Zhang Yanhao, Zhang Hao, Wang Ji, Liu Chao, Xing Hanlei, Jiang Yuhao, Li Xinsong
School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, P. R. China.
Mol Pharm. 2023 May 1;20(5):2513-2526. doi: 10.1021/acs.molpharmaceut.2c01107. Epub 2023 Apr 18.
Docetaxel (DTX), a semisynthetic analogue of paclitaxel, is often used to treat cancers. Owing to its poor aqueous solubility, the current formulation of DTX for clinical applications involves using high surfactant and ethanol concentrations, causing hypersensitivity reactions. To overcome this issue, we developed a reduction-responsive DTX prodrug encapsulated within human serum albumin (HSA) nanoparticles (DTX-SS-COOH/HSA NPs). First, the DTX prodrug was conjugated to undecanoic acid through a disulfide bond (DTX-SS-COOH) via a four-step reaction. Subsequently, DTX-SS-COOH/HSA NPs were prepared via the desolvation method. The NPs exhibited a spherical structure with a diameter range of 140-220 nm, as revealed by dynamic light scattering and transmission electron microscopy. Fluorescence quenching analysis confirmed the formation of DTX-SS-COOH/HSA, which was ascribed to electrostatic interactions and hydrophobic forces. Notably, NPs with a feed mole ratio corresponding to DTX-SS-COOH/HSA = 9:1 demonstrated high drug-loading and encapsulation efficiency of 12.84 and 93.11%, respectively, alongside good stability. Moreover, the reduced responsiveness experiment revealed an accelerated DTX release in the presence of glutathione. An pharmacokinetic study indicated that DTX-SS-COOH/HSA NPs demonstrated considerably a prolonged circulation time (6.2-fold) compared to that of free DTX. Ultimately, the antitumor test of MDA-MB-231 tumor-bearing mice revealed that DTX-SS-COOH/HSA NPs were superior to DTX/HSA NPs for tumor growth inhibition. Thus, DTX-SS-COOH/HSA NPs represent a promising DTX nanoformulation for clinical application.
多西他赛（DTX）是紫杉醇的半合成类似物，常用于治疗癌症。由于其水溶性差，目前临床应用的DTX制剂需要使用高浓度的表面活性剂和乙醇，这会引起过敏反应。为了克服这个问题，我们开发了一种包裹在人血清白蛋白（HSA）纳米颗粒（DTX-SS-COOH/HSA NPs）中的还原响应型DTX前药。首先，通过四步反应，将DTX前药通过二硫键与十一烷酸偶联（DTX-SS-COOH）。随后，通过去溶剂化法制备了DTX-SS-COOH/HSA NPs。动态光散射和透射电子显微镜显示，这些纳米颗粒呈球形结构，直径范围为140-220nm。荧光猝灭分析证实了DTX-SS-COOH/HSA的形成，这归因于静电相互作用和疏水作用力。值得注意的是，进料摩尔比对应于DTX-SS-COOH/HSA = 9:1的纳米颗粒表现出高载药量和包封率，分别为12.84%和93.11%，同时具有良好的稳定性。此外，还原响应实验表明，在谷胱甘肽存在下，DTX的释放加速。一项药代动力学研究表明，与游离DTX相比，DTX-SS-COOH/HSA NPs的循环时间显著延长（6.2倍）。最终，对携带MDA-MB-231肿瘤的小鼠进行的抗肿瘤试验表明，DTX-SS-COOH/HSA NPs在抑制肿瘤生长方面优于DTX/HSA NPs。因此，DTX-SS-COOH/HSA NPs是一种有前途的用于临床应用的DTX纳米制剂。
