Preparation And Mitochondrial Targeting Of Triphenylphosphine-modified Polyphosphate-polyethylene Glycol-polylactic Acid Triblock Copolymer Nanoparticle

Objective:Diverse combinations of block copolymers are an important approach to obtain novel nanocarrier materials,which are widely used in various fields.Block copolymers enable nano-delivery systems that can significantly improve the bioavailability of drugs.However,the lack of targeting can cause serious damage to normal cells,so we introduced lipophilic cations based on the study of block copolymers to achieve mitochondrial targeting.This enables further concentration of the drug in tumor cells and reduces the toxicity of the drug to normal cells.Methods:Amphiphilic triblock copolymers consisting of poly(lactic acid),poly(ethylene glycol)and poly(phosphate)were synthesized by two ring-opening polymerizations,to which lipophilic cationic triphenylphosphine groups with mitochondrial targeting were introduced as nanocarrier materials for the delivery of the antitumour drug ursolic acid.The copolymer structure was verified by ~1H NMR,FT-IR and UV methods for characterisation.The nanoparticle solutions were prepared by emulsification-solvent evaporation method,and the particle size,charge,encapsulation rate and stability of the nanoparticles were investigated by dynamic light scattering and dialysis methods.The biocompatibility of ursolic acid nanoparticles was briefly evaluated by erythrocyte haemolysis assay,the mitochondrial targeting ability of fluorescently labelled nanoparticles was evaluated by laser confocal microscopy,and finally in vitro cell proliferation assay and scratch migration assay were performed to compare the difference in anti-tumour effect between ursolic acid and ursolic acid nanoparticles.Results:Carrier materials with grafting ratios of 1∶1,1∶3 and 1∶5 between triphenylphosphine and triblock copolymers were successfully synthesised and nanoparticle solutions I,II and III were prepared in turn.Among them,nanoparticles II are more compliant,with a mean particle size and surface charge of 180.07±1.67nm and+15.57±1.33 m V,respectively,and are more stable.Laser confocal microscopy also observed the best localization of mitochondria in II.The results of the cell proliferation and scratch assays show that the II nanoparticles have a better effect on inhibiting tumour proliferation and migration compared to ursolic acid.Conclusion:Triphenylphosphorus-modified triblock copolymers have good mitochondrial targeting and improve the low bioavailability of ursolic acid,and ursolic acid nanoparticles exhibit more pronounced anti-tumour capabilities and are a promising route for the delivery of therapeutic oncology drugs.