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Light-activated arginine-rich peptide-modified nanoparticles for deep-penetrating chemo-photo-immunotherapy of solid tumor

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Nano Research 2023年第7期16卷 9804-9814页

作者： Yonghua Gong Jinyang Zhang Yan Lu Dong Wan Jie Pan Guilei Ma Key Laboratory of Biomaterials and Nanotechnology for Cancer Immunotherapy The Tianjin Key Laboratory of BiomaterialsInstitute of Biomedical EngineeringPeking Union Medical College&Chinese Academy of Medical SciencesTianjin 300192China School of Environmental and Chemical Engineering Tiangong UniversityTianjin 300387China

Poor permeation of drugs and“immune-cold”tumor microenvironment in solid tumors are the two major challenges which lead to the inefficient therapeutic efficacy for cancer treatment.Here,light-activated penetrable nanoparticles(PEGVAL&DOX&ICG@RNPs)for co-delivery of the chemotherapeutic drug doxorubicin(DOX),the photosensitizer agent indocyanine green(ICG),and the angiotensin II receptor blockers valsartan(VAL)were developed to achieve deep drug penetration and synergistic photo-chemo-immunotherapy of solid tumor.Studies showed that under the first-wave of laser irradiation,the polyethylene glycol(PEG)hydrophilic layer as an“inert”surface could detach from the nanoparticles,release VAL and expose the arginine-rich peptide modified-cores that can facilitate deep drug penetration via a transcytosis pathway.When exposed to the second-wave of laser irradiation,the synergistic chemo-photo-immunotherapy can be achieved.As expected,in 4T1 tumorbearing mice,PEG-VAL&DOX&ICG@RNPs treatment could effectively inhibit the growth of tumors,down-regulateα-smooth muscle actin expression level of cancer-associated fibroblasts cells in tumors,induce dendritic cells(DCs)maturation,and promote intratumoral infiltration of cytotoxic T lymphocytes.Moreover,combination therapy by PEG-VAL&DOX&ICG@RNPs and anti-PD-1 monoclonal antibody can elicit memory T cell response for preventing tumor recurrence and metastasis in vivo.This work provides a promising delivery strategy to overcome the current limitations of nanomedicine for achieving more effective therapeutic index of“immune-cold”solid tumor treatment.

关键词： light-activated nanoparticles transcytosis deep penetration chemo-photo-immunotherapy solid tumor

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Thiol-mediated transportation pathway:an approach for improving tumor penetration of nanomedicines in vivo

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Science China Chemistry 2024年第1期67卷 383-389页

作者： Junjie Zhang Weican Sun Xing Wang Senyan Chen Jingying Li Huanghao Yang New Cornerstone Science Laboratory Key Laboratory for Analytical Science of Food Safety and Biology(Ministry of Education)College of ChemistryFuzhou UniversityFuzhou 350116China Department of Chemistry and College of Biological Science and Engineering Fuzhou UniversityFuzhou 350116China

Abnormal tumor microenvironment imposes barriers to tumor penetration of nanomedicine,which remains a major challenge for effective anti-tumor.Herein,we present disulfide-based nanoparticles that actively penetrate deep tumors in vivo through a thiol-mediated transportation pathway.To achieve active tumor accumulation in vivo,disulfide-based nanoparticles are modified with folic acid units(FA-DBNPs).It is gratifying that FA-DBNPs still enter cells via the thiol-mediated pathway,which facilitates transcellular transportation and tumor penetration both in vitro and in vivo.Besides,FA-DBNPs exhibit GSH concentration-dependent depolymerization characterization,indicating that the GSH level in tumor tissues regulates the penetration depth of FA-DBNPs.Benefiting from these advantages,FA-DBNPs showed potent anti-tumor activity in mouse models,leading to the significant regression of tumors.The current study lays a foundation that thiol-mediated transportation is a promising approach in nanomedicine design for solid tumor therapy.

关键词： deep penetration thiol-mediated pathway transcellular transportation solid tumor

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Enhancement of T cell infiltration via tumor-targeted Th9 cell delivery improves the efficacy of antitumor immunotherapy of solid tumors

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Bioactive Materials 2023年第5期23卷 508-523页

作者： Tao Chen Yucheng Xue Shengdong Wang Jinwei Lu Hao Zhou Wenkan Zhang Zhiyi Zhou Binghao Li Yong Li Zenan Wang Changwei Li Yinwang Eloy Hangxiang Sun Yihang Shen Mohamed Diaty Diarra Chang Ge Xupeng Chai Haochen Mou Peng Lin Xiaohua Yu Zhaoming Ye Orthopaedic Oncology Services Department of OrthopaedicsThe Second Affiliated Hospital of Zhejiang University School of MedicineHangzhou310009China Orthopaedic Research Institute Zhejiang UniversityHangzhou310009China Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province Hangzhou310009China The Second Clinical Medical College of Zhejiang Chinese Medical University Hangzhou310009China Qingtian People’s Hospital Department of OrthopedicsLishui323900China Department of Orthopedics Shanghai Key Laboratory for the Prevention and Treatment of Bone and Joint DiseasesShanghai Institute of Traumatology and OrthopedicsRuijin HospitalShanghai Jiao Tong University School of MedicineShanghai20025China Department of Radiology The Second Affiliated HospitalZhejiang University School of MedicineHangzhou310009China

Insufficient infiltration of T cells severely compromises the antitumor efficacy of adoptive cell therapy(ACT)against solid tumors.Here,we present a facile immune cell surface engineering strategy aiming to substantially enhance the anti-tumor efficacy of Th9-mediated ACT by rapidly identifying tumor-specific binding ligands and improving the infiltration of infused cells into solid tumors.Non-genetic decoration of Th9 cells with tumor-targeting peptide screened from phage display not only allowed precise targeted ACT against highly heterogeneous solid tumors but also substantially enhanced infiltration of CD8+T cells,which led to improved antitumor outcomes.Mechanistically,infusion of Th9 cells modified with tumor-specific binding ligands facilitated the enhanced distribution of tumor-killing cells and remodeled the immunosuppressive microenvironment of solid tumors via IL-9 mediated immunomodulation.Overall,we presented a simple,cost-effective,and cell-friendly strategy to enhance the efficacy of ACT against solid tumors with the potential to complement the current ACT.

