Remodeling tumor microenvironment(TME)is a very promising and effective strategy to enhance the effects of chemotherapy,photodynamic therapy,and immunotherapy.Normalization of tumor vasculature as well as depletion of...Remodeling tumor microenvironment(TME)is a very promising and effective strategy to enhance the effects of chemotherapy,photodynamic therapy,and immunotherapy.Normalization of tumor vasculature as well as depletion of glutathione(GSH)can improve the TME.Here,we developed a novel therapeutic nanoparticle functional enzyme ultra QDAU5 nanoparticles(FEUQ Nps)based on a fluorescence-on and releasable strategy by combining a vascular normalization inducer,a GSH depleting agent,and an activated fluorophore.In which the cleavage of disulfide bonds releases active molecules that induce vascular normalization and improve the hypoxic microenvironment.In addition,it may deplete GSH in cancer cells,thus inducing the production of reactive oxygen species(ROS)and lipid peroxide(LPO)and promoting iron toxicity.It may also lead to endoplasmic stress and release of calmodulin,which activates the immune system.Meanwhile,quenched fluorophores are turned on in the presence of galactosidase(GLU)for tumor-specific labeling.In summary,we developed novel therapeutic agent nanoparticles with the function of vascular normalization inducers to achieve specific labeling of hepatocellular carcinoma while exerting efficient antitumor effects in vivo.展开更多
The changes of blood perfusion and oxygen transport in tumors during tumor vascular normalization are studied with 3-dimensional mathematical modeling and numerical simulation. The models of tumor angiogenesis and vas...The changes of blood perfusion and oxygen transport in tumors during tumor vascular normalization are studied with 3-dimensional mathematical modeling and numerical simulation. The models of tumor angiogenesis and vascular-disrupting are used to simulate ＂un-normalized＂ and ＂normalized＂ vasculatures. A new model combining tumor hemodynamics and oxygen transport is developed. In this model, the intravasculartransvascular-interstitial flow with red blood cell（RBC） delivery is tightly coupled, and the oxygen resource is produced by heterogeneous distribution of hematocrit from the flow simulation. The results show that both tumor blood perfusion and hematocrit in the vessels increase, and the hypoxia microenvironment in the tumor center is greatly improved during vascular normalization. The total oxygen content inside the tumor tissue increases by about 67%, 51%, and 95% for the three approaches of vascular normalization,respectively. The elevation of oxygen concentration in tumors can improve its metabolic environment, and consequently reduce malignancy of tumor cells. It can also enhance radiation and chemotherapeutics to tumors.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
Pathological angiogenesis frequently occurs in tumor tissue, limiting the efficiency of chemotherapeutic drug delivery and accelerating tumor progression. However, traditional vascular normalization strategies are not...Pathological angiogenesis frequently occurs in tumor tissue, limiting the efficiency of chemotherapeutic drug delivery and accelerating tumor progression. However, traditional vascular normalization strategies are not fully effective and limited by the development of resistance. Herein, inspired by the intervention of endogenous bioelectricity in vessel formation, we propose a wireless electrical stimulation therapeutic strategy, capable of breaking bioelectric homeostasis within cells, to achieve tumor vascular normalization. Polarized barium titanate nanoparticles with high mechano-electrical conversion performance were developed, which could generate pulsed open-circuit voltage under low-intensity pulsed ultrasound. We demonstrated that wireless electrical stimulation significantly inhibited endothelial cell migration and differentiation in vitro. Interestingly, we found that the angiogenesis-related eNOS/NO pathway was inhibited, which could be attributed to the destruction of the intracellular calcium ion gradient by wireless electrical stimulation. In vivo tumor-bearing mouse model indicated that wireless electrical stimulation normalized tumor vasculature by optimizing vascular structure, enhancing blood perfusion, reducing vascular leakage, and restoring local oxygenation. Ultimately, the anti-tumor efficacy of combination treatment was 1.8 times that of the single chemotherapeutic drug doxorubicin group. This work provides a wireless electrical stimulation strategy based on the mechano-electrical conversion performance of piezoelectric nanoparticles, which is expected to achieve safe and effective clinical adjuvant treatment of malignant tumors.展开更多
