NIR-triggered thermo-responsive biodegradable hydrogel with combination of photothermal and thermodynamic therapy for hypoxic tumor

Hypoxia is a typical feature of solid tumors,which highly limits the application of the oxygen-dependent therapy.Also,the dense and hyperbaric tumor tissues impede the penetration of nanoparticles into the deep tumor.Thereby,we designed a novel localized injectable hydrogel combining the photothermal therapy(PTT)and the thermodynamic therapy(TDT),which is based on the generation of free radicals even in the absence of oxygen for hypoxic tumor therapy.In our study,gold nanorods(Au NRs)and 2,2-Azobis[2-(2-imidazalin-2-yl)propane]dihydrochlaride(AIPH)were incorporated into the hydrogel networks,which were formed by the copolymerization of hydrophobic N-isopropyl acrylamide(NIPAM)and hydrophilic glycidyl methacrylate modified hyaluronic acid(HAGMA)to fabricate an injectable and near-infrared(NIR)responsive hydrogel.The crosslinked in situ forming hydrogel could not only realize PTT upon the NIR laser irradiation,but also generate free radicals even in hypoxic condition.Meanwhile the shrink of hydrogels upon thermal could accelerate the generation of free radicals to further damage the tumors,achieving the controlled drug release on demand.The designed hydrogel with a sufficient loading capacity,excellent biocompatibility and negligible systemic toxicity could serve as a long-acting implant for NIR-triggered thermo-responsive free radical generation.The in vitro cytotoxicity result and the in vivo antitumor activity illustrated the excellent therapeutic effect of hydrogels even in the absence of oxygen.Therefore,this innovative oxygen-independent platform combining the antitumor effects of PTT and TDT would bring a new insight into hypoxic tumor therapy by the application of alkyl free radical.

Targeting Hypoxic Tumors with Hybrid Nanobullets for Oxygen-Independent Synergistic Photothermal and Thermodynamic Therapy

Hypoxia is a feature of solid tumors and it hinders the therapeutic efficacy of oxygen-dependent cancer treatment.Herein,we have developed all-organic oxygen-independent hybrid nanobullets ZPA@HA-ACVA-AZ for the“precise strike”of hypoxic tumors through the dual-targeting effects from surface-modified hyaluronic acid(HA)and hypoxia-dependent factor carbonic anhydrase IX(CA IX)-inhibitor acetazolamide(AZ).The core of nanobullets is the special zinc(II)phthalocyanine aggregates(ZPA)which could heat the tumor tissues upon 808-nm laser irradiation for photothermal therapy(PTT),along with the alkyl chain-functionalized thermally decomposable radical initiator ACVA-HDA on the side chain of HA for providing oxygen-independent alkyl radicals for ablating hypoxic cancer cells by thermodynamic therapy(TDT).The results provide important evidence that the combination of reverse hypoxia hallmarks CA IX as targets for inhibition by AZ and synergistic PTT/TDT possess incomparable therapeutic advantages over traditional(reactive oxygen species(ROS)-mediated)cancer treatment for suppressing the growth of both hypoxic tumors and their metastasis.