Department of Clinical Pharmacy, The First Clinical School of Xuzhou Medical University, Xuzhou, Jiangsu Province 221004, People's Republic of China.
Department of Orthopedics, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical University, Xuzhou, Jiangsu Province 221006, People's Republic of China.
Mol Pharm. 2022 Sep 5;19(9):3075-3084. doi: 10.1021/acs.molpharmaceut.1c00827. Epub 2022 Aug 8.
Our previous study demonstrated that metformin plays an anti-fibrotic role in addition to its hypoglycemic effect. Worryingly, it often requires more than 5 times the hypoglycemic dose to achieve a satisfactory anti-fibrotic effect, which greatly increases the risk of systemic acidosis caused by metformin overdose. Low-molecular-weight chitosan (LMWC) has natural kidney-targeting properties and good biocompatibility and degradability. Thus, we synthesized a novel carrier metformin-grafted chitosan (CS-MET) based on an imine reaction between oxidized chitosan and metformin. Then, GFP was recruited to form GFP-loaded CS-MET nanoparticles (CS-MET/GFP NPs) with controllable particle size. We hypothesized that CS-MET/GFP NPs would enrich in the kidney and be absorbed by HK-2 cells via megalin-mediated endocytosis by intravenous injection, which may avoid systemic acidosis caused by metformin overdose. Subsequently, the nanoparticle ruptures and releases metformin to exert its anti-apoptotic, anti-inflammatory, and anti-fibrotic effects. Our results showed that CS-MET/GFP NPs have great transfection efficiency and could enter HK-2 cells mainly through megalin-mediated endocytosis. Compared to the free metformin, CS-MET/GFP NPs showed similar anti-apoptotic ability but better therapeutic effects on cellular inflammation and fibrosis in vitro. On the other hand, CS-MET/GFP NPs showed great kidney-targeting ability and superior anti-apoptotic, anti-inflammatory, and anti-fibrotic effects in vivo.
我们之前的研究表明，二甲双胍除了具有降血糖作用外，还具有抗纤维化作用。令人担忧的是，为了达到令人满意的抗纤维化效果，通常需要超过 5 倍的降血糖剂量，这大大增加了二甲双胍过量引起的全身酸中毒的风险。低分子量壳聚糖（LMWC）具有天然的肾脏靶向特性、良好的生物相容性和可降解性。因此，我们基于壳聚糖和二甲双胍之间的席夫碱反应，合成了一种新型载体二甲双胍接枝壳聚糖（CS-MET）。然后，我们招募 GFP 形成具有可控粒径的 GFP 负载 CS-MET 纳米颗粒（CS-MET/GFP NPs）。我们假设 CS-MET/GFP NPs 会在肾脏中蓄积，并通过静脉注射被 HK-2 细胞通过巨胞饮作用内吞，这可能避免二甲双胍过量引起的全身酸中毒。随后，纳米颗粒破裂并释放二甲双胍，发挥其抗凋亡、抗炎和抗纤维化作用。我们的结果表明，CS-MET/GFP NPs 具有很高的转染效率，可以主要通过巨胞饮作用进入 HK-2 细胞。与游离二甲双胍相比，CS-MET/GFP NPs 具有相似的抗凋亡能力，但在体外对细胞炎症和纤维化具有更好的治疗效果。另一方面，CS-MET/GFP NPs 在体内具有很强的肾脏靶向能力和优越的抗凋亡、抗炎和抗纤维化作用。
