State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun, Jilin 130022, PR China; University of Science and Technology of China, Hefei 230026, PR China.
State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun, Jilin 130022, PR China.
J Control Release. 2017 May 28;254:23-33. doi: 10.1016/j.jconrel.2017.03.391. Epub 2017 Mar 27.
Poor water solubility and adverse side effects pose a challenge for clinical application of paclitaxel (PTX). In this work, a series of PTX dimers are synthesized by coupling two PTX molecules with dicarboxylic acids. As-synthesized PTX dimers form stable nanoparticles in aqueous solution without using any surfactants or adjuvants, and the solubility of PTX in water increases by 2500-fold compared to that of free PTX. These nanoparticles with high content of PTX are internalized by cancer cells and exhibit comparable cytotoxicity with Taxol. Furthermore, when the PTX dimers are incorporated into methoxypoly(ethylene glycol)-block-poly(d, l-lactide) (PEG-PDLLA) micelles, the loading content of PTX dimers is as high as 85wt%. The formed nanoparticles possess the high stability in biological conditions. Both in vitro and in vivo experiments show that these (PTX dimer)/PEG-PDLLA formulations possess effective cellular uptake and potent cytotoxicity, and exhibit reduced systemic toxicity and enhanced antitumor efficacy towards human cervical tumor. We believe these PTX dimers-based nanoparticles would be an alternative formulation for PTX, and such drug dimer assembling behaviors could be extended to other therapeutic agents.
紫杉醇（PTX）的水溶性差和副作用大，这对其临床应用构成了挑战。在这项工作中，通过将两个 PTX 分子与二羧酸偶联，合成了一系列 PTX 二聚体。所合成的 PTX 二聚体在水溶液中形成稳定的纳米颗粒，无需使用任何表面活性剂或助剂，与游离 PTX 相比，PTX 在水中的溶解度提高了 2500 倍。这些含有高浓度 PTX 的纳米颗粒被癌细胞内化，并表现出与 Taxol 相当的细胞毒性。此外，当将 PTX 二聚体掺入甲氧基聚乙二醇-嵌段-聚（D，L-丙交酯）（PEG-PDLLA）胶束中时，PTX 二聚体的载药量高达 85wt%。形成的纳米颗粒在生物条件下具有高稳定性。体外和体内实验均表明，这些（PTX 二聚体）/PEG-PDLLA 制剂具有有效的细胞摄取和强大的细胞毒性，并表现出降低的全身毒性和增强的人宫颈肿瘤的抗肿瘤功效。我们相信，这些基于 PTX 二聚体的纳米颗粒将是 PTX 的另一种制剂选择，并且这种药物二聚体组装行为可以扩展到其他治疗剂。
