Human papillomavirus(HPV)is a highly prevalent venereal pathogen accounting for genital warts and various cancers like cervical,anal,and oropharyngeal cancers.Although imiquimod,a topical medication,is commonly used t...Human papillomavirus(HPV)is a highly prevalent venereal pathogen accounting for genital warts and various cancers like cervical,anal,and oropharyngeal cancers.Although imiquimod,a topical medication,is commonly used to treat genital warts induced by HPV,its potential as an in situ immune response regulator for HPV-related cancers has rarely been explored.In this study,we developed an innovative synergistic therapeutic platform by integrating near-infrared-II(NIR-II)absorbing aggregationinduced emission(AIE)agent(TPE-BT-BBTD)and imiquimod into an injectable hydrogel named TIH.TPE-BT-BBTD molecule that serves as a photothermal agent,with exposure to a 1064 nm laser,effectively destroys tumor cells and releases tumor-related antigens.During the thermogenesis process,the hydrogel melts and releases imiquimod.The released imiquimod,in conjunction with the dead tumor antigens,stimulates dendritic cellmaturation,activating the immune system to ultimately eliminate residual cancer cells.This novel approach combines the immunomodulatory effects of imiquimod with a 1064 nm-excitable photothermal agent in a hydrogel delivery system,offering a promising tactic for combating HPV-associated cancers.展开更多
Among tumor microenvironment(TME),the entire metabolic characteristics of tumorresident cells are reprogrammed to benefit the expansion of tumor cells,which count on glutamine in large part to fuel the tricarboxylic a...Among tumor microenvironment(TME),the entire metabolic characteristics of tumorresident cells are reprogrammed to benefit the expansion of tumor cells,which count on glutamine in large part to fuel the tricarboxylic acid cycle for energy generation and anabolic metabolism support.Endothelial cells that are abducted by tumor cells to form a pathological tumor vascular network for constructing the hypoxic immunosuppressive TME,also rely on glutaminolysis as the“engine”of angiogenesis.Additionally,the glutamine metabolic preference benefits the polarization of TAMs towards pro-tumoral M2 phenotype as well.Herein,we developed a type of siRNA micelleplexes(MH@siGLS1)to reverse immunosuppressive TME by targeting glutaminolysis within tumor-resident cells for tumor vasculature normalization-and TAMs repolarization-enhanced photo-immunotherapy.Tumor cell starvation and antioxidant system destruction achieved by MH@siGLS1-mediated glutaminolysis inhibition could promote photodynamic therapy efficacy,which was available to trigger immunogenic cell death for adaptive antitumor immune responses.Meanwhile,glutaminolysis inhibition of tumor endothelial cells and TAMs could realize tumor vascular normalization and TAMs repolarization for antitumor immunity amplification.This study provides a unique perspective on cancer treatments by focusing on the interrelations of metabolic characteristics and the biofunctions of various cell types within TME.展开更多
Microtubules(MTs)are key players in cell division,migration,and signaling,and they are regarded as important targets for cancer treatment.In this work,two fullerene(C_(60))-functionalized Ir(Ⅲ)complexes(Ir-C_(60)1 an...Microtubules(MTs)are key players in cell division,migration,and signaling,and they are regarded as important targets for cancer treatment.In this work,two fullerene(C_(60))-functionalized Ir(Ⅲ)complexes(Ir-C_(60)1 and Ir-C_(60)2)are rationally designed as dual reactive oxygen species(ROS)regulators and MT-targeted Type Ⅰ/Ⅱ photosensitizers.In the dark,Ir-C_(60)1 and Ir-C_(60)2 serve as ROS scavengers to eliminate O_(2)·^(−)and·OH,consequently reducing the dark cytotoxicity and reversing dysfunctional T cells.Due to the efficiently populated C_(60)-localized intraligand triplet state,Ir-C_(60)1 and Ir-C_(60)2 can be excited by green light(525 nm)to produce O_(2)·^(−)and·OONO−(Type Ⅰ)and ^(1)O_(2)(Type Ⅱ)to overcome tumor hypoxia.Moreover,Ir-C_(60)1 is also able to photooxidize tubulin,consequently interfering with the cellular cytoskeleton structures,inducing immunogenic cell death and inhibiting cell proliferation and migration.Finally,Ir-C_(60)1 exhibits promising photo-immunotherapeutic effects both in vitro and in vivo.In all,we report here the first MT stabilizing photosensitizer performing through Type I/II photodynamic therapy pathways,which provides insights into the rational design of new photo-immunotherapeutic agents targeting specific biomolecules.展开更多