Angiogenesis is considered a hallmark pathophysiological process in tumor development. Aberrant vasculature resulting from tumor angiogenesis plays a critical role in the development of resistance to breast cancer tre...Angiogenesis is considered a hallmark pathophysiological process in tumor development. Aberrant vasculature resulting from tumor angiogenesis plays a critical role in the development of resistance to breast cancer treatments, via exacerbation of tumor hypoxia, decreased effective drug concentrations within tumors, and immune-related mechanisms. Antiangiogenic therapy can counteract these breast cancer resistance factors by promoting tumor vascular normalization. The combination of antiangiogenic therapy with chemotherapy, targeted therapy, or immunotherapy has emerged as a promising approach for overcoming drug resistance in breast cancer. This review examines the mechanisms associated with angiogenesis and the interactions among tumor angiogenesis, the hypoxic tumor microenvironment, drug distribution, and immune mechanisms in breast cancer. Furthermore, this review provides a comprehensive summary of specific antiangiogenic drugs, and relevant studies assessing the reversal of drug resistance in breast cancer. The potential mechanisms underlying these interventions are discussed, and prospects for the clinical application of antiangiogenic therapy to overcome breast cancer treatment resistance are highlighted.展开更多
Cancer stem cells(CSCs)are proposed to account for the progression,metastasis,and recurrence of diverse malignancies.However,the disorganized vasculars in tumors hinder the accumulation and penetration of nanomedicine...Cancer stem cells(CSCs)are proposed to account for the progression,metastasis,and recurrence of diverse malignancies.However,the disorganized vasculars in tumors hinder the accumulation and penetration of nanomedicines,posing a challenge in eliminating CSCs located distantly from blood vessels.Herein,a pair of twin-like small-sized nanoparticles,sunitinib(St)-loaded ROS responsive micelles(RM@St)and salinomycin(SAL)-loaded GSH responsive micelles(GM@SAL),are developed to normalize disordered tumor vessels and eradicate CSCs.RM@St releases sunitinib in response to the abundant ROS in the tumor extracellular microenvironment for tumor vessel normalization,which improved intratumor accumulation and homogeneous distribution of small-sized GM@SAL.Sequentially,GM@SAL effectively accesses CSCs and achieves reduction-responsive drug release at high GSH concentrations within CSCs.More importantly,RM@St significantly extends the window of vessel normalization and enhances vessel integrity compared to free sunitinib,thus further amplifying the anti-tumor effect of GM@SAL.The combination therapy of RM@St plus GM@SAL produces considerable depression of tumor growth,drastically reducing CSCs fractions to 5.6%and resulting in 78.4%inhibition of lung metastasis.This study offers novel insights into rational nanomedicines designed for superior therapeutic effects by vascular normalization and anti-CSCs therapy.展开更多
Photodynamic immunotherapy is a promising strategy for cancer treatment.However,the dysfunctional tumor vasculature results in tumor hypoxia and the low efficiency of drug delivery,which in turn restricts the anticanc...Photodynamic immunotherapy is a promising strategy for cancer treatment.However,the dysfunctional tumor vasculature results in tumor hypoxia and the low efficiency of drug delivery,which in turn restricts the anticancer effect of photodynamic immunotherapy.In this study,we designed photosensitive lipid nanoparticles.The synthesized PFBT@Rox Lip nanoparticles could produce type Ⅰ/Ⅱ reactive oxygen species(ROS)by electron or energy transfer through PFBT under light irradiation.Moreover,this nanosystem could alleviate tumor hypoxia and promote vascular normalization through Roxadustat.Upon irradiation with white light,the ROS produced by PFBT@Rox Lip nanoparticles in situ dysregulated calcium homeostasis and triggered endoplasmic reticulum stress,which further promoted the release of damage-associated molecular patterns,enhanced antigen presentation,and stimulated an effective adaptive immune response,ultimately priming the tumor microenvironment(TME)together with the hypoxia alleviation and vessel normalization by Roxadustat.Indeed,in vivo results indicated that PFBT@Rox Lip nanoparticles promoted M1 polarization of tumor-associated macrophages,recruited more natural killer cells,and augmented infiltration of T cells,thereby leading to efficient photodynamic immunotherapy and potentiating the anti-primary and metastatic tumor efficacy of PD-1 antibody.Collectively,photodynamic immunotherapy with PFBT@Rox Lip nanoparticles efficiently program TME through the induction of immunogenicity and oxygenation,and effectively suppress tumor growth through immunogenic cell death and enhanced anti-tumor immunity.展开更多
