AIM To investigate near-infrared photoimmunotherapeutic effect mediated by an anti-tissue factor(TF) antibody conjugated to indocyanine green(ICG) in a pancreatic cancer model.METHODS Near-infrared photoimmunotherapy(...AIM To investigate near-infrared photoimmunotherapeutic effect mediated by an anti-tissue factor(TF) antibody conjugated to indocyanine green(ICG) in a pancreatic cancer model.METHODS Near-infrared photoimmunotherapy(NIR-PIT) is a highly selective tumor treatment that utilizes an antibody-photosensitizer conjugate administration, followed by NIR light exposure. Anti-TF antibody 1849-ICG conjugate was synthesized by labeling of rat IgG2 b anti-TF monoclonal antibody 1849(anti-TF 1849) to a NIR photosensitizer,ICG. The expression levels of TF in two human pancreatic cancer cell lines were examined by western blotting. Specific binding of the 1849-ICG to TF-expressing BxPC-3 cells was examined by fluorescence microscopy. NIR-PITinduced cell death was determined by cell viability imaging assay. In vivo longitudinal fluorescence imaging was used to explore the accumulation of 1849-ICG conjugate in xenograft tumors. To examine the effect of NIRPIT, tumor-bearing mice were separated into 5 groups:(1) 100 μg of 1849-ICG i.v. administration followed by NIR light exposure(50 J/cm2) on two consecutive days(Days 1 and 2);(2) NIR light exposure(50 J/cm2) only on two consecutive days(Days 1 and 2);(3) 100 μg of 1849-ICG i.v. administration;(4) 100 μg of unlabeled antiTF 1849 i.v. administration; and(5) the untreated control. Semiweekly tumor volume measurements, accompanied with histological and immunohistochemical(IHC) analyses of tumors, were performed 3 d after the 2nd irradiation with NIR light to monitor the effect of treatments. RESULTS High TF expression in BxPC-3 cells was observed via western blot analysis, concordant with the observed preferential binding with intracellular localization of 1849-ICG via fluorescence microscopy. NIR-PIT-induced cell death was observed by performing cell viability imaging assay. In contrast to the other test groups, tumor growth was significantly inhibited by NIR-PIT with a statistically significant difference in relative tumor volumes for 27 d after the treatment start date [2.83 ± 0.38(NIR-PIT) vs 5.42 ± 1.61(Untreated), vs 4.90 ± 0.87(NIR), vs 4.28 ±1.87(1849-ICG), vs 4.35 ± 1.42(anti-TF 1849), at Day 27, P < 0.05]. Tumors that received NIR-PIT showed evidence of necrotic cell death-associated features upon hematoxylin-eosin staining accompanied by a decrease in Ki-67-positive cells(a cell proliferation marker) by IHC examination.CONCLUSION The TF-targeted NIR-PIT with the 1849-ICG conjugate can potentially open a new platform for treatment of TF-expressing pancreatic cancer.展开更多
Photoimmunotherapy (PIT), developed by the National Cancer Institute, involves Cetuximab sarotalocan sodium infusion followed by laser irradiation. PIT exerts specific antitumor effects on a variety of carcinomas that...Photoimmunotherapy (PIT), developed by the National Cancer Institute, involves Cetuximab sarotalocan sodium infusion followed by laser irradiation. PIT exerts specific antitumor effects on a variety of carcinomas that express epidermal growth factor receptors. PIT is a new cancer treatment option approved by Japan ahead of other countries worldwide. As of 2022, PIT is indicated in “unresectable, locally advanced, or locally recurrent head and neck cancer, with priority given to standard treatments such as chemotherapy when available”. The conventional treatment for unresectable locally advanced or locally recurrent head and neck cancer is palliative. Whether photoimmunotherapy can be curative for unresectable locally advanced head and neck cancers depends on the case. Herein, we report a case of locally recurrent nasopharyngeal carcinoma, treated with photoimmunotherapy via the nasal cavity, along with a literature review. Preoperative simulation provided considerable information on device selection, numbers of devices, and availability of working space. As a result, a complete response was obtained following a cylindrical diffuser puncture. Cases of local recurrence of nasopharyngeal carcinoma are considered a good indication for PIT. However, since the follow-up period after treatment was short in this case, we will continue to conduct strict follow-ups and accumulate more cases.展开更多
