| In order to overcome the off-targeting drawback of traditional anticancer drugs,we designed a new type of active passive anticancer polymer micellar pro-drug,which was capable of killing tumor cells with better efficiency and selectivity.A hydrophilic polymer micelle carrier N-(2-hydroxypropyl)methacrylamide(HPMA)was selected,in which Gambogic Acid(GA)and targeted D-galactose/folic acid were coupled through hydrolytic ester bonds and amide bonds to form two different targeted amphiphilic copolymer.D-galactoacid-HPMA polymer precursor(HPMA-D-Gal-GA)andfolicacidmodifiedHPMApolymerprecursor(HPMA-FA-GA)were used as the driving force of intermolecular force in water,which were self-assembled into a spherical nuclear shell structure,and this structure was capable of increasing drug solubility and reducing side effects.In particular,the shell was able to protect the drug by improving drug stability and achieving sustained release.The degree of polymerization of polymer micelles of garcinic acid was determined by ultraviolet spectrophotometry.The structure was confirmed by infrared spectrophotometry(IR),nuclear magnetic resonance(1H NMR)and mass spectrometry(MS).The self-assembled polymer micelles were prepared by gel permeation chromatography(GPC),transmission electron microscopy(TEM),scanning electron microscopy(SEM)and laser particle size analyzer to achieve characterizat molecular weight,surface structure,particle size,potential.Consequently,the targeting properties of copolymers were evaluated by tissue distribution in mice.The cytotoxicity of K562 cells,H460 cells,MKN45 cells and GIST882 cells were evaluated by MTT tests,and S180 ascites tumor cells was also used to evaluate its antitumor activity.The synthesis of two kinds of polymer micelles was confirmed by IR,~1H NMR and MS(MS).The degree of polymerization of HPMA-D-Gal-GA and HPMA-FA-GA was 7.5±0.1684mol%and 9.5±0.2137mol%by UV visible spectrophotometry,the apparent molecular weight of HPMA-D-Gal-GA was17144Da with PDI of 1.8478 and HPMA-FA-GA was 27729Da with PDI of 1.0566,indicating that the molecular weight distribution of the two polymers is narrow.TEM and SEM images were observed the uniform morphology of polymer micelles,in which HPMA-D-Gal-GA showed smooth spherical structure of dispersed surface,and HPMA-FA-GA was cross-linked like spherical structure.The particle size of HPMA-D-Gal-GA was between 200nm-430nm with zeta potential at 15mV.The particle size of HPMA-FA-GA is between 490nm-700nm with zeta potencial at 25mV.The results showed that the IC50 values of HPMA-D-Gal-GA to K562 cells,H460cells,MKN45 cells and GIST882 cells were 0.21,1.94,1.17 and 0.36 respectively.The inhibitory effects exhibited dose dependent manner and the values were 0.23,1.79,0.94,and 0.45g/mL respectively.Compared with GA and glycolic acid ethanolamide,the toxicity was reduced.In comparision with GA,these two polymer prodrugs were stable in mice and showed a sustained release manner with similar blood concentration(P>0.05).The tissue distribution study showed HPMA-D-Gal-GA polymer prodrug preformed better liver targeting properties,and HPMA-FA-GA polymer prodrug was able to achieve lung targeting.The S180 ascites tumor bearing mice showed that the inhibition rate of HPMA-D-Gal-GA polymer precursor was 19.61%,40.62%and64.71%respectively.The inhibition rate of HPMA-FA-GA polymer precursor was28.29%,45.87%and 57.42%respectively,indicating that HPMA-D-Gal-GA and HPMA-FA-GA was able to achieve antitumor effects in dose dependence manner.Two kinds of HPMA polymer precursor prepared in this study were modified by D-galactose/folic acid to form a proactive polymer with targeting properties in tumor cell,and these polymers showed sustained release profiles.In situ transplantation tumor test also showed a better antitumor effect than GA.The linkage between HPMA and D-and galactose/folic acid is the first attempt both in domestic and foreign investigations... |
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