Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China.
Nano Lett. 2023 Feb 22;23(4):1530-1538. doi: 10.1021/acs.nanolett.2c04976. Epub 2023 Jan 31.
Albumin has emerged as a versatile drug carrier. To harness albumin as a carrier for doxorubicin (DOX), we synthesized three acid-labile DOX prodrugs using stearic acid (SA), oleic acid (OA), and linoleic acid (LA) as the albumin-binding motif, respectively. Different from conventional albumin nanodrugs (such as Abraxane, with a drug loading of 10%), the DOX prodrugs assembled albumin nanoparticles (NPs) have an ultrahigh drug loading (>35%). Noteworthy, we demonstrated that the saturation of fatty acids exerted great influence on colloidal stability of prodrug NPs, thus affecting their pharmacokinetics, tumor accumulation and antitumor efficacy. Furthermore, the hydrazone bond-bridged DOX prodrugs could remain intact in the bloodstream but allow DOX to be released in the acidic tumor environment, resulting in improved antitumor efficacy and safety. Our work gives novel insights into the structure-to-efficacy relationship of albumin-bound fatty acid prodrugs and provides a simple strategy for advanced albumin-bound nanomedicines.
白蛋白已成为一种多功能药物载体。为了将白蛋白用作阿霉素（DOX）的载体，我们分别使用硬脂酸（SA）、油酸（OA）和亚油酸（LA）作为白蛋白结合基序，合成了三种酸敏感的 DOX 前药。与传统的白蛋白纳米药物（如载药率为 10%的 Abraxane）不同，DOX 前药组装的白蛋白纳米颗粒（NPs）具有超高的载药率（>35%）。值得注意的是，我们证明了脂肪酸的饱和对前药 NPs 的胶体稳定性有很大影响，从而影响其药代动力学、肿瘤积累和抗肿瘤功效。此外，腙键桥接的 DOX 前药在血液中保持完整，但允许 DOX 在酸性肿瘤环境中释放，从而提高了抗肿瘤功效和安全性。我们的工作为白蛋白结合脂肪酸前药的结构-功效关系提供了新的见解，并为先进的白蛋白结合纳米药物提供了一种简单的策略。