Pyroptosis is an inflammatory form of programmed cell death with great potential in cancer immunotherapies.Photodynamic therapy(PDT)represents a promising treatment modality to trigger pyroptosis.However,the hypoxic m...Pyroptosis is an inflammatory form of programmed cell death with great potential in cancer immunotherapies.Photodynamic therapy(PDT)represents a promising treatment modality to trigger pyroptosis.However,the hypoxic microenvironment inside the tumors often induces limited therapeutic efficacy.Herein,in this work,the first type of mitochondrial-targeting oxime-ester photogenerator(T-Oximer)was constructed to boost type-I ROS/aryl free radicals which could induce DNA damage by DNA cleaving and facilitate high-efficiency pyroptosis-mediated photoimmunotherapy.Detailed mechanism investigations revealed that T-Oximer could produce aryl free radicals via photolysis reaction and generate type-I ROS(O_(2)^(·-)and·OH)based on the type-I electron transfer process.Meanwhile,T-Oximer could accumulate in the mitochondria,boost mitochondrial radicals,and damage mitochondria in hypoxic tumor cells.Of peculiar interest,T-Oixmer could bind with DNA and cleave DNA to induce DNA damage.Combined mitochondrial damage with DNA cleavage,T-Oximer can initiate pyroptosis,activate the ICD effect,and trigger robust systemic antitumor immunity for efficient tumor regression and metastasis suppression.Our finding provides a new strategy for constructing oxygen-independent photogenerator for high-efficiency pyroptosis-mediated anti-hypoxia photoimmunotherapy.展开更多
Prostate cancer is an epithelial malignancy with a high incidence among elderly men.Photochemistry-based dye photodrugs(known as photosensitizers)offer a promising clinical approach for treating tumors.These agents wo...Prostate cancer is an epithelial malignancy with a high incidence among elderly men.Photochemistry-based dye photodrugs(known as photosensitizers)offer a promising clinical approach for treating tumors.These agents work by inducing immunogenic cell death(ICD),which activates antitumor immune response.This approach is favored owing to its minimal invasiveness,low toxicity,and high efficiency.However,the immunosuppressive microenvironment of characteristics of“cold”tumors significantly restricts the clinical efficacy of photodrugs.Developing an advanced nanocarrier system to deliver photodrugs and immune agonists for efficient drug delivery to tumor lesion sites and to reshape the immunosuppressive microenvironment is crucial in clinical practice.Therefore,in this study,we designed an integrin-targeted,activatable nano photodrug co-assembly with an immune agonist(RPST@IMQ)for enhancing photoimmunotherapy in prostate cancer via the reprogramming of tumor-associated macrophages.The active-targeted nanosystem enhanced the dosage of photodrug at the lesion site through systemic administration.High doses of glutathione at the tumor site cleaved the disulfide bonds of RPST@IMQ,releasing the photodrug and the immune agonist imiquimod(IMQ).Under photoirradiation,the photodrug generated significant doses of singlet oxygen to eliminate tumor cells,thereby inducing ICD to activate antitumor immune responses.Simultaneously,the released IMQ reprograms immunosuppressive M2-type tumor-associated macrophages(TAMs)in the tumor microenvironment into M1-type TAMs with tumor-killing capabilities,thereby converting“cold”tumors into“hot”tumors.This conversion enhances the therapeutic efficacy against primary and distant tumors in vivo.This study offers new insights into the development of innovative,smart,activatable nano photodrugs to enhance anticancer therapeutic outcomes.展开更多
Photoimmunotherapy(PIT)combines the specificity of antibodies with the cytotoxicity of light activatable photosensitizers(PS)and is a promising new cancer therapy.We designed and synthesized,in a highly convergent man...Photoimmunotherapy(PIT)combines the specificity of antibodies with the cytotoxicity of light activatable photosensitizers(PS)and is a promising new cancer therapy.We designed and synthesized,in a highly convergent manner,the silicon phthalocyanine dye WB692-CB2,which is novel for being the first light-activatable PS that can be directly conjugated via a maleimide linker to cysteines.In the present study we conjugated WB692-CB2 to a humanized antibody with engineered cysteines in the heavy chains that specifically targets the prostate-specific membrane antigen(PSMA).The resulting antibody dye conjugate revealed high affinity and specificity towards PSMA-expressing prostate cancer cells and induced cell death after irradiation with red light.Treated cells exhibited morphological characteristics associated with