Kidney-Targeted Drug Delivery System Based on Metformin-Grafted Chitosan for Renal Fibrosis Therapy.

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.