Fabrication And Antitumor Properties Research Of PEGylated Nanodrugs

Conventional cancer chemotherapy is lack of tumor selectivity,which leads to serious side effects.Nowadays,PEGylated nanodrugs are promising candidates for cancer chemocherapy due to their reduced reticuloendothelial system uptake,prolonged blood circulation,and selective deposition in tumor sites.However,nanodrugs prepared by self-assembly usually disintegrate during blood circulation because of their high critical micellar concentrations(CMC),which greatly induces insufficient therapeutic efficacy.In this dissertation,three kind of PEGylated nanodrugs with crosslinked structures have been prepared,which provides new strategies for the development of PEGylated nanodrugs.Polymeric micelles self-assembled from block copolymers have attracted much attention in the development of nanodrugs.A facile method to prepare reduction-responsive core-crosslinked PEGylated nanodrug has been developed.PEGylated polyesters with multiblock structure and abundant thiols in hydrophobic blocks were synthesized by "one-pot" polycondensation without thiol protection.Paclitaxel could be incorporated into the hydrophobic micellar core when self-assembled into micelles.Thereafter,core-crosslinked micelles were prepared by oxidation of thiols or in situ thiol-ene "click" crosslinking.The PEGylated nano-drugs exhibit reduction-responsive behaviors and cellular proliferation inhibition towards HeLa cells,which could serve as biodegradable nanocarriers for large-scale production.Nanodrugs with specific and simple chemical components are prefered for clinical translation and commercialization.Herein,we describe the construction of core-crosslinked PEGylated nanodrugs with only two components.Two-mole admantane modified camptothecin prodrug and multiple p-cyclodextrin modified amphiphilic block copolymers were first synthesized seperatedly.The amphiphilic block copolymer can self-assembled into micelles.Meanwhile,the "conjugation" of drug and the core crosslinking of micelles can be achieved simultaneously via host-guest supramolecular interaction between adamantane and cyclodextrin moeities.Compared with the nanodrugs crosslinked by complicated traditional chemical-crosslinking,this kind of supramolecular crosslinked PEGylated nanodrugs can by prepared by a simple method with specific chemical structure and composition,which is promising for clinical application.Nanodrugs self-assembled from oligo(ethylene glycol)-drug conjugastes usually have high CMC.The stability of this kind of nanodrugs can be improved by crosslinking.Nevertheless,the uncontrollable chemical crosslinking results in nanodrugs with ambiguous chemical structures,which can't be driven in clinical research process.Herein,supramolecular PEGylated camptothecin that relies on noncovalent,host-guest interactions between PEGylated ?-cyclodextrin and admantane modified camptothecin have been developed,which could self-assembled into nanodrug in aqueous solution.,the stability of nanodrug get improved by crosslinking PEGylated ?-cyclodextrin.This supramolecular PEGylated nano-drug could keep stability at dilute solutions and afford unchanged chemical structure of prodrug.Camptothecin could be released by the cleavage of disulfide bonds at tumor sites.Furthermore,the in vivo antitumor experiment in mice exhibits excellent anti-tumor activity and low side effects.This study provide new strategy to design PEGylated nanodrug.