pyroptosis.Mechanistic studies revealed the generation of reactive oxygen species,triggering a cascade of intracellular events involving lipid peroxidation,caspase-1 activation,gasdermin D cleavage and membrane rupture followed by release of pro-inflammatory cellular contents.In first in vivo experiments,PIT with our antibody dye conjugate led to a significant reduction of tumor growth and enhanced overall survival in mice bearing subcutaneous prostate tumor xenografts.Our study highlights the future potential of the new phthalocyanine dye WB692-CB2 as PS for the fluorescence-based detection and PIT of cancer,including local prostate tumor lesions,and systemic activation of anti-tumor immune responses by the induction of pyroptosis.展开更多
Immunotherapy assays using immunoadjuvants and tumor antigens could greatly increase the survival rates of patients with malignant tumors.As effective carriers,metal-organic frameworks(MOFs)have been widely utilized i...Immunotherapy assays using immunoadjuvants and tumor antigens could greatly increase the survival rates of patients with malignant tumors.As effective carriers,metal-organic frameworks(MOFs)have been widely utilized in cancer therapy due to their remarkable histocompatibility and low toxicity.Herein,we constructed a multimodal imaging-guided synergistic cancer photoimmunotherapy by employing a specific MOF(MIL101-NH2)as the core carrier;the MOF was dual-dressed with photoacoustic and fluorescent signal donors(indocyanine green,ICG)and immune adjuvants(cytosine-phosphate-guanine sequence,CpG)and named ICGCpG@MOF.This nanocarrier could passively target the tumor site through the EPR effect and achieve multimodal imaging(fluorescence,photoacoustic,photothermal and magnetic resonance imaging)of the tumor.Synergistic cancer photoimmunotherapy was achieved via simultaneous photodynamic and photothermal methods with 808 nm laser irradiation.ICG-CpG@MOF achieved the GSH-controlled release of immunoadjuvant into the tumor microenvironment.Furthermore,the released tumor-associated antigen along with CpG could induce the transformation of tumor cells from cold to hot by activating the immune system,which significantly enhanced tumor cytotoxicity and achieved high cure rates with minimal side-effects.This strategy utilizing multimodal imaging and synergistic cancer photoimmunotherapy provides a promising approach for the diagnosis and treatment of cancer.展开更多
Phototherapy and immunotherapy in combination is regarded as the ideal ther-apeutic modality to treat both primary and metastatic tumors.Immunother-apy uses different immunological approaches to stimulate the immune s...Phototherapy and immunotherapy in combination is regarded as the ideal ther-apeutic modality to treat both primary and metastatic tumors.Immunother-apy uses different immunological approaches to stimulate the immune system to identify tumor cells for targeted elimination.Phototherapy destroys the pri-mary tumors by light irradiation,which induces a series of immune responses through triggering immunogenic cancer cell death.Therefore,when integrat-ing immunotherapy with phototherapy,a novel anti-cancer strategy called pho-toimmunotherapy(PIT)is emerging.This synergistic treatment modality can not only enhance the effectiveness of both therapies but also overcome their inherent limitations,opening a new era for the current anti-cancer therapy.Recently,the advancement of nanomaterials affords a platform for PIT.From all these nanomaterials,inorganic nanomaterials stand out as idealmediators in PIT due to their unique physiochemical properties.Inorganic nanomaterials can not only serve as carriers to transport immunomodulatory agents in immunotherapy owing to their excellent drug-loading capacity but also function as photother-mal agents or photosensitizers in phototherapy because of their great optical characteristics.In this review,the recent advances of multifunctional inorganic nanomaterial-mediated drug delivery and their contributions to cancer PIT will be highlighted.展开更多
