Reduction-responsive Nanomaterials To Enhance The Chemotherapy Efficacy Of Doxorubicin For Prostate Cancer Bone Metastases

Objective:To detect the efficiency of chemotherapy assisted with reduction-responsive micelles in the treatment of prostate cancer bone metastases.Methods:Poly(ethylene glycol)-disulfide linkage-poly(lactic-co-glycolic acid)(mPEG-SS-PLGA)was employed as reduction-responsive drug delivery system.Doxorubicin(DOX),as a model antitumor drug,was encapsulated in the nanoparticle to inform DOX-loaded nanogel(NG/DOX).The size,stability,morphology,drug encapsulation percentage,loading efficiency,and drug release of NG/DOX were performed.The cytotoxicity of free DOX and NG/DOX towards RM-1 cells was assessed by MTT assay.Flow cytometer(FCM)and confocal laser scanning microscopy(CLSM)assays were employed to investigate the cell internalization of both DOX formulations.A mouse model of bone metastasis for prostate cancer(PCa)was established by intra-tibial injection of RM-1 cells.Meanwhile,the tissue distribution assay,antitumor efficacy of NG/DOX in PCa bone metastasis mice model were investigated.Furthermore,gait analysis was employed to assess the effect of PCa bone metastasis on the activities of limbs.Results:The nanoparticle size measured by DLS indicated that the hydrodynamic radius(Rh)of NG/DOX was 33.8 � 7.2 nm.NG/DOX exhibited nearly constant sizes under physiological conditions.When NG/DOX was incubated in the reductive environment,the Rh of NG/DOX increased rapidly,which indicated the reduction-response characteristic of NG/DOX in vitro.Compared with free DOX,NG/DOX showed higher proliferation inhibition.Furthermore,there was apparent accumulation of NG/DOX in tumor tissue from 6 h to 24 h,which indicated that the reduction-sensitive drug delivering system could significantly enhance the accumulation of DOX in tumor site and reduce the systemic toxicity.In the gait analysis,there was a significant improvement in the reduced limb dragging in the treatment groups,especially the NG/DOX group.According to the in vivo anti-tumor evaluations,the results revealed that NG/DOX exhibited stronger antitumor efficacy on PCa bone metastasis.Conclusion:1.mPEG-SS-PLGA as the delivery system of chemotherapeutic agents showed great potential for the treatment of PCa bone metastasis.2.NG/DOX showed enhanced therapeutic efficacy and low organ toxicity indicating the great potential of reduction-responsive drug system as platform for the clinical chemotherapy of PCa bone metastasis.