Tumor vasculature is characterized by aberrant structure and function,resulting in immune suppressive profiles of tumor microenvironment through limiting immune cell infiltration into tumors,endogenous immune surveill...Tumor vasculature is characterized by aberrant structure and function,resulting in immune suppressive profiles of tumor microenvironment through limiting immune cell infiltration into tumors,endogenous immune surveillance and immune cell function.Vascular normalization as a novel therapeutic strategy tends to prune some of the immature blood vessels and fortify the structure and function of the remaining vessels,thus improving immune stimulation and the efficacy of immunotherapy.Interestingly,the presence of"immune-vascular crosstalk"enables the formation of a positive feedback loop between vascular normalization and immune reprogramming,providing the possibility to develop new cancer therapeutic strategies.The applications of nanomedicine in vascular-targeting therapy in cancer have gained increasing attention due to its specific physical and chemical properties.Here,we reviewed the recent advances of effective routes,especially nanomedicine,for normalizing tumor vasculature.We also summarized the development of enhancing nanoparticle-based anticancer drug delivery via the employment of transcytosis and mimicking immune cell extravasation.This review explores the potential to optimize nanomedicine-based therapeutic strategies as an alternative option for cancer treatment.展开更多
Aberrant tumor blood vessels are prone to propel the malignant progression of tumors,and targeting abnormal metabolism of tumor endothelial cells emerges as a promising option to achieve vascular normalization and ant...Aberrant tumor blood vessels are prone to propel the malignant progression of tumors,and targeting abnormal metabolism of tumor endothelial cells emerges as a promising option to achieve vascular normalization and antagonize tumor progression.Herein,we demonstrated that salvianic acid A(SAA)played a pivotal role in contributing to vascular normalization in the tumor-bearing mice,thereby improving delivery and effectiveness of the chemotherapeutic agent.SAA was capable of inhibiting glycolysis and strengthening endothelial junctions in the human umbilical vein endothelial cells(HUVECs)exposed to hypoxia.Mechanistically,SAA was inclined to directly bind to the glycolytic enzyme PKM2,leading to a dramatic decrease in endothelial glycolysis.More importantly,SAA improved the endothelial integrity via activating theβ-Catenin/Claudin-5 signaling axis in a PKM2-dependent manner.Our findings suggest that SAA may serve as a potent agent for inducing tumor vascular normalization.展开更多
Epidermal growth factor receptor(EGFR)tyrosine kinase inhibitors(TKI),such as Erlotinib,have demonstrated remarkable efficacy in the treatment of non-small cell lung cancer(NSCLC)patients with mutated EGFR.However,the...Epidermal growth factor receptor(EGFR)tyrosine kinase inhibitors(TKI),such as Erlotinib,have demonstrated remarkable efficacy in the treatment of non-small cell lung cancer(NSCLC)patients with mutated EGFR.However,the efficacy of EGFR-TKIs in wild-type(wt)EGFR tumours has been shown to be marginal.Methods that can sensitize Erlotinib to EGFR wild-type NSCLC remain rare.Herein,we developed a multifunctional superparamagnetic nanotheranostic agent as a novel strategy to potentiate Erlotinib to EGFR-wt NSCLCs.Our results demonstrate that the nanoparticles can co-escort Erlotinib and a vascular epithermal growth factor(VEGF)inhibitor,Bevacizumab(Bev),to EGFR-wt tumours.The nanotheranostic agent exhibits remarkable effects as an inhibitor of EGFR-wt tumour growth.Moreover,Bev normalizes the tumour embedded vessels,further promoting the therapeutic efficacy of Erlotinib.In addition,the tumour engagement of the nanoparticles and the vascular normalization could be tracked by magnetic resonance imaging(MRI).Collectively,our study,for the first time,demonstrated that elaborated nanoparticles could be employed as a robust tool to potentiate Erlotinib to EGFR-wt NSCLC,paving the way for imaging-guided nanotheranostics for refractory NSCLCs expressing EGFR wild-type genes.展开更多
基金supported by the National Natural Science Foundation of China(NSFC,No.82173742)the Science Fund for Distinguished Young Scholars of Shaanxi Province(No.2022JC-54)the Key Research and Development Program of Shaanxi Province(No.2023-YBSF-131).
