Clinical Research Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, 100045, People's Republic of China.
School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, People's Republic of China.
Int J Nanomedicine. 2021 Feb 12;16:1127-1141. doi: 10.2147/IJN.S290466. eCollection 2021.
Acute lymphoblastic leukemia (ALL) is the most common hematologic malignancy in children. It requires a long and rigorous course of chemotherapy treatments. 6-Mercaptopurine (6-MP) is one of the primary drugs used in chemotherapy. Unfortunately, its efficacy has been limited due to its insolubility, poor bioavailability and serious adverse effects. To overcome these drawbacks, we constructed 6-mercaptopurine (6-MP)-loaded nanomedicines (6-MPNs) with biodegradable poly(lactide-co-glycolide) (PLGA) to enhance the anticancer efficacy of 6-MP.
We prepared the 6-MPNs using a double-emulsion solvent evaporation method, characterizing them for the physicochemical properties. We then investigated the plasma, intestinal region and other organs in Sprague Dawley (SD) rats for pharmacokinetics. Additionally, we evaluated its anticancer efficacy in vitro on the human T leukemia cell line Jurkat and in vivo on the ALL model mice.
The 6-MPNs were spherical in shape with uniform particle size and high encapsulation efficiency. The in vitro release profile showed that 6-MPNs exhibited a burst release that a sustained release phase then followed. The apoptosis assay demonstrated that 6-MPNs could improve the in vitro cytotoxicity in Jurkat cells. Pharmacokinetics profiles revealed that 6-MPNs had improved oral bioavailability. Tissue distribution experiments indicated that 6-MPNs increased the duodenum absorption of 6-MP, at the same time having a low accumulation of the toxic metabolites of 6-MP. The in vivo pharmacodynamics study revealed that 6-MPNs could prolong the survival time of the ALL model mice. The prepared 6-MPNs, therefore, have superior properties in terms of anticancer efficacy against ALL with reduced systemic toxicity.
Our nanomedicines provide a promising delivery strategy for 6-MP; they offer a simple preparation method and high significance for clinical translation.
急性淋巴细胞白血病（ALL）是儿童中最常见的血液系统恶性肿瘤。它需要长期、严格的化疗治疗。巯基嘌呤（6-MP）是化疗中使用的主要药物之一。不幸的是，由于其不溶性、生物利用度差和严重的不良反应，其疗效受到限制。为了克服这些缺点，我们用可生物降解的聚（乳酸-共-乙醇酸）（PLGA）构建了负载巯基嘌呤（6-MP）的纳米药物（6-MPNs），以增强 6-MP 的抗癌疗效。
我们采用双乳液溶剂蒸发法制备 6-MPNs，对其理化性质进行了表征。然后研究了 Sprague Dawley（SD）大鼠的血浆、肠道区域和其他器官的药代动力学。此外，我们还在体外人 T 白血病细胞系 Jurkat 和体内 ALL 模型小鼠上评估了其抗癌疗效。
6-MPNs 呈球形，粒径均匀，包封率高。体外释放曲线表明，6-MPNs 表现出突释，随后是持续释放阶段。凋亡试验表明，6-MPNs 可以提高 Jurkat 细胞的体外细胞毒性。药代动力学研究表明，6-MPNs 提高了 6-MP 的口服生物利用度。组织分布实验表明，6-MPNs 增加了 6-MP 在十二指肠的吸收，同时降低了 6-MP 毒性代谢物的蓄积。体内药效学研究表明，6-MPNs 可以延长 ALL 模型小鼠的生存时间。因此，与全身毒性降低的 ALL 相比，所制备的 6-MPNs 在抗癌疗效方面具有优越的特性。
我们的纳米药物为 6-MP 提供了一种有前途的给药策略；它们提供了一种简单的制备方法，对临床转化具有重要意义。
