Effects Of TPGS On The Drug Encapsulation Of Folate Targeting Pluronic/polylactic Acid Copolymers

Traditional Taxol injections,are non-selective and normally lead to many serious side effects.Compared with them,targeting polymeric nanocarriers delivery systems loading anti-cancer drugs such as paclitaxel(PTX)are more effective due to their selectivity and targeting behaviors to tumor organs.Moreover,the addition of D-a-tocopheryl polyethylene glycol 1000 succinate(TPGS)to nanocarriers could further improve the loading efficiency and loading capacity of PTX,enhance the absorption of nanoparticles into cancer cells,avoid multi drug resistance(MDR),and eventually improve the therapy efficiency.In this paper,we prepared mixed nanoparticles by adding TPGS into folate-targeting polymeric nanoparticles in order to develop a new PTX delivery system,and study its applications in cancer therapy.Folate-conjugated FA-Pluronic-(poly lactic acid)(FA-Pluronic-PLA)and FA-Pluronic-[poly(lactic-co-glycolic acid)](FA-Pluronic-PLGA)block copolymers were synthesized in this paper.Mixed nanoparticles with different ratios of copolymers to TPGS were prepared through dialysis method.The diameter and morphology of mixed nanoparticles were determined by dynamic light scattering(DLS)and transmission electron microscope(TEM).Compared with nanoparticles without TPGS,mixed nanoparticles were slightly smaller.The loading efficiency and loading capacity of mixed nanoparticles were determined by high performance liquid chromatography(HPLC).It was found that the loading efficiency was the highest(5.84%-6.79%)when the mass ratio of polymer to TPGS was 5:3.Therefore we chose the mass ratio 5:3 for the following study.According to in vitro release studies of PTX-loaded mixed nanoparticles,an initial burst release were observed in the first 11h,followed by a relatively slow but sustained release.Finally,90.4%-93.2%of encapsulated PTX released from mixed nanoparticles,while there were only 65.3%-67.5%of encapsulated PTX were released from nanoparticles without TPGS.In vitro antitumor effects of mixed nanoparticles were studied on OVCAR-3 cells though MTT assays.It was found that nanoparticles without TPGS were nontoxic,while TPGS were toxic to OVCAR-3 cells.PTX-loaded mixed nanoparticles showed a strong cytotoxicity to OVCAR-3 cells.The cytotoxicity of PTX-loaded mixed nanoparticles became more significant with increasing the treatment time.Pharmacokinetics and tissue distribution studies showed that the area under the curve(AUC)of the loaded TPGS-mixed nanoparticles was more larger than that of PTX injection.The concentration of drug in the lung increased,but drug’s concentrations in other normal organs tissues were reduced.Furthermore,a small amount of PTX-loaded mixed nanoparticles can cross the blood brain barrier into the brain tissue.Compared with PTX injection,these results showed that PTX-loaded mixed nanoparticles exhibited more desirable drug distribution and drug treatment efficacy.After establishing OVCAR-3 nude mice model,PTX-loaded mixed nanoparticles were administrated through intraperotoneal injections.Compared with PTX-loaded nanoparticles without TPGS,PTX-loaded mixed nanoparticles showed better performance in inbiting tumor growth.The above results indicate that PTX-loaded mixed nanoparticles could be developed as an effective antitumor drug delivery system.