| Self-assembled polymeric nanoparticles are new anti-tumor drug delivery system,and holds great promise in reacent years.Self-assembled polymeric nanoparticles could self-assemble into core-shell nanoparticles in selective media through the molecular forces such as electrostatic interaction,hydrogen bonding,hydrophobic interaction.The internal hydrophibic core can provide a storeoom for hydrophobic drug,and the outer hydrophilic shell can maintain the stability of the nanoparticles in aqueous media,thereby allow a long circulation of drugs in vivo.Though chemical modification,self-assembled polymeric nanoparticles can achieve smart environmental response,active targeting,etc.Due to its small particle size,nanoparticles can target the areas and minimize undesirable side effects via enhanced permeability and retention(EPR).Gambogic acid(GA)selectively induce apoptosis in tumor cells,and exhibits potent anticancer activity in vivo and in vitro.It exerts less toxicity tonormal cells compared with cancer cells.However,the poor aqueous solubility(～10 μg/mL),short half-life,and wide distribution in vivo impede its clinical application,resulting in low bioavailability.In addition,gambogic acid had an inseparable C-2 epimeric mixture(R,S contrifuge).In this paper,the amphiphilic triblock polymers were synthesized,the to construct self-assembled polymeric nanoparticles of gambogic acid,to solve the problem of hydrophobic drug and realize the effective delivery of gambogic acid.In this paper,amphiphilic triblock polymers polycaprolactone-polyethylene glycol-polycaprolactone(PCL-PEG-PCL)were designed and synthesized,which using polyethylene glycol(PEG)as hydrophilic segment and polycaprolactone(PCL)as hydrophobic segment.PCL-PEG-PCL were synthesized by ring-opening polymerization of ε-CL intiated by PEG.The structure of polymer was confirmed by FT-IR,1HNMR,GPC.The critical micelle concentration was determined by a fluorescence probe method,and about 0.02 mg/mL.The cell cytotoxicity experiment investigated that polymer was non-toxic and biocompatible.Preparation of self-assembled polymeric nanoparticles using thin film-hydrationsonication method,and the nanoparticles were characterized in terms of particle size,PDI,encapsulation efficiency.Through single factor selecting the best prescription and preparation was determined,and nanoparticles particle size were spherical with particle size 226.5 nm,PDI of 0.208 and encapsulation efficiency of 92.69%.The in vitro release data indicated that nanoparticles released slowly and duration,which need to diffuse out from the hydrophobic core and then into the surrounding solution.The anti-tumor effects of 2R-GA and 2S-GA to BGC-823 cell and Hela cell were evaluated.With increasing of drug concerntration,cell inhibition of 2R-GA,2S-GA were enhanced.There has no significantly difference between 2R-GA and 2S-GA.Compared with gambogic acid,Self-assembled polymeric nanoparticles had a low cell inhibition at 24 h.While prolongeing incubation time to 36 h and 48 h,nanoparticles had a higher cell inhibition than gambogic acid.Eventually,Self-assembled polymeric nanoparticles showed good antitumor effect and good sustained release effect.The UHPLC-MS/MS method was established to determine the concentration of 2R-GA,2S-GA in rat plasma,and methodological validation were approved.Pharmacokinetics of 2R-GA,gambogic acid and nanoparticles were investgated.2R-GA can not transfer to 2S-GA.Compared with gambogic acid,the MRT0-∞ and AUC 0-∞ of self-assembled polymeric nanoparticles were increased and showed good sustained release effect.The CL was decreased and Cmax was increased.All of these showed nanoparticles can change pharmacokinetic characteristics in rats.In conclusion,self-assembled polymeric nanoparticles had high encapsulation efficiency,sustained release and showed good antitumor effect.The study had a very important significance for the clinical application of Gambogic acid. |
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