Tumor-promoting inflammation is accompanied by cancer initiation,progression,and metastasis.Cyclooxygenase-2(COX-2)and its downstream product,prostaglandin E2(PGE2),play critical roles in tumor-promoting inflammation....Tumor-promoting inflammation is accompanied by cancer initiation,progression,and metastasis.Cyclooxygenase-2(COX-2)and its downstream product,prostaglandin E2(PGE2),play critical roles in tumor-promoting inflammation.Several studies have revealed the potential of COX-2 inhibition in improving cancer response to chemotherapy,as well as immunotherapy.Aspirin,a nonsteroidal anti-inflammatory drug,has been reported as a COX-2 inhibitor.However,as a small molecule drug with a carboxyl group,there is still the lack of effective methods of preparing polymer–aspirin conjugates with tumor stimuli-responsive release properties.Herein,we synthesized a reactive oxygen species(ROS)-responsive aspirin polymeric prodrug(P3C-Asp)via Passerini three-component reaction between aspirin,4-formylbenzeneboronic acid pinacol ester,and 5-isocyanopent-1-yne,followed by copper(I)-catalyzed alkyne-azide cycloaddition“click”reaction of the aspirin prodrug with dextran(DEX).The P3C-Asp could release aspirin and salicylic acid in response to tumor-specific stimuli.In the murine colorectal cancer model,P3C-Asp suppressed tumor growth effectively without significant side effects and eradicated tumors when combined with the immune checkpoint inhibitor,anti-PD-1 antibody(aPD-1).Further analysis revealed that the suppression was attributable to changes in the immune microenvironment,including reduced PGE2 content,as well as increased infiltration of CD8+T cells and M1 macrophages.The results mentioned above proved that targeting COX-2 pathway with a proper polymeric prodrug might be a useful strategy for cancer immunotherapy.展开更多
The key to improve the therapeutic efficacy for cancer treatment is to increase the delivery of drugs to tumors.For this purpose, tumor-microenvironment stimuliresponsive materials have great potential. Here, we prepa...The key to improve the therapeutic efficacy for cancer treatment is to increase the delivery of drugs to tumors.For this purpose, tumor-microenvironment stimuliresponsive materials have great potential. Here, we prepared a new nanomedicine by bonding the conjugate of honokiol(HNK) and 5,6-dimethylxanthenone-4-acetic acid(DMXAA)to a glutathione(GSH)-responsive nanocarrier, poly(α-lipoic acid) polyethylene glycol. The nanomedicine would disintegrate due to the high level of GSH at the tumor sites,achieving the co-delivery of HNK and DMXAA, and realizing the combination therapy through close-range killing by HNK and long-range striking by DMXAA together. In a murine 4T1 breast tumor model, this strategy exhibited high tumor inhibition rate of 93%, and provided a valuable therapeutic choice for cancer therapy.展开更多
In the version of the article originally published in the volume 63,issue 2,2020 of Sci China Mater(2020,63(2):307–315,https://doi.org/10.1007/s40843-019-1183-0),the affiliations of two of the authors(Zhaohui Tang an...In the version of the article originally published in the volume 63,issue 2,2020 of Sci China Mater(2020,63(2):307–315,https://doi.org/10.1007/s40843-019-1183-0),the affiliations of two of the authors(Zhaohui Tang and Xuesi Chen)were incompletely labeled.The corrected version of the authors’affiliations is as below.展开更多
The application of chimeric antigen receptor T(CAR-T)cell therapy against solid tumors is often hindered by the dense and rigid tumor extracellular matrix(ECM).While combining CAR-T with hyaluronidase(HAase)to reduce ...The application of chimeric antigen receptor T(CAR-T)cell therapy against solid tumors is often hindered by the dense and rigid tumor extracellular matrix(ECM).While combining CAR-T with hyaluronidase(HAase)to reduce ECM is apparent,the efficacy is limited because of low accumulation and penetration efficiency of HAase inside the tumor tissue.Herein,we report a stimuli-responsive HAase-loaded nanogels(H-NGs)which are conjugated on the surface of CAR-T cells for synergistically improving HAase accumulation,ECM degradation and CAR-T cell efficacy.The conjugation of H-NGs on the T cell