文摘Remodeling tumor microenvironment(TME)is a very promising and effective strategy to enhance the effects of chemotherapy,photodynamic therapy,and immunotherapy.Normalization of tumor vasculature as well as depletion of glutathione(GSH)can improve the TME.Here,we developed a novel therapeutic nanoparticle functional enzyme ultra QDAU5 nanoparticles(FEUQ Nps)based on a fluorescence-on and releasable strategy by combining a vascular normalization inducer,a GSH depleting agent,and an activated fluorophore.In which the cleavage of disulfide bonds releases active molecules that induce vascular normalization and improve the hypoxic microenvironment.In addition,it may deplete GSH in cancer cells,thus inducing the production of reactive oxygen species(ROS)and lipid peroxide(LPO)and promoting iron toxicity.It may also lead to endoplasmic stress and release of calmodulin,which activates the immune system.Meanwhile,quenched fluorophores are turned on in the presence of galactosidase(GLU)for tumor-specific labeling.In summary,we developed novel therapeutic agent nanoparticles with the function of vascular normalization inducers to achieve specific labeling of hepatocellular carcinoma while exerting efficient antitumor effects in vivo.
基金Project supported by the National Natural Science Foundation of China(Nos.11102113 and81301816)the New Teachers Start Program of Shanghai Jiao Tong University+1 种基金the Chenxing Young Scholars Program B of Shanghai Jiao Tong University(No.13X100010070)the Natural Science Research Foundation of Shanghai Jiao Tong University School of Medicine(No.13XJ10037)
文摘The changes of blood perfusion and oxygen transport in tumors during tumor vascular normalization are studied with 3-dimensional mathematical modeling and numerical simulation. The models of tumor angiogenesis and vascular-disrupting are used to simulate ＂un-normalized＂ and ＂normalized＂ vasculatures. A new model combining tumor hemodynamics and oxygen transport is developed. In this model, the intravasculartransvascular-interstitial flow with red blood cell（RBC） delivery is tightly coupled, and the oxygen resource is produced by heterogeneous distribution of hematocrit from the flow simulation. The results show that both tumor blood perfusion and hematocrit in the vessels increase, and the hypoxia microenvironment in the tumor center is greatly improved during vascular normalization. The total oxygen content inside the tumor tissue increases by about 67%, 51%, and 95% for the three approaches of vascular normalization,respectively. The elevation of oxygen concentration in tumors can improve its metabolic environment, and consequently reduce malignancy of tumor cells. It can also enhance radiation and chemotherapeutics to tumors.
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the National Natural Science Foundation of China(Nos.51932002,52072127,51903087,52003085,21975079)the Science and Technology Program of Guangzhou(No.202002030308).
