University Paris-Est Créteil, INSERM, IMRB, F-94010, Créteil, France.
ICMPE (UMR 7182), CNRS, UPEC, University Paris Est, F-94320 Thiais, France.
Pharmacol Res. 2023 May;191:106770. doi: 10.1016/j.phrs.2023.106770. Epub 2023 Apr 15.
Metal carbonyls have been developed as carbon monoxide-releasing molecules (CO-RMs) to deliver CO for therapeutic purposes. The manganese-based CORM-401 has been recently reported to exert beneficial effects in obese animals by reducing body weight gain, improving glucose metabolism and reprogramming adipose tissue towards a healthy phenotype. Here, we report on the synthesis and characterization of glyco-CORMs, obtained by grafting manganese carbonyls on dextrans (70 and 40 kDa), based on the fact that polysaccharides facilitate the targeting of drugs to adipose tissue. We found that glyco-CORMs efficiently deliver CO to cells in vitro with higher CO accumulation in adipocytes compared to other cell types. Oral administration of two selected glyco-CORMs (5b and 6b) resulted in CO accumulation in various organs, including adipose tissue. In addition, glyco-CORM 6b administered for eight weeks elicited anti-obesity and positive metabolic effects in mice fed a high fat diet. Our study highlights the feasibility of creating carriers with multiple functionalized CO-RMs.
金属羰基化合物已被开发为一氧化碳释放分子（CO-RMs），以输送 CO 用于治疗目的。最近有报道称，基于锰的 CORM-401 通过降低体重增加、改善葡萄糖代谢和使脂肪组织向健康表型重编程，对肥胖动物发挥有益作用。在这里，我们报告了基于多糖有助于将药物靶向脂肪组织的事实，通过将锰羰基化合物嫁接到葡聚糖（70 和 40 kDa）上而获得的糖基化 CORM 的合成和表征。我们发现糖基化 CORM 能够有效地将 CO 递送到体外细胞中，与其他细胞类型相比，在脂肪细胞中 CO 积累更高。两种选定的糖基化 CORM（5b 和 6b）的口服给药导致 CO 在包括脂肪组织在内的各种器官中的积累。此外，在高脂肪饮食喂养的小鼠中，给予糖基化 CORM 6b 八周可引起抗肥胖和积极的代谢作用。我们的研究强调了创建具有多种功能化 CO-RMs 的载体的可行性。
