Co-delivery Of Doxorubicin And Paclitaxel By Reduction And PH Dual Responsive Nanocarriers For Combination Osteosarcoma Therapy

Objective:Osteosarcoma is one of the most common malignant bone cancers in adolescents with a very high mortality rate.The standard treatment methods for osteosarcoma include preoperative chemotherapy,surgery and postoperative adjuvant chemotherapy.The most widely used chemotherapy approach for osteosarcoma treatment involves using a single drug.Although single drug chemotherapy has favorable therapeutic effect and improved survival rate,it also has the limitations of poor targeting ability,limited anticancer effects,severe systemic toxicity,and possible development of drug resistance.Besides,the inefficient drug release in cells reduces the therapeutic efficacy of cancer nanomedicines.Here,we put forward on the basis of the nanoparticles drug delivery system of combined treatment for cancer,it has a dual responsiveness reducibility and pH,internal release chemotherapy drugs to selectively in cancer cells,greatly reduce the side effects,improve the treatment effect,but also has good biocompatibility,and the use of two drugs play a synergistic antitumor effect,reduce the single drug resistance.It provides a promising platform for improving the therapeutic effect,prognosis and quality of life of osteosarcoma.Methods:Herein,a PEGylated poly(?-lipoic acid)copolymer(m PEG-P?LA)was prepared and used as a reduction/pH dual responsive nanocarrier to simultaneously deliver paclitaxel(PTX)and doxorubicin(DOX)for combination osteosarcoma therapy.The amphiphilic mPEG-P?LA could efficiently encapsulate both PTX and DOX during its self-assembly into micelles in aqueous solution to generate NP-PTX-DOX.The as-prepared NP-PTX-DOX showed enhanced PTX and DOX release in response to reductive and acidic stimuli.Moreover,the dual-drug loaded nanoparticles were efficiently internalized by K7 osteosarcoma cells and released drugs intracellularly,as confirmed by flow cytometry analysis and confocal laser scanning microscopy.Results:Compared with the PBS,free DOX,free PTX,NP-DOX and NP-PTX treatment groups,the NP-PTX-DOX treatment group had lower tumor cell activity and smaller tumor volume,showing a higher inhibitory effect on tumor cell growth.In addition,the CI value was 0.84(<1),which proved that DOX and PTX released from nanoparticles had a good synergistic anti-tumor effect.H&E staining showed thatNP-PTX-DOX had good biocompatibility.Conclusion:Combination therapy has the advantages of enhanced anticancer efficacy and reduced side effects.Nanoparticle-based DDS offers a promising route for combination cancer therapy by concurrently loading two or more kinds of chemotherapeutics.However,inefficient drug release from the nanomedicines in cancer cells may reduce the antitumor effects.Herein,a reduction/pH dual responsive nanocarrier mPEG-P?LA was developed which could self-assemble into micelles in aqueous media and concurrently encapsulate PTX and DOX.This dual-drug loaded micellar nanoparticle exhibited efficient drug release based on reduction/pH dual response and could be internalized by K7 osteosarcoma cells.Furthermore,the dual-drug loaded mPEG-P?LA micelles exerted effective synergistic anticancer effects both in vitro and in vivo in a murine K7 osteosarcoma model because of the synergy between PTX and DOX and the improved biodistribution of the nanoparticles.In conclusion,this work demonstrates the excellent potential of mPEG-P?LA copolymer as a reduction/pH dual responsive nanocarrier to co-deliver anticancer drugs for combination osteosarcoma therapy.