单酰基甘油脂肪酶 (MAGL) 是癌症治疗的一个有前景的靶标，因为它参与脂质代谢及其对细胞增殖、迁移和肿瘤进展等癌症标志的影响。我们小组最近开发了一种有效的可逆 MAGL 抑制剂 MAGL23，显示出有前景的抗癌活性。为了增强其药理学特性，制备了一种使用白蛋白包被的纳米晶体的纳米制剂（MAGL23AF）。在之前的工作中，配制的抑制剂显示出在卵巢和结肠癌细胞系中保持其 IC50 效力，并且在小鼠身上测试了该制剂以评估其生物相容性、器官生物分布和毒性。在目前的工作中，我们扩大了研究范围以评估 MAGL23AF 的体内应用潜力。血清和人源微粒体的稳定性测定显示 MAGL23AF 在生理条件下具有良好的结构稳定性。对患有卵巢癌肿瘤的小鼠进行的抗肿瘤功效测试表明，与非配制药物相比，MAGL23AF 具有更有效的抗肿瘤功效，并导致坏死驱动的癌细胞死亡。体内研究表明，白蛋白复合纳米晶体改善了 MAGL23 的治疗窗，表现出良好的生物分布，并且在肿瘤中的积累略有增加。总之，MAGL23AF 在反映血流环境和肝脏代谢的条件下表现出更高的体外稳定性，同时具有最佳的体内抗肿瘤功效。这些结果不仅验证了我们配方的功效，而且将其定位为解决与药物在体液中溶解度相关的挑战的有前景的策略。版权所有 © 2024。由 Elsevier B.V. 出版。

Monoacylglycerol lipase (MAGL) is a promising target for cancer therapy due to its involvement in lipid metabolism and its impact on cancer hallmarks like cell proliferation, migration, and tumor progression. A potent reversible MAGL inhibitor, MAGL23, has been recently developed by our group, demonstrating promising anticancer activities. To enhance its pharmacological properties, a nanoformulation using nanocrystals coated with albumin was prepared (MAGL23AF). In a previous work, the formulated inhibitor showed to maintain its potency in ovarian and colon cancer cell lines in terms of IC50, and the formulation was tested on mice in order to assess its biocompatibility, organs biodistribution and toxicity. In the present work, we expanded the investigation to assess the potential in vivo application of MAGL23AF. Stability assays in serum and in human derived microsomes showed a good structural stability in physiological conditions of MAGL23AF. Antitumor efficacy tested on mice bearing ovarian cancer tumor highlighted that MAGL23AF has a more potent antitumor efficacy compared to non-formulated drug and leads to a necrosis-driven cancer cell death. In vivo studies revealed that albumin-complexed nanocrystals improved the therapeutic window of MAGL23, exhibiting a favorable biodistribution with slightly increased accumulation in the tumor. In conclusion, the MAGL23AF showed increased in vitro stability in conditions mirroring the bloodstream environment and hepatic metabolism coupled with an optimal antitumor efficacy in vivo. These results not only validates the efficacy of our formulation but also positions it as a promising strategy for addressing challenges related to the solubility of drugs in body fluids.Copyright © 2024. Published by Elsevier B.V.