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Chinese Chemical Letters 2024年第2期35卷 329-334页

作者： Jin Wang Qingqing Zhang Yanchen Li Xiaoyan Pan Yuanyuan Shan Jie Zhang School of Pharmacy Health Science CenterXi'an Jiaotong UniversityXi'an 710061China Department of Pharmacy The First Affiliated Hospital of Xi'an Jiaotong UniversityXi'an 710061China

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.

关键词： vascular normalization Tumor microenvironment GSH depletion Ferroptosis Activated immune

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3D numerical study of tumor blood perfusion and oxygen transport during vascular normalization

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Applied Mathematics and Mechanics(English Edition) 2015年第2期36卷 153-162页

作者： Jie WU Yan CAI Yi FU Zhujun TAN Ren SUN Shixiong XU Zurong DING Cheng DONG Ministry of Education of China(MOE)Key Laboratory of Hydrodynamics Shanghai Jiao Tong University School of Naval Architecture Ocean and Civil EngineeringShanghai Jiao Tong University School of Biological Science and Medical Engineering Southeast University Institute of Biliary Tract Disease Xinhua Hospital Department of Mechanics and Engineering Science Fudan University Department of Biomedical Engineering The Pennsylvania State University

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.

关键词： tumor hypoxia environment oxygen transport red blood cell（RBC） delivery vascular normalization numerical simulation

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Antiphospholipid autoantibodies promote breast tumor progression by tissue factor-dependent vascular normalization

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中国药理学与毒理学杂志 2019年第10期 889-890页

作者： WU Yuan-yuan NGUYEN ANDrew WU Xiao-xuan RAND Jacob LINE laine LU Yin Jiangsu Key Laboratory of Pharmacology and Safety Evaluation of Chinese Materia Medica School of Pharmacy Nanjing University of Chinese Medicine Department of Biological Sciences and Geology The City University of New York Department of Pathology Weil Cornel Medical College Department of Radiation Oncology New York University

OBJECTIVE To identify antiphospholipid autoantibodies(a PLs) as one of patientcharacteristics in breast tumor progression and explore the underlying mechanism. METHODS We examined the circulating a PLs levels in breast cancer patients. We determined the effects of human a PLs on tumor progression in multiple in vivo models of breast cancer and evaluatedthe histopathological characteristics by hemotoxylin and eosin staining and immunohistochemistry staining. Knockdown and neutralization studies were incorporated to confirm the effects of a PLs. RESULTS We observed that high levels of circulating a PLs among breast cancer patients is specifically associated with invasive-stage tumors. a PL Ig G from patients’ serum rapidly stimulated tumor angiogenesis and consequent tumor progression, specifically in slow-growing avascular tumors in breast tumor mouse models. a PLs elicited leukocytic infiltration in the tumor site. Tumor cells treated with a PL Ig G expressed multiple proangiogenic genes, including vascular endothelial growth factor, tissue factor(TF), and colony-stimulating factor 1. Knockdown and neutralization studies demonstrated that the effects of a PLs on tumor angiogenesis and growth were dependent on tumor cel derived TF. Tumorderived TF induced by Apl was essential for vascular normalization by improving pericyte coverage of tumor microvessels mediated by chemokine ligand 2. CONCLUSION Antiphospholipid autoantibodies action as a potential patient-specific endogenous factor promoting the transition of indolent tumors to an angiogenic malignant state through a TF-mediated pathogenic mechanism.

关键词： antiphospholipid antibodies tumor progression tissue factor angiogenesis vascular normalization

Novel oncolytic adenovirus mediates vascular normalization and tertiary lymphoid structure formation by activating the STING pathway of DCs

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Novel oncolytic adenovirus mediates vascular normalization a...

Manipulation of immune-vascular crosstalk:new strategies towards cancer treatment

第十四届全国免疫学学术大会

作者： Teng He Zhixing Hao Mingjie Lin Zhongwei Xin Yongyuan Chen Feng Xu Ping Wu The Second Affiliated Hospital Zhejiang University school of Medicine

Background: Immunotherapy has become an important treatment for tumor patients. However, the structural abnormalities, dysfunction of tumor blood vessels and the formation of hypoxic microenvironment hinder the infiltration of immune cells. In this study, we report the construction and evaluation of a novel oncolytic adenovirus, which can play an antitumor role by promoting tumor vascular normalization(VN) and the formation of tertiary lymphatic structure(TLS).Methods: E1ACR2-deleted oncolytic adenovirus was specifically activated by human telomerase reverse transcriptase(hTERT) and armed with mIL-15 to produce Ad-IL15. The antitumor efficacy of Ad-IL15 was characterized in vitro and in vivo. The effects of Ad-IL15 on tumor vessels and TLS formation were analyzed by polychromatic immunofluorescence and qPCR, and the role and specific mechanism of dendric cells(DCs) were explored by RNA-seq.Results: Compared with non-infected cells, Ad-IL15 showed the ability to kill tumor cells efficiently in vitro. Intratumoral injection of Ad-IL15 can exert antitumor effect by increasing tumor infiltrating lymphocytes(TILs). Moreover, intratumoral treatment with Ad-IL15 resulted in vascular normalization(VN) in tumor microenvironment(TME)(i.e., reduced vascular leakage and intratumoral hypoxia and increased PDGFRβ and VCAM-1 vessels), and promoted the local formation of TLS. Concomitantly, Ad-IL15-activated mCD11cDCs exhibited upregulated expression of vascular maturity and TLS promoting factors, and activation of STING-TBK1-IRF3 pathway in vitro.Conclusions: Our findings supported the notion that this novel mIL-15-armed oncolytic adenovirus increases the activation and infiltration of immune cells, which supports VN improvement and TLS formation. The mechanism might be related to the activation of STING(interferon gene stimulating factor) pathway in DCs. This discovery provided a theoretical basis for the development and treatment of oncolytic virus.

关键词： Oncolytic Adenovirus dendritic cells CD8-positive T-lymphocytes tertiary lymphoid structures vascular normalization

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Acta Pharmaceutica Sinica B 2020年第11期10卷 2018-2036页

作者： Yang Zhao Xiangrong Yu Jia Li Centre for the Endothelium Vascular Biology ProgramCentenary InstituteThe University of SydneySydney NSW 2042Australia Department of Radiology Zhuhai People’s HospitalJinan UniversityZhuhai 519000China Department of Biomedical Sciences Faculty of MedicineHealth and Human SciencesMacquarie UniversitySydney NSW 2109Australia

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.

关键词： Immune-vascular crosstalk vascular normalization Nanoparticles Transcytosis Immune cells Antiangiogenesis Immunotherapy Tumor microenvironment

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Pigment Epithelium-Derived Factor Enhances Tumor Response to Radiation by Normalizing Vasculature in Xenografted Model of Lung Cancer

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Pigment Epithelium-Derived Factor Enhances Tumor Response to...