Composite Thermo-sensitive Hydrogel Loaded Paclitaxel Anddoxorubicin Liposomes For The Local Treatment Of Hepatocelluar Carcinoma

Hepatocellular carcinoma(HCC)is one of the most common malignancies in Asian countries.Surgery is the main treatment.However HCC patients are often not effective treatment and lead to disease progression or recurrence(5-year recurrence rate of up to 70%)as a result of potential tumors and the tumor metastasis of remaining liver tissue after surgical resection.The drug bioavailability of conventional intravenous chemotherapy is low and also has dose-dependent side effects.Therefore,to find effective treatment and improve the survival of liver cancer patients is very important.In order to get a better therapeutic effect and reduce multi-drug resistance,two or more drugs combined chemotherapy has been widely used in clinical.Paclitaxel is a novel anti-microtubule drug,which belongs to the cell cycle-specific drugs,inhibit the promotion of tubulin polymerization.But it has poor water solubility and can cause serious bone marrow suppression,neurotoxicity and other side effects through systemic administration.Doxorubicin is a broad spectrum of anti-cancer drugs,it belongs to the cycle of non-specific drugs.The main role of doxorubicin is embedded in DNA which inhibit the synthesis of nucleic acid,but its systemic administration can lead to certain cardiac toxicity and renal toxicity.Studies have shown that,combining PTX with DOX can play a synergistic effect through different anti-tumor mechanisms which effectively inhibit tumor growth.The nanoparticles,micelles and gels as a drug delivery carrier can significantly reduce its toxicity and enhance the anti-cancer effect of drugs.Thermo-sensitive hydrogel is sensitive to temperature changes.As a result,it can extend the drug stagnation time and improve drug efficacy.Compared with traditional chemotherapy,local treatment has better targeting and drug sustained effect.Thermo-sensitive hydrogel as a drug carrier,not only can improve the tumor tissue drug concentration,but also enhance the drug treatment.Based on above characteristics,this paper designed and prepared a co-loaded paclitaxel and doxorubicin thermo-sensitive hydrogel delivery system to extend the drug release time and enhance the anti-tumor effect of drugs through the arterial embolization chemotherapy and intratumoral injection of drugs.In this study,Poloxamer 407,sodium alginate and HPMC were used to prepare thermo-sensitive hydrogel.The optimal formulation of the thermo-sensitive hydrogel was optimized by considering the gelation temperature,time and rheological properties.The gelation temperature was 26.5 ?,the gelation time was 85.20 s.In vitro erosion experiments showed that the thermo-sensitive hydrogel has calcium dependent properties which significantly slowed the rate of erosion.In vivo rabbit renal embolization experiments showed that the thermo-sensitive hydrogel can be a good embolization of renal artery which can still be observed after 4 weeks embolization.At the same time,rabbit liver cancer model was established and embolized by arterial catheterization.The results showed that thermo-sensitive hydrogel had good anti-tumor growth effect and low systemic toxicity.The optimal synergistic effect of DOX and PTX was determined by Chou-Talalay analysis.In vitro cell proliferation inhibition experiment results show that when the presence of PTX: DOX = 1:2(w/w),synergistic inhibitory effect on SMMC-7721 was the strongest.In order to further improve the anti-cancer effect,this paper prepared paclitaxel liposomes by emulsification solvent evaporation and doxorubicin liposomes by the method of pH difference transmembrane transport.The particle sizes of PTX-LPs and DOX-LPs were 109.70 ± 0.48 nm and 171.27 ± 1.42 nm,respectively.PTX-LPs and DOX-LPs can rapidly release DOX and PTX under acidic conditions.Compared with free drug release,drug-loaded liposomes have certain sustained-release capacity.Subsequently,the optimal formulation of DOX and PTX was used to prepare co-loaded paclitaxel doxorubicin liposomes by emulsification solvent evaporation and pH difference transmembrane transport method.Cell experiments showed that the liposomes were endocytosed by the cell,which enhance the antitumor effect of the drug.Co-loaded paclitaxel doxorubicin liposomes thermo-sensitive hydrogels was prepared by mixing of Poloxamer 407,SA,HPMC and co-loaded paclitaxel doxorubicin liposomes.The results of in vitro and in vivo experiments showed that co-loaded paclitaxel doxorubicin liposomes thermo-sensitive hydrogels could inhibit the growth of hepatocellular carcinoma and have potential clinical value in the local treatment of liver cancer.