Studies On The Effects Of PEGylated Chitosan And Its Stealth Nanoparticle Drug Delivery System

In this study,methoxy polyethylene glycol(mPEG)and chitosan(CS)were employed to synthesize the methoxy polyethylene glycol grafted chitosan(mPEG-g-CS).Methotrexate loaded mPEG-g-CS nanoparticles(MTX/mPEG-g-CS NPs)were prepared and characterized both in vitro and in vivo.MPEG with different molecular weight(Mn=750,2000,5000)were modified to chitosan through acylation to acquire mPEG-g-CS with different degrees of substitution(DS)and MTX/mPEG750-g-CS(DS=9.1),MTX/mPEG2000-g-CS(DS=4.1,DS=8.5,DS=18.2,DS=40.3)as well as MTX/mPEG5000-g-CS(DS=8.7)were chosen for further investigation.MTX was selected as a model drug,and all MTX/mPEG-g-CS NPs were prepared via ionic-crosslinking method.The entrapment efficiency and loading efficiency of MTX/mPEG-g-CS NPs was 84.3?88.1%and 17.1?18.4%,respectively.The nanoparticles exhibited uniform size(109.7?171.2 nm),positive zeta potential(7.4?35 mV)and spherical morphology.MTX release from MTX/mPEG-g-CS NPs had a burst release in initial and followed by a sustained-release in pH 7.4 PBS.Accumulative release of MTX was increased when DS or molecular weight of mPEG increased.In vitro cytotoxicity study demonstrated that MTX/mPEG-g-CS NPs had higher IC50 values in MCF-7 cells compared to that of MTX/CS NPs and IC50 values increased when DS or molecular weight of mPEG raised.J774A.1 macrophage cellular uptake suggested that MTX accumulation was decreased with DS or molecular weight of mPEG increased.The pharmacokinetic study on Sprague Dawley rats and biodistribution research on ICR mice were carried out to investigate the in vivo influence brought by DS and molecular weight of mPEG on MTX/CS NPs.MTX/mPEG-g-CS NPs could significantly alter the pharmacokinetic parameters and biodistribution of MTX in vivo.With a constant of mPEG molecular weight,area under the curve(AUC)of MTX soared with DS increased,at the meantime,MTX accumulation in liver,spleen and lung,decreased correspondingly.AUC of MTX increased with the molecular weight of mPEG raised,when keeping DS of mPEG constant.