| Chemotherapy is currently one of the most effective cancer therapies.As a DNA crosslinking molecule with remarkable antitumor efficacy,platinum drug has become a commonly used drug in cancer chemotherapy.However,chemotherapy with platinum drug is accompanied by serious side effects and drug resistance,which greatly limits its clinical application.The main mechanisms of platinum resistance include the reduced intracellular accumulation of platinum ions,the increased detoxification of abundant glutathione(GSH),and the up-regulation of DNA repair mechanisms.At present,the discovery of tetravalent platinum prodrug(Pt(Ⅳ))and its nanoparticlebased drug delivery systems(NDDSs)have greatly improved the stability of bivalent platinum drug(Pt(Ⅱ))and reduced its side effects,which is expected to reverse the platinum resistance.Therefore,this paper constructed platinum-contained multifunctional nanomedicines to improve the therapeutic effects of platinum drugs and reverse the drug resistance.The major studies could be summarized as bellows:1.In order to simultaneously realize the sensitization and the visualized therapy of platinum drug,gold nanoclusters with bifunctions of NIR-Ⅱ imaging and glutathionescavenging were used to deliver Pt(Ⅳ)to construct a theranostic nanomedicine(AuNCs-Pt).AuNCs-Pt depleted intracellular GSH by forming Au-S bonds to minimize platinum detoxification,effectively maximizing the therapeutic efficacy of platinum.In addition,AuNCs-Pt with NIR-Ⅱ imaging capability enabled platinum tracking in the deep tumor,thus facilitating it to be a promising tool for monitoring platinum transportation.AuNCs-Pt was used to eradicate the tumor burden on a fatal high-grade serous ovarian cancer and a patient-derived tumor xenograft of hepatocellular carcinoma.2.To overcome the drug resistance and limitations of platinum-based chemotherapy,light-activatable liposomes(Pt/Ce6-LP)integrated with both a chlorin e6(Ce6)photodynamic component and a Pt(Ⅳ)chemotherapeutic component were engineered.Under laser irradiation,Pt/Ce6-LP generated reactive oxygen species(ROS)and released Pt(Ⅳ),which is reduced to toxic Pt(Ⅱ)under the action of GSH,thus performing chemotherapy/photodynamic therapy(PDT)effect GSH consumption during the conversion from Pt(Ⅳ)to Pt(Ⅱ)can avoid the annihilation of ROS generated by PDT.Pt(Ⅱ)can activate the H2O2 generation due to its enzyme-like functions.This positive feedback loop appeared to remodel the redox balance of H2O2 and GSH in tumors,alleviating the hypoxic tumor microenvironment caused by PDT.The alleviated hypoxia is found to be critical to the enhancement of PDT efficacy,the reversal of platinum resistance in tumors,and immunopotentiation.Pt/Ce6-LP demonstrated significant antitumor effect and persistent post-medication inhibition in patient-derived tumor xenograft of hepatocellular carcinoma.3.In order to further systematically reverse platinum resistance,a cascade targeted and mitochondrion-dysfunctional nanomedicine(Gal-NP@TPt)comprising bifunctional amphiphiles and tetravalent platinum prodrugs possessing mitochondriontargeting function was elaborated.Gal-NP@TPt reversed platinum resistance by simultaneously overcoming the following cascaded drug resistance problems:(1)GalNP@TPt with sequential targeting functions towards tumors and mitochondria improved the spatiotemporal level of platinum in mitochondria.(2)The degradation process of Gal-NP@TPt depleted intracellular GSH,reducing the detoxification of platinum drugs.(3)The strategical transportation of platinum to mitochondria lacking DNA repair machinery by Gal-NP@TPt lowered the possibility of platinum deactivation.Eventually,Gal-NP@TPt demonstrated appreciable anti-tumor effects for systemic treatment of patient-derived tumor xenograft of hepatocellular carcinoma.In conclusion,several Pt(Ⅳ)-based multifunctional nanomedicines constructed in this paper partly reversed platinum resistance,exhibiting good therapeutic effects in different tumor treatment scenarios. |
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