surface was achieved through metabolic oligosaccharide engineering(MOE)in a semi-quantitatively controlled manner.Intravenous injection of H-NGs armed CAR-T cells resulted in more ECM degradation than co-injection of CAR-T cells and free H-NGs,leading to an 83.2%tumor inhibition rate and relieving tumor suppressive microenvironment in the Raji solid tumor model.Proteomic analysis of the harvested tumor tissues indicated that the combining of H-NGs and CAR-T cell collaboratively reduces cell adhesion and enhanced leukocyte transendothelial migration.Overall,this work simultaneously boosts the efficacy of hyaluronidase and CAR-T cells in combating solid tumor,which has broad application potential in cancer combination therapy.展开更多
Primary bile acids were reported to augment secretion of chemokine(C-X-C motif)ligand16(CXCL16)from liver sinusoidal endothelial cells(LSECs)and trigger natural killer T(NKT)cellbased immunotherapy for liver cancer.Ho...Primary bile acids were reported to augment secretion of chemokine(C-X-C motif)ligand16(CXCL16)from liver sinusoidal endothelial cells(LSECs)and trigger natural killer T(NKT)cellbased immunotherapy for liver cancer.However,abundant expression of receptors for primary bile acids across the gastrointestinal tract overwhelms the possibility of using agonists against these receptors for liver cancer control.Taking advantage of the intrinsic property of LSECs in capturing circulating nanoparticles in the circulation,we proposed a strategy using nanoemulsion-loaded obeticholic acid(OCA),a clinically approved selective farnesoid X receptor(FXR)agonist,for precisely manipulating LSECs for triggering NKT cell-mediated liver cancer immunotherapy.The OCA-nanoemulsion(OCA-NE)was prepared via ultrasonic emulsification method,with a diameter of 184 nm and good stability.In vivo biodistribution studies confirmed that the injected OCA-NE mainly accumulated in the liver and especially in LSECs and Kupffer cells.As a result,OCA-NE treatment significantly suppressed hepatic tumor growth in a murine orthotopic H22 tumor model,which performed much better than oral medication of free OCA.Immunologic analysis revealed that the OCA-NE resulted in augmented secretion of CXCL16 and IFN-g,as well as increased NKT cell populations inside the tumor.Overall,our research provides a new evidence for the antitumor effect of receptors for primary bile acids,and should inspire using nanotechnology for precisely manipulating LSECs for liver cancer therapy.展开更多
Oncolytic viruses have emerged as new powerful therapeutic agents for cancer therapy by specifically lysing cancer cells while activating innate immune responses at the same time.However,due to the thorny issues of sa...Oncolytic viruses have emerged as new powerful therapeutic agents for cancer therapy by specifically lysing cancer cells while activating innate immune responses at the same time.However,due to the thorny issues of safety concerns and host immune reaction,the clinical application of oncolytic viruses is still limited.Herein,we report a rationally designed oncolytic virus-like nanoparticles(OV-NPs)composed of stimulator of interferon genes(STING)-stimulating polymer loaded with therapeutic genes for cancer immunotherapy.After injection into tumor,the OV-NPs carrying OX40L plasmid could reprogram tumor cells to express OX40L immune checkpoint molecules and activate the STING pathway for cooperatively enhancing antitumor immunity,with a tumor suppression rate of 92.3%in B16F10 tumor model and 78.7%in MC38 tumor model without causing any toxicity.The OV-NPs could be further applied in carrying other plasmids(IL-12)and utilization in gene combination therapy.This study should inspire designing synthetic OV-NPs as alternative strategies for extending oncolytic virus application in cancer immunotherapy.展开更多