文摘Pathological angiogenesis frequently occurs in tumor tissue, limiting the efficiency of chemotherapeutic drug delivery and accelerating tumor progression. However, traditional vascular normalization strategies are not fully effective and limited by the development of resistance. Herein, inspired by the intervention of endogenous bioelectricity in vessel formation, we propose a wireless electrical stimulation therapeutic strategy, capable of breaking bioelectric homeostasis within cells, to achieve tumor vascular normalization. Polarized barium titanate nanoparticles with high mechano-electrical conversion performance were developed, which could generate pulsed open-circuit voltage under low-intensity pulsed ultrasound. We demonstrated that wireless electrical stimulation significantly inhibited endothelial cell migration and differentiation in vitro. Interestingly, we found that the angiogenesis-related eNOS/NO pathway was inhibited, which could be attributed to the destruction of the intracellular calcium ion gradient by wireless electrical stimulation. In vivo tumor-bearing mouse model indicated that wireless electrical stimulation normalized tumor vasculature by optimizing vascular structure, enhancing blood perfusion, reducing vascular leakage, and restoring local oxygenation. Ultimately, the anti-tumor efficacy of combination treatment was 1.8 times that of the single chemotherapeutic drug doxorubicin group. This work provides a wireless electrical stimulation strategy based on the mechano-electrical conversion performance of piezoelectric nanoparticles, which is expected to achieve safe and effective clinical adjuvant treatment of malignant tumors.
基金supported by the National Natural Science Foundation of China (Grant No. 81973861)Zhejiang Provincial Ministry Medical and Health Co-construction Major Project (Grant No. 20214355173)+2 种基金Zhejiang Science and Technology Department“Vanguard”“Leading Goose”research (Grant No. 2023C03044)Zhejiang Provincial Health“Leading Talents”ProjectZhejiang Medical and Health Science and Technology Project (Grant No. 2022KY558)。
文摘Angiogenesis is considered a hallmark pathophysiological process in tumor development. Aberrant vasculature resulting from tumor angiogenesis plays a critical role in the development of resistance to breast cancer treatments, via exacerbation of tumor hypoxia, decreased effective drug concentrations within tumors, and immune-related mechanisms. Antiangiogenic therapy can counteract these breast cancer resistance factors by promoting tumor vascular normalization. The combination of antiangiogenic therapy with chemotherapy, targeted therapy, or immunotherapy has emerged as a promising approach for overcoming drug resistance in breast cancer. This review examines the mechanisms associated with angiogenesis and the interactions among tumor angiogenesis, the hypoxic tumor microenvironment, drug distribution, and immune mechanisms in breast cancer. Furthermore, this review provides a comprehensive summary of specific antiangiogenic drugs, and relevant studies assessing the reversal of drug resistance in breast cancer. The potential mechanisms underlying these interventions are discussed, and prospects for the clinical application of antiangiogenic therapy to overcome breast cancer treatment resistance are highlighted.
基金supported by the National Natural Science Foundation of China(NSFC52173294 and 52273162),Demonstration Project of Modern Agricultural Machinery Equipment&Technology in Jiangsu Province(NJ2022-11,China)Jiangsu Funding Program for Excellent Postdoctoral Talent(2023ZB585,China)+1 种基金Fundamental Research Funds for the Central Universities(2632023FY03,China)Postgraduate Research&Practice Innovation Program of Jiangsu Province(KYCX23_0883,China).
文摘Cancer stem cells(CSCs)are proposed to account for the progression,metastasis,and recurrence of diverse malignancies.However,the disorganized vasculars in tumors hinder the accumulation and penetration of nanomedicines,posing a challenge in eliminating CSCs located distantly from blood vessels.Herein,a pair of twin-like small-sized nanoparticles,sunitinib(St)-loaded ROS responsive micelles(RM@St)and salinomycin(SAL)-loaded GSH responsive micelles(GM@SAL),are developed to normalize disordered tumor vessels and eradicate CSCs.RM@St releases sunitinib in response to the abundant ROS in the tumor extracellular microenvironment for tumor vessel normalization,which improved intratumor accumulation and homogeneous distribution of small-sized GM@SAL.Sequentially,GM@SAL effectively accesses CSCs and achieves reduction-responsive drug release at high GSH concentrations within CSCs.More importantly,RM@St significantly extends the window of vessel normalization and enhances vessel integrity compared to free sunitinib,thus further amplifying the anti-tumor effect of GM@SAL.The combination therapy of RM@St plus GM@SAL produces considerable depression of tumor growth,drastically reducing CSCs fractions to 5.6%and resulting in 78.4%inhibition of lung metastasis.This study offers novel insights into rational nanomedicines designed for superior therapeutic effects by vascular normalization and anti-CSCs therapy.
