Sustained and localized delivery of gemcitabine using chitosan-PVA-TPP polymeric implant enhances antitumor efficacy and delays surgical relapse in pancreatic cancer

Gemcitabine (GEM), one of the first lines of therapy in pancreatic cancer (PC) patients, has certain limitations, such as, low plasma half-life, limited bioavailability and treatment index. To address these issues, a localized and sustained delivery approach is undertaken, where we have developed a biodegradable polymeric film implant, by solvent casting method, using chitosan, polyvinyl alcohol (PVA), and sodium tripolyphosphate (TPP). Incorporating PVA and crosslinker TPP with chitosan enhances the mechanical strength of the chitosan film, evident from reduction of elastic modulus from 18.51 to 0.19 MPa. Under in vitro conditions, the film gradually releases GEM, exhibiting increased cell-killing capabilities in both 2D and 3D cell models and enhanced efficacy against GEM-resistant PC cells. Delivery through implant induces alteration of the lipid content of cells and significantly (p < 0.0001) enhances DNA double-strand break and antiproliferative properties. Furthermore, antitumor efficacy of GEM-loaded film (GEM-film) in pre-clinical settings significantly (p < 0.05) impairs tumor growth in advanced subcutaneous models and mitigates therapy resistance. GEM-film implants have proven ~7 times more effective in orthotopic models and have also delayed surgical relapse in PC mice models. Our study demonstrates that the delivery of GEM using the polymeric composite film is advantageous over that of free GEM in a pre-clinical context.