Department of Hematology, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huai'an City, 223001, Jiangsu Province, China.
Department of Brain Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou City, 221006, Jiangsu Province, China.
J Nanosci Nanotechnol. 2021 Feb 1;21(2):1001-1007. doi: 10.1166/jnn.2021.18695.
As a first-line drug widely used in the treatment of leukemia, 6-MP has obvious effects on leukemia. However, 6-MP disadvantages such as poor solubility in water, easy binding with serum proteins, short circulation time, and large toxic and side effects greatly limit the application of 6-MP. For this reason, various 6-MP nano drug-loading systems have been designed to increase the water solubility of 6-MP, extend the circulation time, and increase the bioavailability of 6-MP to a certain extent, reducing its toxic and side effects. However, its therapeutic effect and is still far from expectations, and there is a lot of room for improvement. In order to solve the above problems encountered in the clinical application of 6-MP, we have tried two ways of polymer prodrugs and drug-loaded vesicles to achieve efficient targeted delivery and treatment of 6-MP. We designed hyaluronic acid (HA)-based gluteal-skin-responsive 6-MP polymer prodrug (HA-GS-MP) for highly effective targeted therapy of acute myeloid leukemia. Hyaluronic acid is a natural polysaccharide, which has excellent biocompatibility and biodegradability, and has a good ability to actively target malignant tumor cells overexpressing the CD receptor. 6-MP is connected to the HA chain through a vinyl sulfide bond, which is stable under physiological conditions (no drug release), and under intracellular reducing conditions, the connection bond is broken and 6-MP is quickly released. HA-GS-MP has a simple preparation process, good water solubility, long cycle time, and strong targeting ability. This GSH-responsive CD targeted 6-MP polymer prodrug is expected to improve the therapeutic effect on acute myeloid leukemia cells.
作为一种广泛用于治疗白血病的一线药物，6-MP 对白血病具有明显的疗效。然而，6-MP 存在水溶性差、易与血清蛋白结合、循环时间短、毒性和副作用大等缺点，极大地限制了 6-MP 的应用。为此，设计了各种 6-MP 纳米载药系统，以提高 6-MP 的水溶性、延长循环时间、在一定程度上提高 6-MP 的生物利用度，降低其毒性和副作用。然而，其治疗效果仍远未达到预期，还有很大的改进空间。为了解决 6-MP 临床应用中遇到的上述问题，我们尝试了聚合物前药和载药囊泡两种方法，以实现 6-MP 的高效靶向递送和治疗。我们设计了基于透明质酸（HA）的臀皮响应性 6-MP 聚合物前药（HA-GS-MP），用于急性髓系白血病的高效靶向治疗。透明质酸是一种天然多糖，具有优异的生物相容性和可降解性，对过度表达 CD 受体的恶性肿瘤细胞具有良好的主动靶向能力。6-MP 通过乙烯基硫醚键连接到 HA 链上，在生理条件下（无药物释放）稳定，在细胞内还原条件下，连接键断裂，6-MP 迅速释放。HA-GS-MP 具有制备工艺简单、水溶性好、循环时间长、靶向能力强等优点。这种 GSH 响应性 CD 靶向 6-MP 聚合物前药有望提高对急性髓系白血病细胞的治疗效果。
