Metformin Encapsulated Biodegradable Nanoparticles as a Novel Strategy for Pancreatic Cancer Therapy

Abstract

Pancreatic cancer is one of the most fatal cancers because of its rapid degree of progression and difficulty in diagnosing it at an early stage. Limited survival benefits and serious adverse effects associated with mainstream chemotherapy regimens for pancreatic cancer has prompted research for better treatment options. In this thesis work we investigated the repurposing of metformin, an antidiabetic drug, for application in pancreatic cancer using a nano-formulation route. The objective was to determine whether a nano-formulation of metformin, a drug less toxic than chemotherapeutic drugs and known to have action against pancreatic cancer, could be used as a combination therapy with established chemo drugs to reduce toxicity and increase efficacy of approved pancreatic cancer treatment. For this purpose, metformin loaded nanoparticles (NPs) with improved pharmacokinetic profile were developed without compromising the anticancer efficacy of the drug, and the combinatorial cytotoxic effect of the metformin loaded NPs with chemo-drugs as well as with a chemo drug in nano-form was studied. The first part of the thesis was focused on the development and characterization of metformin loaded polymeric nanoparticles capable of improving in vivo retention of metformin. Two different metformin loaded nanoparticles (NPs) were developed, (i) metformin loaded O-CMC NPs prepared using ionic gelation technique and (ii) metformin loaded PLGA NPs prepared using modified nanoprecipitation technique. The metformin loaded PLGA NPs showed better encapsulation efficiency and loading efficiency compared to O-CMC-met NPs suggesting its advantage for drug delivery application. Also, the PLGA NPs could release and deliver all of the encapsulated drug whereas release was limited in the O-CMC system. The in vivo studies of O-CMC-met NPs showed complete in vivo clearance of the NPs within 48h, so that the NPs could only partially release the drug (~64% of its metformin payload) before its clearance. ( attached)