Photoimmunotherapy(PIT)is an emerging therapeutic approach that integrates phototherapy and immunotherapy to eliminate primary tumors under an appropriate dosage of local light irradiation,while simultaneously prevent...Photoimmunotherapy(PIT)is an emerging therapeutic approach that integrates phototherapy and immunotherapy to eliminate primary tumors under an appropriate dosage of local light irradiation,while simultaneously preventing tumor metastasis and recurrence by activating the host antitumor immune response.Tumor-responsive dynamic nanoassemblies(TDNs)have evolved from being a mere curiosity to a promising platform for high-performance PIT.However,the dynamic nano-bio interaction between TDNs and tumor microenvironment remains poorly understood,which shall be critical for precise control of TDNs assembling/disassembling behavior and superior PIT efficacy.To deepen the understanding of the structure–function relationship of TDNs,this review introduces the rational design,nano-bio interactions,and controllable functionalities of cutting-edge TDNs for enhanced PIT.Moreover,the synergetic mechanism between TDNs-based PIT and immunomodulatory agents-mediated immunomodulation is particularly emphasized.Finally,the challenges and future perspectives in this emerging field are assessed.展开更多
Phototherapy has emerged as a promising modality in cancer treatment,garnering considerable attention for its minimal side effects,exceptional spatial selectivity,and optimal preservation of normal tissue function.Thi...Phototherapy has emerged as a promising modality in cancer treatment,garnering considerable attention for its minimal side effects,exceptional spatial selectivity,and optimal preservation of normal tissue function.This innovative approach primarily encompasses three distinct paradigms:Photodynamic Therapy(PDT),Photothermal Therapy(PTT),and Photoimmunotherapy(PIT).Each of these modalities exerts its antitumor effects through unique mechanisms—specifically,the generation of reactive oxygen species(ROS),heat,and immune responses,respectively.However,significant challenges impede the advancement and clinical application of phototherapy.These include inadequate ROS production rates,subpar photothermal conversion efficiency,difficulties in tumor targeting,and unfavorable physicochemical properties inherent to traditional phototherapeutic agents(PTs).Additionally,the hypoxic microenvironment typical of tumors complicates therapeutic efficacy due to limited agent penetration in deep-seated lesions.To address these limitations,ongoing research is fervently exploring innovative solutions.The unique advantages offered by nano-PTs and nanocarrier systems aim to enhance traditional approaches’effectiveness.Strategies such as generating oxygen in situ within tumors or inhibiting mitochondrial respiration while targeting the HIF-1αpathway may alleviate tumor hypoxia.Moreover,utilizing self-luminescent materials,near-infrared excitation sources,non-photoactivated sensitizers,and wireless light delivery systems can improve light penetration.Furthermore,integrating immunoadjuvants and modulating immunosuppressive cell populations while deploying immune checkpoint inhibitors holds promise for enhancing immunogenic cell death through PIT.This review seeks to elucidate the fundamental principles and biological implications of phototherapy while discussing dominant mechanisms and advanced strategies designed to overcome existing challenges—ultimately illuminating pathways for future research aimed at amplifying this intervention’s therapeutic efficacy.展开更多
Mild photothermal therapy combined with immune checkpoint blockade has received increasing attention for the treatment of advanced or metastatic cancers due to its good therapeutic efficacy.However,it remains a challe...Mild photothermal therapy combined with immune checkpoint blockade has received increasing attention for the treatment of advanced or metastatic cancers due to its good therapeutic efficacy.However,it remains a challenge to facilely integrate the two therapies and make it potential for clinical translation.This work designed a peptide-photosensitizer conjugate(PPC),which consisted of a PD-L1 antagonist peptide(CVRARTR),an MMP-2 specific cleavable sequence,a self-assembling motif,and the photosensitizer Purpurin 18.The single-component PPC can self-assemble into nanospheres which is suitable for intravenous injection.The PPC nanosphere is cleaved by MMP-2 when it accumulates in tumor sites,thereby initiating the cancer-specific release of the antagonist peptide.Simultaneously,the nanospheres gradually transform into co-assembled nanofibers,which promotes the retention of the remaining parts within the tumor.In vivo studies demonstrated that PPC nanospheres under laser irradiation promote the infiltration of cytotoxic T lymphocytes and maturation of DCs,which sensitize 4T1 tumor cells to immune checkpoint blockade therapy.Therefore,PPC nanospheres inhibit tumor growth efficiently both in situ and distally and blocked the formation of lung metastases.The present study provides a simple and efficient integrated strategy for breast cancer photoimmunotherapy.展开更多