Phototherapies offer promising alternatives to traditional cancer therapies.Phototherapies mainly rely on manipulation of target tissue through photothermal,photochemical,or photomechanical interactions.Combining phot...Phototherapies offer promising alternatives to traditional cancer therapies.Phototherapies mainly rely on manipulation of target tissue through photothermal,photochemical,or photomechanical interactions.Combining phototherapy with immunotherapy has the benefit of eliciting a systemic immune response.Specifically,photothermal therapy(PTT)has been shown to induce apoptosis and necrosis in cancer cells,releasing tumor associated antigenic peptides while sparing healthy host cells,through temperature increase in targeted tissue.However,the tissue temperature must be monitored and controlled to minimize adverse thermal effects on normal tissue and to avoid the destruction of tumor-specific antigens,in order to achieve the desired therapeutic effects of PTT.Techniques for monitoring PTT have evolved from post-treatment quantification methods like enzyme linked immunosorbent assay,western blot analysis,and flow cytometry to modern methods capable of real-time monitoring,such as magnetic resonance thermometry,computed tomography,and photoacoustic imaging.Monitoring methods are largely chosen based on the type of light delivery to the target tissue.Interstitial methods of thermometry,such as thermocouples and fiber-optic sensors,are able to monitor temperature of the local tumor environment.However,these methods can be challenging if the phototherapy itself is interstitially administered.Increasingly,non-invasive therapies call for non-invasive monitoring,which can be achieved through magnetic resonance thermometry,computed tomography,and photoacoustic imaging techniques.The purpose of this review is to introduce the feasible methods used to monitor tissue temperature during PTT.The descriptions of different techniques and the measurement examples can help the researchers and practitioners when using therapeutic PTT.展开更多
基金the National Natural Science Foundation of China(No.82371613 to F.S.)the National Key Research and Development Program of China(No.2021YFC2700200 to F.S.)+5 种基金the Key Research and Development Program of Zhejiang Province(No.2023C03035 to F.S.)the Key Research and Development Program of Ningxia Hui Autonomous Region(No.2021BEG02029 to F.S.)the 2024 Zhejiang Medicine and Health Technology Plan(No.2024KY100 to X.Y.)the 2024 Zhejiang Traditional Chinese Medicine Science and Technology Plan(No.2024ZL597 to X.Y.)the Zhejiang Provincial Natural Science Foundation of China(No.LQ24H180003 to X.Y.)the 2023 Clinical Medical Research Special Key Project Fund of the Zhejiang Medical Association(2023ZYC-Z05 to X.Y.)for financial support.
文摘Human papillomavirus(HPV)is a highly prevalent venereal pathogen accounting for genital warts and various cancers like cervical,anal,and oropharyngeal cancers.Although imiquimod,a topical medication,is commonly used to treat genital warts induced by HPV,its potential as an in situ immune response regulator for HPV-related cancers has rarely been explored.In this study,we developed an innovative synergistic therapeutic platform by integrating near-infrared-II(NIR-II)absorbing aggregationinduced emission(AIE)agent(TPE-BT-BBTD)and imiquimod into an injectable hydrogel named TIH.TPE-BT-BBTD molecule that serves as a photothermal agent,with exposure to a 1064 nm laser,effectively destroys tumor cells and releases tumor-related antigens.During the thermogenesis process,the hydrogel melts and releases imiquimod.The released imiquimod,in conjunction with the dead tumor antigens,stimulates dendritic cellmaturation,activating the immune system to ultimately eliminate residual cancer cells.This novel approach combines the immunomodulatory effects of imiquimod with a 1064 nm-excitable photothermal agent in a hydrogel delivery system,offering a promising tactic for combating HPV-associated cancers.
基金National Key Research and Development Program of China(2023YFD1800105)National Natural Science Foundation of China(32322043,32171313,and 82272154)+4 种基金Tianjin Science Fund for Distinguished Young Scholars(22JCJQJC00120,China)Shenzhen Science and Technology Program(RCYX20210706092104033,and JCYJ20210324124402006,China)the Fundamental Research Funds for the Central Universities(2021-RC310-005,China)Science and Technology Program of Tianjin City(the Basic Research Cooperation Special Foundation of Beijing-Tianjin-Hebei Region,22JCZXJC00060,China)Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(2024-I2M-TS-028,2021-I2M-5-012,2021-I2M-1-058,and 2022-I2M-2-003,China).