Certain chemo drugs have been reported to potentially induce tumor-specific immune recognition by triggering immunogenic cell death(ICD),which provides a promising alternative way for cancer immunotherapy.However,the ...Certain chemo drugs have been reported to potentially induce tumor-specific immune recognition by triggering immunogenic cell death(ICD),which provides a promising alternative way for cancer immunotherapy.However,the immunogenic effects of such treatments are still weak and robust systemic antitumor immune responses are rarely seen when these agents were used alone.Herein,we proposed a trinity immune enhancing nanoparticles(TIENs)for boosting antitumor immune responses of chemo agents.The TIENs was constructed with Food and Drug Administration(FDA)approved polylactic acid(PLA),canonical proton-sponging cationic polymer polyethyleneimine(PEI),and Toll-like receptor 9(TLR9)agonist cytosine phosphate guanine oligodeoxynucleotide(CpG-ODN).In in vitro studies,the TIENs was proved to(1)promote antigen capturing,(2)antigen-presenting cells(APCs)activation,and(3)antigen cross-presentation.In in vivo studies,intratumorally injected TIENs greatly enhanced antitumor effect and robust immune responses of oxaliplatin and doxorubicin in murine CT26 and 4T1 tumor models,respectively.Furthermore,after decoration with a detachable shielding,the TIENs was proved to be effective in promoting the antitumor effects of chemo agents after intravenous injection.The combination of TIENs with clinically widely used chemo agents should be meaningful in boosting effective antitumor immune responses and cancer therapy.展开更多
基金supported by the National Natural Science Foundation of China(51673185,51973215,51673189,51833010,51829302,and 51520105004)the Jilin Province Science and Technology Development Plan(20170101100JC and 20190103112JH)Ministry of Science and Technology of China(2016YFC1100701).
文摘Tumor-promoting inflammation is accompanied by cancer initiation,progression,and metastasis.Cyclooxygenase-2(COX-2)and its downstream product,prostaglandin E2(PGE2),play critical roles in tumor-promoting inflammation.Several studies have revealed the potential of COX-2 inhibition in improving cancer response to chemotherapy,as well as immunotherapy.Aspirin,a nonsteroidal anti-inflammatory drug,has been reported as a COX-2 inhibitor.However,as a small molecule drug with a carboxyl group,there is still the lack of effective methods of preparing polymer–aspirin conjugates with tumor stimuli-responsive release properties.Herein,we synthesized a reactive oxygen species(ROS)-responsive aspirin polymeric prodrug(P3C-Asp)via Passerini three-component reaction between aspirin,4-formylbenzeneboronic acid pinacol ester,and 5-isocyanopent-1-yne,followed by copper(I)-catalyzed alkyne-azide cycloaddition“click”reaction of the aspirin prodrug with dextran(DEX).The P3C-Asp could release aspirin and salicylic acid in response to tumor-specific stimuli.In the murine colorectal cancer model,P3C-Asp suppressed tumor growth effectively without significant side effects and eradicated tumors when combined with the immune checkpoint inhibitor,anti-PD-1 antibody(aPD-1).Further analysis revealed that the suppression was attributable to changes in the immune microenvironment,including reduced PGE2 content,as well as increased infiltration of CD8+T cells and M1 macrophages.The results mentioned above proved that targeting COX-2 pathway with a proper polymeric prodrug might be a useful strategy for cancer immunotherapy.
基金supported by the Ministry of Science and Technology of China (2018ZX09711003-012)the National Natural Science Foundation of China (51873206, 51673189, 51829302, 51503202, 51833010 and 51520105004)the Program of Scientific Development of Jilin Province (20190103033JH)
文摘The key to improve the therapeutic efficacy for cancer treatment is to increase the delivery of drugs to tumors.For this purpose, tumor-microenvironment stimuliresponsive materials have great potential. Here, we prepared a new nanomedicine by bonding the conjugate of honokiol(HNK) and 5,6-dimethylxanthenone-4-acetic acid(DMXAA)to a glutathione(GSH)-responsive nanocarrier, poly(α-lipoic acid) polyethylene glycol. The nanomedicine would disintegrate due to the high level of GSH at the tumor sites,achieving the co-delivery of HNK and DMXAA, and realizing the combination therapy through close-range killing by HNK and long-range striking by DMXAA together. In a murine 4T1 breast tumor model, this strategy exhibited high tumor inhibition rate of 93%, and provided a valuable therapeutic choice for cancer therapy.
