School of Pharmacy, Key Laboratory of Sichuan Province for Specific Structure of Small Molecule Drugs, Chengdu Medical College, Chengdu, China.
Department of Pharmaceutics, College of Pharmacy, Chongqing Medical University, Chongqing 400016, China.
Int J Pharm. 2021 Mar 15;597:120369. doi: 10.1016/j.ijpharm.2021.120369. Epub 2021 Feb 10.
Self-delivering nanocarrier based on the small-molecule prodrug nanoassemblies (NAs) have been widely used for the efficient delivery of chemotherapeutics, but the effect of kinetic stability of NAs on their delivery performance has not been illuminated. In this study, two camptothecin (CPT)-oleic acid (OA) prodrugs were used to fabricate self-assembling nanorods with similar size distribution, zeta potential and morphology but having sharply different kinetic stability, which provided an ideal platform to investigate the effects of kinetic stability. It is found that the nanorods with high kinetic stability showed a lower in vitro cytotoxicity, but were more effective to inhibit the tumor growth probably by decreasing the premature CPT release and subsequent generation of the inactive carboxylate CPT. However, such kinetically stable nanorods also resulted in the increased toxicity, probably due to the high prodrug accumulation in tissues after multiple injections. These results outlined the pivotal role of kinetic stability in determining antitumor efficacy of prodrug NAs, which provided a new insight into the delivery mechanism for the small-molecule prodrug self-delivering nanosystems.
基于小分子前药纳米组装体（NAs）的自递药纳米载体已被广泛用于高效递送化疗药物，但 NAs 的动力学稳定性对其递药性能的影响尚未得到阐明。在本研究中，使用两种喜树碱（CPT）-油酸（OA）前药制备了具有相似粒径分布、zeta 电位和形态但动力学稳定性差异很大的自组装纳米棒，为研究动力学稳定性的影响提供了理想的平台。结果发现，动力学稳定性高的纳米棒表现出较低的体外细胞毒性，但通过减少过早的 CPT 释放和随后产生无活性的羧酸酯 CPT，对肿瘤生长的抑制作用更有效。然而，这种动力学稳定的纳米棒也导致了毒性的增加，可能是由于多次注射后组织中前药的积累增加。这些结果概述了动力学稳定性在确定前药 NAs 的抗肿瘤疗效中的关键作用，为小分子前药自递药纳米系统的递药机制提供了新的见解。
