Center for Bionanoengineering and Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Zheda Road 38, Hangzhou 310007, China.
Center for Bionanoengineering and Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Zheda Road 38, Hangzhou 310007, China; ZJU-Hangzhou Global Scientific and Technological Innovation Center, Hangzhou, Zhejiang 311215, China.
J Control Release. 2021 Feb 10;330:362-371. doi: 10.1016/j.jconrel.2020.12.035. Epub 2020 Dec 24.
Albumin-based nanomedicines are important nanoplatforms for cancer drug delivery. The drugs are either physically encapsulated or covalently conjugated to albumin or albumin-based nanosystems. Physical encapsulation is advantageous due to requiring no chemical modification of drug molecules, but many drugs, for instance, camptothecin (CPT) and curcumin (CCM), though very hydrophobic, can't be loaded in or form nanoformulations with albumin. Herein, we demonstrate prodrugs readily binding to proteins via iminoboronates and forming nanoparticles for cancer drug delivery. CPT and CCM were functionalized with 2-acetylphenylboronic acid (2-APBA) to produce prodrugs CPT-SS-APBA and CCM- APBA. The prodrugs bound to bovine serum albumin (BSA) via formation of iminoboronates and the produced BSA/prodrug readily self-assembled into well-defined nanoparticles with high loading efficiency, improved colloidal stability, and much-improved pharmacokinetics. The nanoparticles effectively released drugs in the intracellular acidic environment or the cytosol rich in glutathione (GSH). In vivo, the nanoparticles showed enhanced anticancer efficacy compared with clinically used irinotecan or sorafenib in subcutaneous 4 T1 or HepG2 tumor models. This work demonstrates a versatile protein-binding prodrug platform applicable to protein-based drug formulations and even antibody-drug conjugates.
基于白蛋白的纳米药物是癌症药物递送的重要纳米平台。药物要么被物理包裹，要么通过共价键与白蛋白或基于白蛋白的纳米系统结合。物理包封是有利的，因为不需要对药物分子进行化学修饰，但许多药物，例如喜树碱（CPT）和姜黄素（CCM），尽管非常疏水，但不能被白蛋白加载或形成纳米制剂。在此，我们展示了通过亚胺硼酸酯易于与蛋白质结合并形成用于癌症药物递送的纳米颗粒的前药。CPT 和 CCM 用 2-乙酰苯硼酸（2-APBA）功能化，得到前药 CPT-SS-APBA 和 CCM-APBA。前药通过形成亚胺硼酸酯与牛血清白蛋白（BSA）结合，所产生的 BSA/前药很容易自组装成具有高载药效率、改善胶体稳定性和大大改善药代动力学的定义明确的纳米颗粒。纳米颗粒在细胞内酸性环境或富含谷胱甘肽（GSH）的细胞质中有效释放药物。在体内，与临床使用的伊立替康或索拉非尼相比，纳米颗粒在皮下 4T1 或 HepG2 肿瘤模型中显示出增强的抗癌疗效。这项工作展示了一种通用的蛋白质结合前药平台，适用于蛋白质药物制剂，甚至适用于抗体药物偶联物。