文摘Among tumor microenvironment(TME),the entire metabolic characteristics of tumorresident cells are reprogrammed to benefit the expansion of tumor cells,which count on glutamine in large part to fuel the tricarboxylic acid cycle for energy generation and anabolic metabolism support.Endothelial cells that are abducted by tumor cells to form a pathological tumor vascular network for constructing the hypoxic immunosuppressive TME,also rely on glutaminolysis as the“engine”of angiogenesis.Additionally,the glutamine metabolic preference benefits the polarization of TAMs towards pro-tumoral M2 phenotype as well.Herein,we developed a type of siRNA micelleplexes(MH@siGLS1)to reverse immunosuppressive TME by targeting glutaminolysis within tumor-resident cells for tumor vasculature normalization-and TAMs repolarization-enhanced photo-immunotherapy.Tumor cell starvation and antioxidant system destruction achieved by MH@siGLS1-mediated glutaminolysis inhibition could promote photodynamic therapy efficacy,which was available to trigger immunogenic cell death for adaptive antitumor immune responses.Meanwhile,glutaminolysis inhibition of tumor endothelial cells and TAMs could realize tumor vascular normalization and TAMs repolarization for antitumor immunity amplification.This study provides a unique perspective on cancer treatments by focusing on the interrelations of metabolic characteristics and the biofunctions of various cell types within TME.
基金National Natural Science Foundation of China,Grant/Award Number:22177142Basic and Applied Basic Research Foundation of Guangdong Province,Grant/Award Numbers:2022A1515111089,2023A1515010625,2024B1515040028。
文摘Microtubules(MTs)are key players in cell division,migration,and signaling,and they are regarded as important targets for cancer treatment.In this work,two fullerene(C_(60))-functionalized Ir(Ⅲ)complexes(Ir-C_(60)1 and Ir-C_(60)2)are rationally designed as dual reactive oxygen species(ROS)regulators and MT-targeted Type Ⅰ/Ⅱ photosensitizers.In the dark,Ir-C_(60)1 and Ir-C_(60)2 serve as ROS scavengers to eliminate O_(2)·^(−)and·OH,consequently reducing the dark cytotoxicity and reversing dysfunctional T cells.Due to the efficiently populated C_(60)-localized intraligand triplet state,Ir-C_(60)1 and Ir-C_(60)2 can be excited by green light(525 nm)to produce O_(2)·^(−)and·OONO−(Type Ⅰ)and ^(1)O_(2)(Type Ⅱ)to overcome tumor hypoxia.Moreover,Ir-C_(60)1 is also able to photooxidize tubulin,consequently interfering with the cellular cytoskeleton structures,inducing immunogenic cell death and inhibiting cell proliferation and migration.Finally,Ir-C_(60)1 exhibits promising photo-immunotherapeutic effects both in vitro and in vivo.In all,we report here the first MT stabilizing photosensitizer performing through Type I/II photodynamic therapy pathways,which provides insights into the rational design of new photo-immunotherapeutic agents targeting specific biomolecules.
基金This work was supported in part by grants from the U.S.National Institutes of Health,No.R01 CA205348(to WRC)the Oklahoma Center for Advancement of Science and Technology,No.HR16-085(to WRC).
文摘Phototherapies offer promising alternatives to traditional cancer therapies.Phototherapies mainly rely on manipulation of target tissue through photothermal,photochemical,or photomechanical interactions.Combining phototherapy with immunotherapy has the benefit of eliciting a systemic immune response.Specifically,photothermal therapy(PTT)has been shown to induce apoptosis and necrosis in cancer cells,releasing tumor associated antigenic peptides while sparing healthy host cells,through temperature increase in targeted tissue.However,the tissue temperature must be monitored and controlled to minimize adverse thermal effects on normal tissue and to avoid the destruction of tumor-specific antigens,in order to achieve the desired therapeutic effects of PTT.Techniques for monitoring PTT have evolved from post-treatment quantification methods like enzyme linked immunosorbent assay,western blot analysis,and flow cytometry to modern methods capable of real-time monitoring,such as magnetic resonance thermometry,computed tomography,and photoacoustic imaging.Monitoring methods are largely chosen based on the type of light delivery to the target tissue.Interstitial methods of thermometry,such as thermocouples and fiber-optic sensors,are able to monitor temperature of the local tumor environment.However,these methods can be challenging if the phototherapy itself is interstitially administered.Increasingly,non-invasive therapies call for non-invasive monitoring,which can be achieved through magnetic resonance thermometry,computed tomography,and photoacoustic imaging techniques.The purpose of this review is to introduce the feasible methods used to monitor tissue temperature during PTT.The descriptions of different techniques and the measurement examples can help the researchers and practitioners when using therapeutic PTT.
