Precisely Designed Thermosensitive Platinum-Group Nanoscale Coordination Polymers For Cooperation Cancer Therapy

With the increasing understanding of tumor genesis and development,the cooperation cancer therapy based on nano-drug-delivery systems(NDDSs)has become a new paradigm for tumor therapy.Cooperative cancer therapy is to rationally combine several drugs with different therapeutic modes together,improving therapeutic efficacy and reducing side effects,and ultimately achieving the goal of“1+1>2”.Common cooperation cancer therapy strategies include photothermal therapy(PTT)/chemotherapy,photodynamic therapy(PDT)/PTT/chemotherapy.Although great progress has been made in the field of cooperation cancer therapy,there remain some thorny issues that need to be addressed to promote their clinical translation.(1)PDT-based cooperation cancer therapy faces with the problem of self-aggregation of photosensitizers,which leads to low singlet oxygen quantum yield.(2)The chemotherapy-based cooperation cancer therapy faces with the problem of uncontrollable and/or premature drugs release.(3)Most NDDSs involve complicated synthesis process,harsh synthesis conditions and are not environmentally friendly.(4)The PEG dilemma leads to low tumor delivery efficiency for most NDDSs.(5)Most NDDSs are unsatisfactory in the treatment of drug-resistant and metastatic tumors.Nanoscale coordination polymers(NCPs)are a kind of multifunctional nanomaterials with simple and mild synthesis method,adjustable structure and composition.In this paper,a series of acidic temperature-sensitive polymers were developed as organic bridging ligands,and cytotoxic platinum group metal ions as the metal connection points,to synthesize p H/temperature dual response NCPs in a simple,mild and controllable way,which skillfully circumvents the above problems and be used for the cooperative cancer therapy efficiently.The main innovative results are as follows:(1)A discretely integrated nano-fabrication strategy for photosensitizers was developed.Under room temperature and water system,cisplatin coordinated with photosensitizer indocyanine green(ICG)and polymer poly[2-(2-methoxyethoxy)ethyl methacrylate-co-poly(ethylene glycol)methyl ether methacrylate]-b-poly(sodium p-styrenesulfonate)(PES)to construct Pt/IS-DINs with core—shell structure.By rationally regulating the ratio of ICG/PES,the aggregation degree of ICG can be regulated,and the two contradictory problems of photobleaching and aggregation caused quenching of ICG can be solved.The singlet oxygen quantum yield and photothermal conversion efficiency of ICG can be increased by 7 times(The highest value among the known literatures)and 3times,respectively.Under the excitation of 808 nm laser,the photothermal effect induced the hydrophilicity-hydrophobicity transition of Pt/IS-DINs,achieving photothermal targeting delivery and increasing the tumor accumulation of Pt/IS-DINs by 10 times and overcoming PEG dilemma.Pt/IS-DINs showed a highly effective PDT/PTT/chemotherapy synergistic treatment effect on primary tumors,and effectively induced ICD effect,activating the systemic anti-tumor immune response to significantly inhibite the growth of distant and metastatic tumors.(2)Hexachloroplatinic acid coordinated with acidic temperature-sensitive block polymer poly(N-isopropylacrylamide)-b-poly(acrylic acid)(PNA)to form Pt⁴⁺-PNA nanogels as template to prepare bivalent platinum nanoclusters(Pt NCs)with photothermal Pt⁰ core and chemotherapeutic Pt²⁺shells by a simple,mild and controlled reduction reaction.By adjusting the molar ratio of Pt⁴⁺to PNA,Pt NCs with different Pt²⁺/Pt⁰ ratios can be selectively obtained.Under the excitation of 808 nm laser,the photothermal effect induced the hydrophilicity-hydrophobicity transition of Pt NCs,increasing the tumor accumulation of Pt NCs by 3 times and overcoming PEG dilemma.In addition,Pt NCs show precisely and spatiotemporally controllable photoactivated drug release behavior,which solves the problem of premature drug release and realizes the precise synergistic anti-tumor effect of photoactivated PTT/chemotherapy.(3)Pd-PNS nanogels were prepared by co-assembly of potassium tetrachloropalladium with a temperature-sensitive acid block polymer poly(N-isopropylacrylamide)-b-poly(styrenesulfonate)(PNS).The lower critical solution temperature(LCST)of Pd-PNS nanogels can be regulated by changing the content of Pd²⁺in Pd-PNS nanogels:The LCST of Pd-PNS nanogels decreased with the increase of Pd²⁺content,which was conducive to the intratumoral gelation of Pd-PNS nanogels and enhanced the intratumoral long-term retention of Pd²⁺.The release behavior of Pd²⁺was p H-dependent,that is,the lower the p H value,the faster the release rate of Pd²⁺,ensuring Pd²⁺mainly released at tumor sites.In addition,Pd-PNS nanogels can increase the uptake and reduce the efflux of Pd²⁺by cisplatin resistant MCF-7/Pt tumor cells.Therefore,Pd-PNS nanogels can effectively kill MCF-7/Pt tumor cells and also their tumor stem cells,thus completely inhibiting the growth of MCF-7/Pt tumor.In this paper,aiming at the existing problem of cooperative cancer therapy,the preparation of several acidic temperature-sensitive NCP with platinum chemotherapy drugs,through the photothermal-directed tumor targeting delivery and controlled release,achieving precise synergistic cancer PTT/chemotherapy and PDT/PTT/chemotherapy,and the induced cancer immunogenic cell death(ICD),activating systemic antitumor immune response and efficiently inhibiting resistance and metastatic tumors.This study provides a new insight for realizing precise cooperative cancer therapy and overcoming tumor drug resistance and metastasis.