文摘In the version of the article originally published in the volume 63,issue 2,2020 of Sci China Mater(2020,63(2):307–315,https://doi.org/10.1007/s40843-019-1183-0),the affiliations of two of the authors(Zhaohui Tang and Xuesi Chen)were incompletely labeled.The corrected version of the authors’affiliations is as below.
基金supported by the National Natural Science Foundation of China(Nos.22222509,22375198,52103194 and 22105199)the Ministry of Science and Technology of China(No.2022YFE0110200)+2 种基金the Jilin Province Science and Technology Development Plan(No.20220402037GH)the Jilin Provincial International Cooperation Key Laboratory of Biomedical Polymers(No.YDZJ202402077CXJD)the Youth Innovation Promotion Association of Chinese Academy of Sciences(No.2020232).
文摘The application of chimeric antigen receptor T(CAR-T)cell therapy against solid tumors is often hindered by the dense and rigid tumor extracellular matrix(ECM).While combining CAR-T with hyaluronidase(HAase)to reduce ECM is apparent,the efficacy is limited because of low accumulation and penetration efficiency of HAase inside the tumor tissue.Herein,we report a stimuli-responsive HAase-loaded nanogels(H-NGs)which are conjugated on the surface of CAR-T cells for synergistically improving HAase accumulation,ECM degradation and CAR-T cell efficacy.The conjugation of H-NGs on the T cell surface was achieved through metabolic oligosaccharide engineering(MOE)in a semi-quantitatively controlled manner.Intravenous injection of H-NGs armed CAR-T cells resulted in more ECM degradation than co-injection of CAR-T cells and free H-NGs,leading to an 83.2%tumor inhibition rate and relieving tumor suppressive microenvironment in the Raji solid tumor model.Proteomic analysis of the harvested tumor tissues indicated that the combining of H-NGs and CAR-T cell collaboratively reduces cell adhesion and enhanced leukocyte transendothelial migration.Overall,this work simultaneously boosts the efficacy of hyaluronidase and CAR-T cells in combating solid tumor,which has broad application potential in cancer combination therapy.
基金financially supported by the National Natural Science Foundation of China(51673189,51973215,51833010and 51520105004)Ministry of Science and Technology of China(Project 2018ZX09711003-012)+1 种基金the Program of Scientific Development of Jilin Province(20170101100JC,20180520207JH,20190103112JH,China)supported by NIH grant CA198999(USA)
文摘Primary bile acids were reported to augment secretion of chemokine(C-X-C motif)ligand16(CXCL16)from liver sinusoidal endothelial cells(LSECs)and trigger natural killer T(NKT)cellbased immunotherapy for liver cancer.However,abundant expression of receptors for primary bile acids across the gastrointestinal tract overwhelms the possibility of using agonists against these receptors for liver cancer control.Taking advantage of the intrinsic property of LSECs in capturing circulating nanoparticles in the circulation,we proposed a strategy using nanoemulsion-loaded obeticholic acid(OCA),a clinically approved selective farnesoid X receptor(FXR)agonist,for precisely manipulating LSECs for triggering NKT cell-mediated liver cancer immunotherapy.The OCA-nanoemulsion(OCA-NE)was prepared via ultrasonic emulsification method,with a diameter of 184 nm and good stability.In vivo biodistribution studies confirmed that the injected OCA-NE mainly accumulated in the liver and especially in LSECs and Kupffer cells.As a result,OCA-NE treatment significantly suppressed hepatic tumor growth in a murine orthotopic H22 tumor model,which performed much better than oral medication of free OCA.Immunologic analysis revealed that the OCA-NE resulted in augmented secretion of CXCL16 and IFN-g,as well as increased NKT cell populations inside the tumor.Overall,our research provides a new evidence for the antitumor effect of receptors for primary bile acids,and should inspire using nanotechnology for precisely manipulating LSECs for liver cancer therapy.
