Key Laboratory of Molecular Pharmacology and Drug Evaluation (Ministry of Education of China), School of Pharmacy, Yantai University, Yantai 264005, China.
Henan-Macquarie University Joint Center for Biomedical Innovation School of Life Science, Henan University, Kaifeng, Henan 475004, China.
Int J Pharm. 2020 Mar 15;577:119049. doi: 10.1016/j.ijpharm.2020.119049. Epub 2020 Jan 23.
Irinotecan (Ir) is a potent antitumor chemotherapeutics in clinic and used for the treatment of a various cancers, but the degree of its application is critically limited by toxic side-effects and marked heterogeneities. Nano-formulation of prodrugs, based on "all-in-one" carrier-free self-assemblies offers an effective approach to alter pharmacokinetics and safety profiles of cytotoxic agents. In this study, a novel vitamin E succinate-based formulation of Ir (VES-Ir) combined with nanoscaled characteristics and synergistic combination was constructed through esterification. The conjugation makes amphiphilic VES-Ir prodrug self-assemble into nanoparticles with a fine diameter (VES-Ir NPs, 75.4 nm) of spherical morphology. Furthermore, VES-Ir NPs with a 1:1 drug-to-drug ratio was demonstrated to possess respectable physiological stability within 72 h test, while can react to pH/esterase-sensitive drug release in lysosomes internalized into tumor cells, potentially highlighting their alleviating side effects. Compared with single and mixture drugs administration, the nanoformulated VES-Ir NPs codelivered both VES and Ir with different anticancer mechanisms to induce the highest suppress proliferation of MCF-7 (IC 0.18 μM) and A549 (IC 0.29 μM) cells in a synergistic way (CI < 1). More importantly, the formulating nanoparticulate Ir is to significantly enhance its bioavailability in vivo with long retention time in bloodstream and thereby, resulting the superior tumor inhibitory rate (TIR) of 85.2% versus controls. This simple nanoformulation of Ir drug deprived from VES conjugation, together with self-delivery and synergistic property, may provide an effective strategy for multiple chemotherapeutics delivery to treat cancers or other diseases.
伊立替康（Ir）是一种临床有效的抗肿瘤化学治疗药物，用于治疗多种癌症，但由于其毒性副作用和明显的异质性，其应用程度受到严重限制。前药的纳米制剂，基于“一体”无载体自组装，为改变细胞毒性药物的药代动力学和安全性提供了有效的方法。在这项研究中，通过酯化作用构建了一种新型的维生素 E 琥珀酸酯（VES）伊立替康（Ir）制剂（VES-Ir），结合了纳米特性和协同组合。这种结合使两亲性 VES-Ir 前药自组装成具有精细直径（VES-Ir NPs，75.4nm）的球形形态的纳米粒子。此外，研究表明，在 72 小时的测试中，具有 1:1 药物比的 VES-Ir NPs 具有良好的生理稳定性，而在溶酶体内化到肿瘤细胞中时，可以对 pH/酯酶敏感的药物释放做出反应，有可能突出其缓解副作用的作用。与单一和混合药物给药相比，纳米制剂的 VES-Ir NPs 同时递送具有不同抗癌机制的 VES 和 Ir，以协同方式诱导 MCF-7（IC 0.18μM）和 A549（IC 0.29μM）细胞的最高抑制增殖（CI<1）。更重要的是，这种制剂纳米粒形式的 Ir 能够显著提高其在体内的生物利用度，在血液中保留时间长，从而使肿瘤抑制率（TIR）提高到 85.2%，优于对照组。这种简单的无载体伊立替康纳米制剂，具有自递药和协同作用，可能为多种化学治疗药物的递送来治疗癌症或其他疾病提供有效的策略。
