Imaging-guided Delivery System Combined With Chemotherapy And Phototherapy For Castration-resistant Prostate Cancer Treatment

Objective:In this study,hydrophobic IR780 and docetaxel(DTX)were encapsulated into human serum albumin(HSA)to form a imaging-guided delivery system(HSA@IR780@DTX NPs)for the combination therapy of photothermal(PTT),photodynamic(PDT)and chemotherapy in castration-resistance prostate cancer(CRPC).We also explore the role and molecular mechanism of HSA@IR780@DTX NPs in docetaxel-resistant CRPC.Methods:The obtained HSA@IR780@DTX nanoparticles were characterized by transmission electron microscopy(TEM),dynamic light scattering(DLS)and ultraviolet-visible(UV-vis)spectrophotometry.The generation of singlet oxygen(1O2)was evaluated by fluorescence staining with SOSG.The photothermal of nanoparticles was recorded by the temperature increased with irradiation time.The cellular uptake,1O2 generation and antitumor efficacy of nanoparticles were evaluated in prostate cancer cells(22RV1)in vitro.The therapeutic efficacy of tumor bearing mice and toxicity tests of the NPs in vivo were also investigated.In the end,we treated 22RV1 with docetaxel to construct docetaxel-resistant cell line 22RV1-R.Cell viability was detected in 22RV1 and 22RV1-R cells treated with HSA@IR780@DTX NPs with or without near infrared(NIR)laser irradiation.Drug resistance and apoptosis genes were detected by western blotting in 22RV1 and 22RV1-R cells with treatments of nanoparticles.Results:The mean diameter was 146.5± 10.8nm determined by DLS.TEM showed the nanoparticle was spherical.UV-vis showed the NPs had a maximum absorbance at 790nm and it had 10nm red shift compared to free IR780.The NPs increased the temperature and generated1O2.The cellular uptake showed that most nanoparticles were entered in the 22RV1 prostate cancer cells.After irradiated with NIR laser,it can produce 1O2 to kill the cancer cells.The cell viability study showed HAS@IR780@DTX killed more cells when compared with single chemotherapy or single phototherapy.The NIR fluorescence in tumor-bearing mice showed the NPs can be highly accumulated in prostate cancer and the tumors were completely controlled.The results showed that the combination of PDT/PTT and chemotherapy can significantly inhibit CRPC tumor in vivo.Finally,we successfully constructed docetaxel-resistant castration-resistance prostate cancer cell line 22RV1-R.The final docetaxel concentration to maintain resistance was 20nM.The Cell viability of 22RV1 and 22RV1-R was significantly decreased when treated with HSA@IR780@DTX with NIR irradiation.The nanoparticles treated with NIR significantly reduced the drug resistant protein expression of ABCB1,AR and AR variant,??-tubulin,enhanced the apoptosis protein expression of Caspase3,PARP and Bax,and reduced the anti-apoptosis protein expression of Bcl-2 and Bcl-xl.Conclusion:HSA@IR780@DTX nanoparticles have the visual and synergistic effect in combination of phototherapy and chemotherapy for CRPC.And furthermore,it can significantly decrease the cell survival rate of docetaxel-resistant CRPC.The main mechanism is that HSA@IR780@DTX nanoparticles can promote prostate cancer cell apoptosis and reduce the expression of drug resistant genes.