基金supported by the National Natural Science Foundation of China (22222509,52025035,51973215,22375198,52103194)Bureau of International Cooperation Chinese Academy of Sciences (121522KYSB20200029)+5 种基金Jilin Province Science and Technology DevelopmentPlan (YDZJ202101ZYTS131,20220402037GH,20210508049RQ)Jilin Provincial International Cooperation Key Laboratory of Biomedical Polymers (20210504001GH)Changchun Science and Technology Development Plan (21ZY09,21ZGY30)the China Postdoctoral Science Foundation (E21S2101)the Youth Talents Promotion Project of Jilin Province (QT202103)the Youth Innovation Promotion Association of Chinese Academy of Sciences (2020232)。
文摘Oncolytic viruses have emerged as new powerful therapeutic agents for cancer therapy by specifically lysing cancer cells while activating innate immune responses at the same time.However,due to the thorny issues of safety concerns and host immune reaction,the clinical application of oncolytic viruses is still limited.Herein,we report a rationally designed oncolytic virus-like nanoparticles(OV-NPs)composed of stimulator of interferon genes(STING)-stimulating polymer loaded with therapeutic genes for cancer immunotherapy.After injection into tumor,the OV-NPs carrying OX40L plasmid could reprogram tumor cells to express OX40L immune checkpoint molecules and activate the STING pathway for cooperatively enhancing antitumor immunity,with a tumor suppression rate of 92.3%in B16F10 tumor model and 78.7%in MC38 tumor model without causing any toxicity.The OV-NPs could be further applied in carrying other plasmids(IL-12)and utilization in gene combination therapy.This study should inspire designing synthetic OV-NPs as alternative strategies for extending oncolytic virus application in cancer immunotherapy.
基金supported by the National Natural Science Foundation of China(Nos.51973215,52025035,52003268,51829302,and 51833010)Bureau of International Cooperation Chinese Academy of Sciences(No.121522KYSB20200029)+1 种基金the Jilin Province Science and Technology Development Plan(No.2020122331JC)support from the Youth Innovation Promotion Association of Chinese Academy of Sciences(No.2020232).
文摘Certain chemo drugs have been reported to potentially induce tumor-specific immune recognition by triggering immunogenic cell death(ICD),which provides a promising alternative way for cancer immunotherapy.However,the immunogenic effects of such treatments are still weak and robust systemic antitumor immune responses are rarely seen when these agents were used alone.Herein,we proposed a trinity immune enhancing nanoparticles(TIENs)for boosting antitumor immune responses of chemo agents.The TIENs was constructed with Food and Drug Administration(FDA)approved polylactic acid(PLA),canonical proton-sponging cationic polymer polyethyleneimine(PEI),and Toll-like receptor 9(TLR9)agonist cytosine phosphate guanine oligodeoxynucleotide(CpG-ODN).In in vitro studies,the TIENs was proved to(1)promote antigen capturing,(2)antigen-presenting cells(APCs)activation,and(3)antigen cross-presentation.In in vivo studies,intratumorally injected TIENs greatly enhanced antitumor effect and robust immune responses of oxaliplatin and doxorubicin in murine CT26 and 4T1 tumor models,respectively.Furthermore,after decoration with a detachable shielding,the TIENs was proved to be effective in promoting the antitumor effects of chemo agents after intravenous injection.The combination of TIENs with clinically widely used chemo agents should be meaningful in boosting effective antitumor immune responses and cancer therapy.
基金financially supported by the National Natural Science Foundation of China (22105199, 82203885, 51833010, 22222509, 22375198, 52103194, 52273310, 52025035)Bureau of International Cooperation Chinese Academy of Sciences (121522KYSB20200029)+4 种基金Jilin Provincial International Cooperation Key Laboratory of Biomedical Polymers (20210504001GH)Jilin Province Science and Technology Development Plan (20220402037GH)China Postdoctoral Science Foundation (BX20220337)Changchun Science and Technology Development Plan (21ZY09)the Youth Innovation Promotion Association of Chinese Academy of Sciences (2020232)
