PTX micelles) than that of Taxol. PTX micelles exhibited more potent cytotoxicity than Taxol in the 4T1 breast cancer cell line. More interestingly, MPEG2K-C28 selectively inhibited the growth of 4T1 cells rather than the normal cells (HEK293 and L929 cell lines), indicating the antitumor activity of octacosanol remained after conjugation with MPEG. Acute toxicity evaluations indicated that MPEG2K-C28 was a safe drug carrier. Pharmacokinetic study revealed that PTX micelles improved the T1/2 and AUC of PTX (compared with Taxol) from 1.910 ± 0.139 h and 13.999 ± 1.109 mg/l × h to 2.876 ± 0.532 h and 76.462 ± 8.619 mg/l × h in vivo, respectively. The maximal tolerated dose (MTD) for PTX micelles (ca. 120 mg PTX/kg) in mice was significantly higher than that for Taxol (ca. 20mg PTX/kg). PTX micelles exhibited slightly better antitumor activity than Taxol but safer in 4T1 breast cancer model in vivo. The cell apoptosis in the immunofluorescent studies and the cell proliferation in the immunohistochemical studies also proved the results. In conclusion, MPEG2K-C28 is a simple, safe and effective drug delivery carrier for PTX, and has some therapeutic effects in 4T1 cells in vitro. PTX micelles showed significant antitumor activity in vivo with low systemic toxicity in 4T1 breast cancer. MPEG2K-C28 micelles entrapping PTX deserve more studies in the future.
在本研究中，成功开发了聚乙二醇衍生化二十八烷醇共聚物，以提高紫杉醇（PTX）市售制剂的抗肿瘤活性并消除其毒性。甲氧基聚乙二醇2000（MPEG2K）与二十八烷醇的结合物MPEG2K-C28易溶于水溶液，并自组装形成小尺寸（<20 nm）的胶束，其能够有效地包封PTX，载药量为9.38±0.18%，包封率为93.90±2.12%。同时，二十八烷醇对人体非常安全，并且通过抑制基质金属蛋白酶（MMPs）的活性和转录因子（核因子-κB，NF-κB）向细胞核的转位而惊人地表现出抗肿瘤活性，这可能能够促进与PTX的协同作用。与紫杉醇相比，（PTX胶束）在体外表现出持续且较慢的释放行为。PTX胶束在4T1乳腺癌细胞系中比紫杉醇表现出更强的细胞毒性。更有趣的是，MPEG2K-C28选择性地抑制4T1细胞的生长，而不是正常细胞（HEK293和L929细胞系）的生长，这表明二十八烷醇与MPEG结合后仍保留抗肿瘤活性。急性毒性评估表明MPEG2K-C28是一种安全的药物载体。药代动力学研究表明，PTX胶束在体内将PTX的半衰期（T1/2）和药时曲线下面积（AUC）（与紫杉醇相比）分别从1.910±0.139小时和13.999±1.109毫克/升×小时提高到2.876±0.532小时和76.462±8.619毫克/升×小时。PTX胶束在小鼠中的最大耐受剂量（MTD）（约120毫克PTX/千克）显著高于紫杉醇（约20毫克PTX/千克）。在4T1乳腺癌体内模型中，PTX胶束比紫杉醇表现出稍好的抗肿瘤活性，但更安全。免疫荧光研究中的细胞凋亡和免疫组织化学研究中的细胞增殖也证实了这些结果。总之，MPEG2K-C28是一种用于PTX的简单、安全且有效的药物递送载体，并且在体外对4T1细胞具有一定的治疗作用。PTX胶束在体内对4T1乳腺癌表现出显著的抗肿瘤活性且全身毒性低。包载PTX的MPEG2K-C28胶束在未来值得更多研究。