基金Supported by a Grant-in-Aid for Scientific Research(C)from the Ministry of Education,Culture,Sports,Science,and Technology,Japan,No.17K10460(to Aung W)
文摘AIM To investigate near-infrared photoimmunotherapeutic effect mediated by an anti-tissue factor(TF) antibody conjugated to indocyanine green(ICG) in a pancreatic cancer model.METHODS Near-infrared photoimmunotherapy(NIR-PIT) is a highly selective tumor treatment that utilizes an antibody-photosensitizer conjugate administration, followed by NIR light exposure. Anti-TF antibody 1849-ICG conjugate was synthesized by labeling of rat IgG2 b anti-TF monoclonal antibody 1849(anti-TF 1849) to a NIR photosensitizer,ICG. The expression levels of TF in two human pancreatic cancer cell lines were examined by western blotting. Specific binding of the 1849-ICG to TF-expressing BxPC-3 cells was examined by fluorescence microscopy. NIR-PITinduced cell death was determined by cell viability imaging assay. In vivo longitudinal fluorescence imaging was used to explore the accumulation of 1849-ICG conjugate in xenograft tumors. To examine the effect of NIRPIT, tumor-bearing mice were separated into 5 groups:(1) 100 μg of 1849-ICG i.v. administration followed by NIR light exposure(50 J/cm2) on two consecutive days(Days 1 and 2);(2) NIR light exposure(50 J/cm2) only on two consecutive days(Days 1 and 2);(3) 100 μg of 1849-ICG i.v. administration;(4) 100 μg of unlabeled antiTF 1849 i.v. administration; and(5) the untreated control. Semiweekly tumor volume measurements, accompanied with histological and immunohistochemical(IHC) analyses of tumors, were performed 3 d after the 2nd irradiation with NIR light to monitor the effect of treatments. RESULTS High TF expression in BxPC-3 cells was observed via western blot analysis, concordant with the observed preferential binding with intracellular localization of 1849-ICG via fluorescence microscopy. NIR-PIT-induced cell death was observed by performing cell viability imaging assay. In contrast to the other test groups, tumor growth was significantly inhibited by NIR-PIT with a statistically significant difference in relative tumor volumes for 27 d after the treatment start date [2.83 ± 0.38(NIR-PIT) vs 5.42 ± 1.61(Untreated), vs 4.90 ± 0.87(NIR), vs 4.28 ±1.87(1849-ICG), vs 4.35 ± 1.42(anti-TF 1849), at Day 27, P < 0.05]. Tumors that received NIR-PIT showed evidence of necrotic cell death-associated features upon hematoxylin-eosin staining accompanied by a decrease in Ki-67-positive cells(a cell proliferation marker) by IHC examination.CONCLUSION The TF-targeted NIR-PIT with the 1849-ICG conjugate can potentially open a new platform for treatment of TF-expressing pancreatic cancer.
文摘Photoimmunotherapy (PIT), developed by the National Cancer Institute, involves Cetuximab sarotalocan sodium infusion followed by laser irradiation. PIT exerts specific antitumor effects on a variety of carcinomas that express epidermal growth factor receptors. PIT is a new cancer treatment option approved by Japan ahead of other countries worldwide. As of 2022, PIT is indicated in “unresectable, locally advanced, or locally recurrent head and neck cancer, with priority given to standard treatments such as chemotherapy when available”. The conventional treatment for unresectable locally advanced or locally recurrent head and neck cancer is palliative. Whether photoimmunotherapy can be curative for unresectable locally advanced head and neck cancers depends on the case. Herein, we report a case of locally recurrent nasopharyngeal carcinoma, treated with photoimmunotherapy via the nasal cavity, along with a literature review. Preoperative simulation provided considerable information on device selection, numbers of devices, and availability of working space. As a result, a complete response was obtained following a cylindrical diffuser puncture. Cases of local recurrence of nasopharyngeal carcinoma are considered a good indication for PIT. However, since the follow-up period after treatment was short in this case, we will continue to conduct strict follow-ups and accumulate more cases.
基金partially funded by the National Natural Science Foundation of China(No.22308192)the Guangdong Provincial Special Support Program for Prominent Talents(2021JC06Y656)+1 种基金the Natural Science Foundation of Guangdong Province,China(No.2023A1515012934)Guangdong Province Marine Economic Development Project(No.GDNRC[2024]27).
