Han Xiaoxiong, Chen Dan, Sun Jing, Zhou Jinsong, Li Duan, Gong Feirong, Shen Yaling
a State Key Laboratory of Bioreactor Engineering, Shanghai Collaborative Innovation Center for Biomanufacturing Technology , East China University of Science and Technology , Shanghai , China.
b School of Biotechnology , East China University of Science and Technology , Shanghai , China.
J Biomater Sci Polym Ed. 2016;27(7):626-42. doi: 10.1080/09205063.2016.1146980. Epub 2016 Feb 25.
Cabazitaxel (CTX) is a second-generation semisynthetic taxane that demonstrates antitumor activity superior to docetaxel. However, the low aqueous solubility of CTX has hampered its use as a therapeutic agent. In this work, CTX-loaded N-t-butoxycarbonyl-L-phenylalanine end-capped monomethyl poly (ethylene glycol)-block-poly (D,L-lactide) (mPEG-PLA-Phe(Boc)/CTX) micelles were prepared to improve the solubility of CTX while retaining its superior stability before accessing the tumor site. The mPEG-PLA-Phe(Boc)/CTX micelles showed excellent stability in vitro compared with mPEG-PLA/CTX micelles. When stored at 25 °C, the mPEG-PLA/CTX micelles tended to aggregate within 1 h, whereas the mPEG-PLA-Phe(Boc)/CTX micelles were uniformly transparent even after three weeks. Dilution of mPEG-PLA/CTX micelles widened their size distribution and decreased the encapsulation efficiency, while significant change was not found in mPEG-PLA-Phe(Boc)/CTX micelles, even when diluted 1000-fold. Pharmacokinetic results in Sprague-Dawley rats indicated that, compared with Jevtana(®), intravenous administration of mPEG-PLA-Phe(Boc)/CTX micelles stably retained the CTX in plasma with 26.03-fold larger of the area under the time-concentration curve, 2.13-fold longer of the half-life, and 9.99-fold higher of the maximum concentration. In conclusion, mPEG-PLA-Phe(Boc) micelle may be a potential nanocarrier not only to improve the solubility of CTX but also to prolong the blood circulation time, which results in improved biological activity.
卡巴他赛（CTX）是一种第二代半合成紫杉烷，其抗肿瘤活性优于多西他赛。然而，CTX的低水溶性阻碍了其作为治疗药物的应用。在本研究中，制备了负载CTX的N-叔丁氧羰基-L-苯丙氨酸封端的单甲氧基聚（乙二醇）-嵌段-聚（D，L-丙交酯）（mPEG-PLA-Phe（Boc）/CTX）胶束，以提高CTX的溶解度，同时在到达肿瘤部位之前保持其优异的稳定性。与mPEG-PLA/CTX胶束相比，mPEG-PLA-Phe（Boc）/CTX胶束在体外表现出优异的稳定性。在25℃储存时，mPEG-PLA/CTX胶束在1小时内趋于聚集，而mPEG-PLA-Phe（Boc）/CTX胶束即使在三周后仍均匀透明。mPEG-PLA/CTX胶束的稀释会扩大其粒径分布并降低包封效率，而mPEG-PLA-Phe（Boc）/CTX胶束即使稀释1000倍也未发现显著变化。在Sprague-Dawley大鼠中的药代动力学结果表明，与Jevtana（®）相比，静脉注射mPEG-PLA-Phe（Boc）/CTX胶束可使CTX在血浆中稳定保留，时间-浓度曲线下面积大26.03倍，半衰期长2.13倍，最大浓度高9.99倍。总之，mPEG-PLA-Phe（Boc）胶束可能是一种潜在的纳米载体，不仅可以提高CTX的溶解度，还可以延长血液循环时间，从而提高生物活性。
