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用于癌症药物递送的重要纳米平台。药物被物理封装或与白蛋白或基于白蛋白的纳米系统共价缀合。物理包封是有利的，因为不需要对药物分子进行化学修饰，但是许多药物，例如喜树碱（CPT）和姜黄素（CCM），尽管疏水性很强，但不能与白蛋白一起装载或形成纳米制剂。在本文中，我们证明了前药易于通过亚氨基硼酸盐与蛋白质结合并形成用于癌症药物递送的纳米颗粒。用2-乙酰基苯基硼酸（2-APBA）将CPT和CCM官能化以产生前药CPT-SS-APBA和CCM-APBA。前药通过以下方式与牛血清白蛋白（BSA）结合亚氨基硼酸酯的形成和产生的BSA /前药易于自组装成具有高负载效率，改善的胶体稳定性和大大改善的药代动力学的明确的纳米粒子。纳米颗粒在细胞内酸性环境或富含谷胱甘肽（GSH）的胞质溶胶中有效释放药物。在体内，与皮下使用的4 T1或HepG2肿瘤模型中的临床使用的伊立替康或索拉非尼相比，纳米颗粒显示出增强的抗癌功效。这项工作展示了通用的蛋白质结合前药平台，适用于基于蛋白质的药物制剂，甚至抗体-药物结合物。