文摘Pyroptosis is an inflammatory form of programmed cell death with great potential in cancer immunotherapies.Photodynamic therapy(PDT)represents a promising treatment modality to trigger pyroptosis.However,the hypoxic microenvironment inside the tumors often induces limited therapeutic efficacy.Herein,in this work,the first type of mitochondrial-targeting oxime-ester photogenerator(T-Oximer)was constructed to boost type-I ROS/aryl free radicals which could induce DNA damage by DNA cleaving and facilitate high-efficiency pyroptosis-mediated photoimmunotherapy.Detailed mechanism investigations revealed that T-Oximer could produce aryl free radicals via photolysis reaction and generate type-I ROS(O_(2)^(·-)and·OH)based on the type-I electron transfer process.Meanwhile,T-Oximer could accumulate in the mitochondria,boost mitochondrial radicals,and damage mitochondria in hypoxic tumor cells.Of peculiar interest,T-Oixmer could bind with DNA and cleave DNA to induce DNA damage.Combined mitochondrial damage with DNA cleavage,T-Oximer can initiate pyroptosis,activate the ICD effect,and trigger robust systemic antitumor immunity for efficient tumor regression and metastasis suppression.Our finding provides a new strategy for constructing oxygen-independent photogenerator for high-efficiency pyroptosis-mediated anti-hypoxia photoimmunotherapy.
基金funded by the National Key Research and Development Program of China 2023YFB3810300the National Natural Science Foundation of China 22090011,22378050,22378051+2 种基金the Science and Technology Plan Project of Liaoning Province 2023JH2/101700296the Fundamental Research Funds for the Central Universities DUT24ZD117,DUT24LAB105the National Research Foundation of Korea 2022R1A2C3005420,RS-2023-00217701.
文摘Prostate cancer is an epithelial malignancy with a high incidence among elderly men.Photochemistry-based dye photodrugs(known as photosensitizers)offer a promising clinical approach for treating tumors.These agents work by inducing immunogenic cell death(ICD),which activates antitumor immune response.This approach is favored owing to its minimal invasiveness,low toxicity,and high efficiency.However,the immunosuppressive microenvironment of characteristics of“cold”tumors significantly restricts the clinical efficacy of photodrugs.Developing an advanced nanocarrier system to deliver photodrugs and immune agonists for efficient drug delivery to tumor lesion sites and to reshape the immunosuppressive microenvironment is crucial in clinical practice.Therefore,in this study,we designed an integrin-targeted,activatable nano photodrug co-assembly with an immune agonist(RPST@IMQ)for enhancing photoimmunotherapy in prostate cancer via the reprogramming of tumor-associated macrophages.The active-targeted nanosystem enhanced the dosage of photodrug at the lesion site through systemic administration.High doses of glutathione at the tumor site cleaved the disulfide bonds of RPST@IMQ,releasing the photodrug and the immune agonist imiquimod(IMQ).Under photoirradiation,the photodrug generated significant doses of singlet oxygen to eliminate tumor cells,thereby inducing ICD to activate antitumor immune responses.Simultaneously,the released IMQ reprograms immunosuppressive M2-type tumor-associated macrophages(TAMs)in the tumor microenvironment into M1-type TAMs with tumor-killing capabilities,thereby converting“cold”tumors into“hot”tumors.This conversion enhances the therapeutic efficacy against primary and distant tumors in vivo.This study offers new insights into the development of innovative,smart,activatable nano photodrugs to enhance anticancer therapeutic outcomes.
基金German Research Foundation(DFG,grant no.WO 2178/3–1 to PW)Federal Ministry of Economic Affairs and Climate Action(BMWK,grant no.03THW15H04 to RB and PW)supported by the Open Access Publication Fund of the University of Freiburg.
文摘Photoimmunotherapy(PIT)combines the specificity of antibodies with the cytotoxicity of light activatable photosensitizers(PS)and is a promising new cancer therapy.We designed and synthesized,in a highly convergent manner,the silicon phthalocyanine dye WB692-CB2,which is novel for being the first light-activatable PS that can be directly conjugated via a maleimide linker to cysteines.In the present study we conjugated WB692-CB2 to a humanized antibody with engineered cysteines in the heavy chains that specifically targets the prostate-specific membrane antigen(PSMA).The resulting antibody dye conjugate revealed high affinity and specificity towards PSMA-expressing prostate cancer cells and induced cell death after irradiation with red light.Treated cells exhibited morphological characteristics associated with pyroptosis.Mechanistic studies revealed the generation of reactive oxygen species,triggering a cascade of intracellular events involving lipid peroxidation,caspase-1 activation,gasdermin D cleavage and membrane rupture followed by release of pro-inflammatory cellular contents.In first in vivo experiments,PIT with our antibody dye conjugate led to a significant reduction of tumor growth and enhanced overall survival in mice bearing subcutaneous prostate tumor xenografts.Our study highlights the future potential of the new phthalocyanine dye WB692-CB2 as PS for the fluorescence-based detection and PIT of cancer,including local prostate tumor lesions,and systemic activation of anti-tumor immune responses by the induction of pyroptosis.
