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“prec...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.展开更多
Combining chemo-therapeutics with immune checkpoint inhibitors facilitates killing cancer cells and activating the immune system through inhibiting immune escape.However,their treatment effects remain limited due to t...Combining chemo-therapeutics with immune checkpoint inhibitors facilitates killing cancer cells and activating the immune system through inhibiting immune escape.However,their treatment effects remain limited due to the compromised accumulation of both drugs and inhibitors in certain tumor tissues.Herein,a new poly(acrylamide-co-acrylonitrile-co-vinylimidazole-co-bis(2-methacryloyl)oxyethyl disulfide)(PAAVB)polymer-based intelligent platform with controllable upper critical solution temperature(UCST)was used for the simultaneous delivery of paclitaxel(PTX)and curcumin(CUR).Additionally,a hyaluronic acid(HA)layer was coated on the surface of PAAVB NPs to target the CD44-overexpressed tumor cells.The proposed nanomedicine demonstrated a gratifying accumulation in tumor tissue and uptake by cancer cells.Then,the acidic microenvironment and high level of glutathione(GSH)in cancer cells could spontaneously decrease the UCST of polymer,leading to the disassembly of the NPs and rapid drug release at body temperature without extra-stimuli.Significantly,the released PTX and CUR could induce the immunogenic cell death(ICD)to promote adaptive anti-tumor immunogenicity and inhibit immunosuppression through suppressing the activity of indoleamine 2,3-dioxygenase 1(IDO1)enzyme respectively.Therefore,the synergism of this intelligent nanomedicine can suppress primary breast tumor growth and inhibit their lung metastasis.展开更多
基金the National Natural Science Foundation of China(51903203,51703178,81770728)the China Postdoctoral Science Foundation(2019M653661,2019M663742)+3 种基金the Natural Science Foundation of Shaanxi Province(2020JQ-046)Natural Science Foundation of Zhejiang Province(LWY20H180002)the Natural Science Foundation of Guangxi Zhuang Autonomous Region(2017GXNSFBA198028).Y.H.,M.G.,Y.S.Z.,G.H.and X.Z.were not supported by any of these fundsinstead,support by MIT,Harvard,Stanford University and the Brigham Research Institute are acknowledged.
文摘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.
基金This research was supported by the National Natural Science Foundation of China(51703178,51903203,81770728)the China Postdoctoral Science Foundation(2019M663742,2019M653661)Natural Science Foundation of Zhejiang Province(LWY20H180002).
文摘Combining chemo-therapeutics with immune checkpoint inhibitors facilitates killing cancer cells and activating the immune system through inhibiting immune escape.However,their treatment effects remain limited due to the compromised accumulation of both drugs and inhibitors in certain tumor tissues.Herein,a new poly(acrylamide-co-acrylonitrile-co-vinylimidazole-co-bis(2-methacryloyl)oxyethyl disulfide)(PAAVB)polymer-based intelligent platform with controllable upper critical solution temperature(UCST)was used for the simultaneous delivery of paclitaxel(PTX)and curcumin(CUR).Additionally,a hyaluronic acid(HA)layer was coated on the surface of PAAVB NPs to target the CD44-overexpressed tumor cells.The proposed nanomedicine demonstrated a gratifying accumulation in tumor tissue and uptake by cancer cells.Then,the acidic microenvironment and high level of glutathione(GSH)in cancer cells could spontaneously decrease the UCST of polymer,leading to the disassembly of the NPs and rapid drug release at body temperature without extra-stimuli.Significantly,the released PTX and CUR could induce the immunogenic cell death(ICD)to promote adaptive anti-tumor immunogenicity and inhibit immunosuppression through suppressing the activity of indoleamine 2,3-dioxygenase 1(IDO1)enzyme respectively.Therefore,the synergism of this intelligent nanomedicine can suppress primary breast tumor growth and inhibit their lung metastasis.