Design Of Reduction-responsive Gemcitabine Nanoprodrug Micelles

Pancreatic cancer is a kind of high-grade malignant tumor,which has a percentage of 1-2%in all malignant tumors.In recent years,the incidence of pancreatic cancer shows a rising trend in our country,and the lethality rate is almost 99%,ranking the fifth in all deadly diseases.In clinical,gemcitabine(GEM)is used as the first kind of antitumor drug in pancreatic cancer.However,the undesirable pharmacokinetics greatly limits its chemotherapeutic efficacy.It is reported that GEM could be rapidly deaminized by cytidine deaminase during blood circulation.Therefore,a high dose is needed to improve the antitumor efficiency,which unavoidably leads to life-threatening side effects.It will be highly desirable to develop efficient drug delivery system of GEM.In this research,we developed reduction-sensitive polymeric GEM prodrug micelles.On the one hand,the stability of GEM can be improved by chemical modification and nanotechnology;On the other hand,a multi-functional drug delivery system can be fabricated by architectural design of polymeric carriers.Our first work was about polyamino acid-based GEM nanocarriers for targeted intracellular drug delivery.Polyamino acids show excellent performance in drug carriers,such as good biocompatibility,excellent designability and easy preparation.We have successfully fabricated a biocompatible polyamino acid-based nanocarrier by ring-opening copolymerization.This prodrug carrier was equipped with reduction-sensitivity,targeting ability and fluorescence property.It could self-assemble into nano-sized micelles in aqueous solution with uniform spherical shape and showed reduction-sensitive drug release.Cell culture demonstrated that the polyamino acid-based GEM nanocarriers showed targeted internalization.What's more,polyamino acid itself showed excellent biocompatibility but high cytotoxicity when conjugated with GEM.Such a biocompatible polyamino acid-based nanocarrier was first used for targeted GEM delivery and might provide a potential strategy for cancer therapy in vivo.In order to develop more flexible synthetic methods,we have designed modularized co-polymerizations to gain unprecedented synthetic versatile polymers with both well-defined final structures and easy-quantified drug contents.First,we synthesized a series of acrylic monomers,and then,we lined up these monomers by free radical copolymerization.In this work,polyethylene glycol,coumarin and reduction-sensitive GEM precursor were used as modular units,whose corresponding functions were "stealth" ability,cross-linking property and reduction-sensitivity respectively.After micellization,the coumarin in nucleus could be cross linked under UV irradiation,forming firmer micelles.In vitro drug release experiment,GEM could be released rapidly in reduction environment.More pleasing,good endocytosis behaviour and favourable antitumor effect were presented in cell culture.As we regard,this work provided an efficient and convenient method to fabricate multi-functionalized drug delivery systems.And through crosslinking,the polymeric prodrug micelles were more stable,which could effectively prevent the disassembly of micelles and premature drug leakage in blood circulation.