基金This work was supported by grants from the National Natural Science Foundation of China,China(21904145,81972019 and 31700150)China Postdoctoral Science Foundation,China(2018M633273)+1 种基金Chen Jingyu team of Sanming Project of Medicine in Shenzhen,China(SZSM201812058)Guangdong Provincial Science and Technology Plan project,China(No.2017B030314108).
文摘Immunotherapy assays using immunoadjuvants and tumor antigens could greatly increase the survival rates of patients with malignant tumors.As effective carriers,metal-organic frameworks(MOFs)have been widely utilized in cancer therapy due to their remarkable histocompatibility and low toxicity.Herein,we constructed a multimodal imaging-guided synergistic cancer photoimmunotherapy by employing a specific MOF(MIL101-NH2)as the core carrier;the MOF was dual-dressed with photoacoustic and fluorescent signal donors(indocyanine green,ICG)and immune adjuvants(cytosine-phosphate-guanine sequence,CpG)and named ICGCpG@MOF.This nanocarrier could passively target the tumor site through the EPR effect and achieve multimodal imaging(fluorescence,photoacoustic,photothermal and magnetic resonance imaging)of the tumor.Synergistic cancer photoimmunotherapy was achieved via simultaneous photodynamic and photothermal methods with 808 nm laser irradiation.ICG-CpG@MOF achieved the GSH-controlled release of immunoadjuvant into the tumor microenvironment.Furthermore,the released tumor-associated antigen along with CpG could induce the transformation of tumor cells from cold to hot by activating the immune system,which significantly enhanced tumor cytotoxicity and achieved high cure rates with minimal side-effects.This strategy utilizing multimodal imaging and synergistic cancer photoimmunotherapy provides a promising approach for the diagnosis and treatment of cancer.
基金support from National Nature Science Foundation of China(Nos.31872756 and 32071387).
文摘Phototherapy and immunotherapy in combination is regarded as the ideal ther-apeutic modality to treat both primary and metastatic tumors.Immunother-apy uses different immunological approaches to stimulate the immune system to identify tumor cells for targeted elimination.Phototherapy destroys the pri-mary tumors by light irradiation,which induces a series of immune responses through triggering immunogenic cancer cell death.Therefore,when integrat-ing immunotherapy with phototherapy,a novel anti-cancer strategy called pho-toimmunotherapy(PIT)is emerging.This synergistic treatment modality can not only enhance the effectiveness of both therapies but also overcome their inherent limitations,opening a new era for the current anti-cancer therapy.Recently,the advancement of nanomaterials affords a platform for PIT.From all these nanomaterials,inorganic nanomaterials stand out as idealmediators in PIT due to their unique physiochemical properties.Inorganic nanomaterials can not only serve as carriers to transport immunomodulatory agents in immunotherapy owing to their excellent drug-loading capacity but also function as photother-mal agents or photosensitizers in phototherapy because of their great optical characteristics.In this review,the recent advances of multifunctional inorganic nanomaterial-mediated drug delivery and their contributions to cancer PIT will be highlighted.