基金supported by National Key Research and Development Program of China(No.2022YFC2303600,2020YFA0908000)Scientific and technological innovation project of China Academy of Chinese Medical Sciences(No.CI2023D003,CI2023D008,CI2021B014)+15 种基金the Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine(No.ZYYCXTD-C-202002,China)the CACMS Innovation Fund(No.CI2023E002,CI2021A05101 and CI2021A05104,China)the Science and Technology Foundation of Shenzhen(No.JCYJ20210324115800001,JCYJ20210324113608023,China)the Science and Technology Foundation of Shenzhen(Shenzhen Clinical Medical Research Center for Geriatric Diseases)the Shenzhen Medical Research Fund(No.B2302051,China)Shenzhen Governmental Sustainable Development Fund(No.KCXFZ20201221173612034,China)Shenzhen Fund for Guangdong Provincial High-level Clinical Key Specialties(No.SZGSP001,China)the Distinguished Expert Project of Sichuan Province Tianfu Scholar(No.CW202002,China)the Shenzhen Science and Technology Innovation Commission(No.JCYJ20200109120205924,JCYJ20210324114202008,China)GuangDong Basic and Applied Basic Research Foundation(No.2021A1515012164,2022A1515110745,China)International Science and Technology Cooperation for Shenzhen Technology Innovation Plan(No.GJHZ20200731095411034,China)Chinese Postdoctoral Science Foundation(No.2022M712190,China)Guang Dong Basic and Applied Basic Research Foundation(No.2022A1515110745,China)The Key Special Project of“Strategic Science and Technology Innovation Cooperation”from the National Key R&D Program of China(No.2023YFE0204500,China)the Shenzhen Science and Technology Innovation Committee(SZSTI)(No.RCYX20221008092950121,China)the National Natural Science Foundation of China(No.82373775,82070517).
文摘Photodynamic immunotherapy is a promising strategy for cancer treatment.However,the dysfunctional tumor vasculature results in tumor hypoxia and the low efficiency of drug delivery,which in turn restricts the anticancer effect of photodynamic immunotherapy.In this study,we designed photosensitive lipid nanoparticles.The synthesized PFBT@Rox Lip nanoparticles could produce type Ⅰ/Ⅱ reactive oxygen species(ROS)by electron or energy transfer through PFBT under light irradiation.Moreover,this nanosystem could alleviate tumor hypoxia and promote vascular normalization through Roxadustat.Upon irradiation with white light,the ROS produced by PFBT@Rox Lip nanoparticles in situ dysregulated calcium homeostasis and triggered endoplasmic reticulum stress,which further promoted the release of damage-associated molecular patterns,enhanced antigen presentation,and stimulated an effective adaptive immune response,ultimately priming the tumor microenvironment(TME)together with the hypoxia alleviation and vessel normalization by Roxadustat.Indeed,in vivo results indicated that PFBT@Rox Lip nanoparticles promoted M1 polarization of tumor-associated macrophages,recruited more natural killer cells,and augmented infiltration of T cells,thereby leading to efficient photodynamic immunotherapy and potentiating the anti-primary and metastatic tumor efficacy of PD-1 antibody.Collectively,photodynamic immunotherapy with PFBT@Rox Lip nanoparticles efficiently program TME through the induction of immunogenicity and oxygenation,and effectively suppress tumor growth through immunogenic cell death and enhanced anti-tumor immunity.
