Li Meng, Zhao Liwen, Zhang Tao, Shu Yue, He Zhonggui, Ma Yan, Liu Dan, Wang Yongjun
Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China.
School of Chinese Materia Medica, Guangzhou University of Chinese Medicine, Guangzhou 510405, China.
Acta Pharm Sin B. 2019 Mar;9(2):421-432. doi: 10.1016/j.apsb.2018.08.008. Epub 2018 Aug 31.
Prodrug nanoassemblies, which can refrain from large excipients, achieve higher drug loading and control drug release, have been placed as the priority in drug delivery system. Reasoning that glutathione (GSH) and reactive oxygen species (ROS) are highly upgraded in tumor tissues which makes them attractive targets for drug delivery system, we designed and synthetized a novel prodrug which utilized mono thioether bond as a linker to bridge linoleic acid (LA) and docetaxel (DTX). This mono thioether-linked conjugates (DTX-S-LA) could self-assemble into nanoparticles without the aid of much excipients. The mono thioether endowed the nanoparticles redox sensitivity resulting in specific release at the tumor tissue. Our studies demonstrated that the nanoassemblies had uniform particle size, high stability and fast release behavior. DTX-S-LA nanoassemblies outperformed DTX solution in pharmacokinetic profiles for it had longer circulation time and higher area under curve (AUC). Compared with DTX solution, the redox dual-responsive nanoassemblies had comparable cytotoxic activity. Besides, the antitumor efficacy was evaluated in mice bearing 4T1 xenograft. It turned out this nanoassemblies could enhance anticancer efficacy by increasing the dose because of higher tolerance. Overall, these results indicated that the redox sensitivity nanoassemblies may have a great potential to cancer therapy.
前药纳米组装体能够避免使用大量辅料，实现更高的载药量并控制药物释放，已被列为药物递送系统的首要研究对象。鉴于谷胱甘肽（GSH）和活性氧（ROS）在肿瘤组织中高度富集，这使其成为药物递送系统颇具吸引力的靶点，我们设计并合成了一种新型前药，该前药利用单硫醚键作为连接子，将亚油酸（LA）和多西他赛（DTX）连接起来。这种单硫醚连接的共轭物（DTX-S-LA）无需借助大量辅料就能自组装成纳米颗粒。单硫醚赋予了纳米颗粒氧化还原敏感性，使其能够在肿瘤组织中实现特异性释放。我们的研究表明，该纳米组装体具有粒径均匀、稳定性高和快速释放的特性。DTX-S-LA纳米组装体在药代动力学方面优于DTX溶液，因为它具有更长的循环时间和更高的曲线下面积（AUC）。与DTX溶液相比，这种氧化还原双响应纳米组装体具有相当的细胞毒性活性。此外，还在携带4T1异种移植瘤的小鼠中评估了其抗肿瘤疗效。结果表明，由于耐受性更高，这种纳米组装体可以通过增加剂量来提高抗癌疗效。总体而言，这些结果表明氧化还原敏感性纳米组装体在癌症治疗方面可能具有巨大潜力。