基金This work was funded by the National Key Research and Development Program of China(Nos.2022YFB3203804,2022YFB3203801,and 2022YFB3203800)the Leading Talent of“Ten Thousand Plan”-National High-Level Talents Special Support Plan,National Natural Science Foundation of China(Nos.32071374 and 32000985)+4 种基金Program of Shanghai Academic Research Leader under the Science and Technology Innovation Action Plan(No.21XD1422100)Program of Shanghai Science and Technology Development(No.22TS1400700)Zhejiang Provincial Natural Science Foundation of China(Nos.LR22C100001 and LQ21H300003)Innovative Research Team of High-Level Local Universities in Shanghai(No.SHSMUZDCX20210900)CAS Interdisciplinary Innovation Team(No.JCTD-2020-08)。
文摘Photoimmunotherapy(PIT)is an emerging therapeutic approach that integrates phototherapy and immunotherapy to eliminate primary tumors under an appropriate dosage of local light irradiation,while simultaneously preventing tumor metastasis and recurrence by activating the host antitumor immune response.Tumor-responsive dynamic nanoassemblies(TDNs)have evolved from being a mere curiosity to a promising platform for high-performance PIT.However,the dynamic nano-bio interaction between TDNs and tumor microenvironment remains poorly understood,which shall be critical for precise control of TDNs assembling/disassembling behavior and superior PIT efficacy.To deepen the understanding of the structure–function relationship of TDNs,this review introduces the rational design,nano-bio interactions,and controllable functionalities of cutting-edge TDNs for enhanced PIT.Moreover,the synergetic mechanism between TDNs-based PIT and immunomodulatory agents-mediated immunomodulation is particularly emphasized.Finally,the challenges and future perspectives in this emerging field are assessed.
基金supported by the Province of Nature Science Foundation of Hunan(2022JJ30798)Jiangsu Department of Education for the School of CHIPS at XJTLU(EFP10120240023 and EFP10120240023)XJTLU Research Development Funding(RDF-21-01-027).
文摘Phototherapy has emerged as a promising modality in cancer treatment,garnering considerable attention for its minimal side effects,exceptional spatial selectivity,and optimal preservation of normal tissue function.This innovative approach primarily encompasses three distinct paradigms:Photodynamic Therapy(PDT),Photothermal Therapy(PTT),and Photoimmunotherapy(PIT).Each of these modalities exerts its antitumor effects through unique mechanisms—specifically,the generation of reactive oxygen species(ROS),heat,and immune responses,respectively.However,significant challenges impede the advancement and clinical application of phototherapy.These include inadequate ROS production rates,subpar photothermal conversion efficiency,difficulties in tumor targeting,and unfavorable physicochemical properties inherent to traditional phototherapeutic agents(PTs).Additionally,the hypoxic microenvironment typical of tumors complicates therapeutic efficacy due to limited agent penetration in deep-seated lesions.To address these limitations,ongoing research is fervently exploring innovative solutions.The unique advantages offered by nano-PTs and nanocarrier systems aim to enhance traditional approaches’effectiveness.Strategies such as generating oxygen in situ within tumors or inhibiting mitochondrial respiration while targeting the HIF-1αpathway may alleviate tumor hypoxia.Moreover,utilizing self-luminescent materials,near-infrared excitation sources,non-photoactivated sensitizers,and wireless light delivery systems can improve light penetration.Furthermore,integrating immunoadjuvants and modulating immunosuppressive cell populations while deploying immune checkpoint inhibitors holds promise for enhancing immunogenic cell death through PIT.This review seeks to elucidate the fundamental principles and biological implications of phototherapy while discussing dominant mechanisms and advanced strategies designed to overcome existing challenges—ultimately illuminating pathways for future research aimed at amplifying this intervention’s therapeutic efficacy.
基金This work was supported by the National Key R&D Program of China(2017YFA0205600)Natural Science Foundation of Hebei Province(H2022206171)。
文摘Mild photothermal therapy combined with immune checkpoint blockade has received increasing attention for the treatment of advanced or metastatic cancers due to its good therapeutic efficacy.However,it remains a challenge to facilely integrate the two therapies and make it potential for clinical translation.This work designed a peptide-photosensitizer conjugate(PPC),which consisted of a PD-L1 antagonist peptide(CVRARTR),an MMP-2 specific cleavable sequence,a self-assembling motif,and the photosensitizer Purpurin 18.The single-component PPC can self-assemble into nanospheres which is suitable for intravenous injection.The PPC nanosphere is cleaved by MMP-2 when it accumulates in tumor sites,thereby initiating the cancer-specific release of the antagonist peptide.Simultaneously,the nanospheres gradually transform into co-assembled nanofibers,which promotes the retention of the remaining parts within the tumor.In vivo studies demonstrated that PPC nanospheres under laser irradiation promote the infiltration of cytotoxic T lymphocytes and maturation of DCs,which sensitize 4T1 tumor cells to immune checkpoint blockade therapy.Therefore,PPC nanospheres inhibit tumor growth efficiently both in situ and distally and blocked the formation of lung metastases.The present study provides a simple and efficient integrated strategy for breast cancer photoimmunotherapy.