文摘Tumor vasculature is characterized by aberrant structure and function,resulting in immune suppressive profiles of tumor microenvironment through limiting immune cell infiltration into tumors,endogenous immune surveillance and immune cell function.Vascular normalization as a novel therapeutic strategy tends to prune some of the immature blood vessels and fortify the structure and function of the remaining vessels,thus improving immune stimulation and the efficacy of immunotherapy.Interestingly,the presence of"immune-vascular crosstalk"enables the formation of a positive feedback loop between vascular normalization and immune reprogramming,providing the possibility to develop new cancer therapeutic strategies.The applications of nanomedicine in vascular-targeting therapy in cancer have gained increasing attention due to its specific physical and chemical properties.Here,we reviewed the recent advances of effective routes,especially nanomedicine,for normalizing tumor vasculature.We also summarized the development of enhancing nanoparticle-based anticancer drug delivery via the employment of transcytosis and mimicking immune cell extravasation.This review explores the potential to optimize nanomedicine-based therapeutic strategies as an alternative option for cancer treatment.
基金This work was financially supported by the projects of National Natural Science Foundation of China(82003991,82101844,and 82304953)Natural Science Foundation of Jiangsu Province(BK20230744,China)+1 种基金Jiangsu Specially Appointed Professorship Foundation(013038021001,China)Postgraduate Research&Practice Innovation Program of Jiangsu Province(KYCX22-2045 and KYCX23-2038,China).
文摘Aberrant tumor blood vessels are prone to propel the malignant progression of tumors,and targeting abnormal metabolism of tumor endothelial cells emerges as a promising option to achieve vascular normalization and antagonize tumor progression.Herein,we demonstrated that salvianic acid A(SAA)played a pivotal role in contributing to vascular normalization in the tumor-bearing mice,thereby improving delivery and effectiveness of the chemotherapeutic agent.SAA was capable of inhibiting glycolysis and strengthening endothelial junctions in the human umbilical vein endothelial cells(HUVECs)exposed to hypoxia.Mechanistically,SAA was inclined to directly bind to the glycolytic enzyme PKM2,leading to a dramatic decrease in endothelial glycolysis.More importantly,SAA improved the endothelial integrity via activating theβ-Catenin/Claudin-5 signaling axis in a PKM2-dependent manner.Our findings suggest that SAA may serve as a potent agent for inducing tumor vascular normalization.
基金supported by the Major Research Project of National Natural Science Foundation of China(92061123)the Key Research Program of the Chinese Academy of Sciences(QYZDJ-SSW-SLH01)the Youth Innovation Promotion Association of CAS(2022036)。
基金This study was supported partly by grants from the Natural Science Foundation of China(81771973,81971672 and 82102005)Key Program of the Natural Science Foundation of Guangdong Province(2018B0303110011)+3 种基金Guangzhou Key Laboratory of Molecular and Functional Imaging for Clinical Translation(201905010003)Fundamental Research Funds for the Central Universities(21620308 and 21620101)JSPS KAKENHI grant Nos.21H02873,21K07659,and 20H03635the AMED Moonshot Research and Development Program(Grant No 21zf0127003h001).
文摘Epidermal growth factor receptor(EGFR)tyrosine kinase inhibitors(TKI),such as Erlotinib,have demonstrated remarkable efficacy in the treatment of non-small cell lung cancer(NSCLC)patients with mutated EGFR.However,the efficacy of EGFR-TKIs in wild-type(wt)EGFR tumours has been shown to be marginal.Methods that can sensitize Erlotinib to EGFR wild-type NSCLC remain rare.Herein,we developed a multifunctional superparamagnetic nanotheranostic agent as a novel strategy to potentiate Erlotinib to EGFR-wt NSCLCs.Our results demonstrate that the nanoparticles can co-escort Erlotinib and a vascular epithermal growth factor(VEGF)inhibitor,Bevacizumab(Bev),to EGFR-wt tumours.The nanotheranostic agent exhibits remarkable effects as an inhibitor of EGFR-wt tumour growth.Moreover,Bev normalizes the tumour embedded vessels,further promoting the therapeutic efficacy of Erlotinib.In addition,the tumour engagement of the nanoparticles and the vascular normalization could be tracked by magnetic resonance imaging(MRI).Collectively,our study,for the first time,demonstrated that elaborated nanoparticles could be employed as a robust tool to potentiate Erlotinib to EGFR-wt NSCLC,paving the way for imaging-guided nanotheranostics for refractory NSCLCs expressing EGFR wild-type genes.
