Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning, China.
Department of Pharmacy, Dalian Municipal Central Hospital, Dalian 116033, Liaoning, China.
Mol Pharm. 2023 May 1;20(5):2642-2649. doi: 10.1021/acs.molpharmaceut.3c00079. Epub 2023 Apr 12.
Liposomes (lipos), one of the most successful nanotherapeutics in the clinic, have made a rapid advance over the past few years. However, still, several challenges exist for lipos for clinical practice, such as low drug loading and premature drug leakage during in vivo circulation. Paclitaxel (PTX), a commonly used first-line drug for cancer chemotherapy, was chosen as the model drug. Due to its non-ionizable and water-insoluble characteristics, the drug-loading efficiency of the marketable PTX lipos, Lipusu, is only 6.76%. Herein, we designed an ionizable PTX prodrug (PTXP) by modifying phenylboronic acid on the C2' hydroxyl group of PTX for the remote loading of liposomal formulations through the pH gradient method. Compared with Lipusu, PTXP lipos displayed a 34% higher loading efficiency and an encapsulation efficiency of approximately 95%. A series of in vitro/vivo experiments indicated that PTXP lipos possess colloidal stability, prolonged blood circulation, high tumor site accumulation, potent anti-tumor effects, and safety. A combination of ionizable prodrugs and remote loading has proved to be an effective and simple strategy to achieve high liposomal encapsulation efficiency of poorly soluble non-ionizable drugs for clinical application.
脂质体（lipos）作为临床中最成功的纳米治疗药物之一，在过去几年中取得了快速发展。然而，脂质体在临床实践中仍然存在一些挑战，例如药物载药量低和体内循环过程中药物过早泄漏。紫杉醇（PTX）是癌症化疗中常用的一线药物，被选为模型药物。由于其非离子化和水溶性差的特点，市售紫杉醇脂质体 Lipusu 的载药量仅为 6.76%。在此，我们通过在 PTX 的 C2' 羟基上修饰苯硼酸，设计了一种可离子化的 PTX 前药（PTXP），通过 pH 梯度法实现了脂质体制剂的远程加载。与 Lipusu 相比，PTXP 脂质体显示出 34%更高的载药效率和约 95%的包封效率。一系列体外/体内实验表明，PTXP 脂质体具有胶体稳定性、延长的血液循环时间、高肿瘤部位积累、强大的抗肿瘤作用和安全性。可离子化前药和远程加载的结合已被证明是一种有效且简单的策略，可以实现临床应用中对疏水性非离子化药物的高脂质体包封效率。
