The Paclitaxel Prodrug Self-assembled Nanoparticles Prepared For Liver Caner Therapy

Liver cancer is a common malignant tumor,and chemotherapy is one of the main therapeutic methods.However,most chemotherapeutic drugs have poor water solubility,quick blood clearance,and more toxic side effects.Targeted delivery of drugs to tumor tissue is an effective means to improve drug efficacy and reduce toxic side effects.Anti-tumor drug paclitaxel（PTX）has some problems,such as poor hydrophilicity,low bioavailability and lack of targeting,so it needs to be developed by means of preparation to enhance its efficacy.In this study,the paclitaxel was connected with polyethylene glycol(NH₂-PEG_2k-COOH,PEG)by ester bond,and the end of the polyethylene glycol was then connected with lactobionic acid（LA）to synthesize the LA-PEG-PTX polymer prodrug.In this polymer prodrug,the lactobionic aciden dowed paclitaxel with hepatocellular carcinoma targeting and polyethylene glycol enhanced its water solubility.The polymer can be self-assembled to form lactose acid-polyethylene glycol-paclitaxel prodrug nanoparticles（LPP NPs）by dialysis.Under transmission electron microscopy（TEM）,the prepared prodrug nanoparticles were spheroid with a particle size about 200 nm,and the Zeta potential was negative.The prodrug nanoparticles have high dilution stability,and the particle size wasn’t changed after storage under different conditions and lyophilized resolution,which can maintain good stability.The hemolysis experiment results showed that the prodrug nanoparticles had almost no hemolysis phenomenon,which indicated that the prodrug nanoparticles had good biocompatibility and safety,and could be used for intravenous injection.The results of drug release of PTX in vitro showed that it was released quickly under acidic condition and slow release under neutral condition.Pharmacokinetic results showed that compared with free PTX solution,the blood drug concentration of paclitaxel prodrug nanoparticles was at a higher level within 24 h,and the C_max,AUC,t_1/2 and MRT of LPP NPs group were higher.The results indicated that the prepared paclitaxel prodrug nanoparticles could improve the bioavailability of PTX,prolong the elimination half-life and retention time of PTX,and thus improve the efficacy of PTX.In vitro cytotoxicity and cell uptake experiments showed that LPP NPs had a good inhibitory effect on the proliferation of Hep G2 cells,and LA had a targeting effect.In vivo anti-tumor experiments showed that LPP NPs group had obvious inhibitory effect on tumor growth in mice,and the anti-tumor effect was the best,and it could reduce the toxic and side effects of PTX.In this study,the paclitaxel prodrug nanoparticles was constructed to solve poor hydrophilicity,poor targeting and low bioavailability of paclitaxel.and it provided a new pharmaceutical formulation for liver cancer therapy,diaplayed promising application prospects in clinical application.