关键词： Adoptive cell therapy(ACT) Phage display Cell surface engineering Th9 cell solid tumor

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Detection of Subclinical Anthracyclines＇ Cardiotoxicity in Children with solid tumor

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Chinese Medical Journal 2018年第12期131卷 1450-1456页

作者： Hui-Min Hu Xiao-Lin Zhang Wei-Ling Zhang Dong-Sheng Huang Zhong-Dong Du Department of Pediatric Cardiology Beijing Children's Hospital Capital Medical University Beijing 100045 China Department of Pediatrics Beijing Tongren Hospital Capital Medical University Beijing 100176 China

Background： Cardiotoxicity is one of the most serious chronic complications ofanthracyclines therapy. Assessment of the left ventricular ejection fraction （LVEF） fails to detect subtle cardiac dysfunction of left ventricular （LV）. This study aimed to detect and evaluate new parameters of subclinical anthracyclines＇ cardiotoxicity in children with solid tumor. Methods： A detailed echocardiographic examination was performed in 36 children with hepatoblastoma or rhabdomyosarcoma after receiving anthracyclines＇ chemotherapy and 36 healthy controls from January 2015 to December 2016. The LVEF, ratio of early diastolic peak velocity of transmitral flow （E） and septal diastolic e＇ mitral annular peak velocity （e＇）, tricuspid annular plane systolic excursion （TAPSE）, and LV global longitudinal strain （GLS） were evaluated using M-mode, tissue Doppler imaging （TDI）, and two-dimensional speckle tracking echocardiography （2D-STE）, respectively. Echocardiographic parameters were compared between patient group and healthy controls. All patients were divided into two subgroups based on their anthracyclines＇ cumulative dosage （〈300 mg/m^2 subgroup and ≥300 mg/m^2 subgroup）. Results： All patients had no presentation of heart failure and LVEF within normal range （65.7 ± 5.1%）. Compared with healthy controls, the mean E/e＇ increased significantly （7.9 ±0.7 vs. 10.2 ± 3.5, t = 3.72, P 〈 0.01 ）, mean TAPSE decreased significantly （ 17.2 ± 1.3 mm vs. 14.2 ± 3.0 mm, t = -4.03, P 〈 0.01）, and mean LV GLS decreased significantly （-22.2% ± 1.9% vs. -17.9% ± 2.9%, t = -5.58, P 〈 0.01） in patient group. Compared with subgroup with anthracyclines＇ cumulative dosage 〈 300 mg/m^2, mean LV GLS decreased significantly （- 18.7 ＋ 2.7% vs. - 16.5 ~ 2. 1%, t = 2.15, P = 0.04）, the mean E/e＇ increased significantly （9.1 ±1.5 vs. 11.5 ± 4.9, t = -2.17, P = 0.04）, and mean TAPSE decreased significantly （14.2±2.1 mm vs. 12.5±2.2 mm, t = -2.82, P = 0.02） in subgroup with anthracyclines＇ cumulative dosage 〉300 mg/m^2. Conclusions： LV GLS is helpful in the

关键词： Anthracyclines Cardiotoxicity Children Echocardiography solid tumor

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T-cell receptor repertoire analysis for the diagnosis and treatment of solid tumor: A methodology and clinical applications

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Cancer Communications 2020年第10期40卷 473-483页

作者： Na Li Jiani Yuan Wenjia Tian Lin Meng Yongyu Liu Department of Central Laboratory Shenyang Tenth People’s HospitalShenyang Chest HospitalShenyangLiaoning 110044P.R.China Novogene Corporation Limited Beijing 100083P.R.China Department of Thoracic Surgery Shenyang Tenth People’s HospitalShenyang Chest HospitalShenyangLiaoning 110044P.R.China

T cells,which are involved in adaptive immunity,are essential in the elimination of tumor cells.Mature T cells can specifically recognize the antigen on the major histocompatibility complex(MHC)molecule through T-cell receptors(TCR).The unique rearrangement mechanisms during T-cell maturation provide great diversity to TCR,ensuring specific recognition between T cells and antigens.Thus,TCR repertoire analysis occupied an important position in T-cell regarding research.Nowadays,next-generation sequencing technology allows the simultaneous detection of TCR sequences with high throughput,and several evaluation indexes facilitate the measure of TCR repertoire.Based on this new methodology,discoveries are made across a range of tumor types.Results have shed light on the TCR repertoire differences between cancer patients and healthy control as well as between individual’s lesions,paracancer,and peripheral blood samples.The potential of TCR repertoire as a biomarker for immunotherapy efficacy is also widely studied as TCR repertoire represents different baseline within individuals and shows dynamic change during treatment.Accurate delineation of the T-cell repertoire can further the understanding of the immune system response to tumorigenesis.Still,existing researches are insufficient to clarify the specific clinical implications of TCR dynamic change and the definite role of TCR repertoire diversity during the treatment process.The results of some studies are even contrary.In this article,we reviewed TCR rearrangement mechanisms and analysis methods.Recent progress of TCR sequencing technology in tumor research is also discussed.In conclusion,intensive studies over an extended range of cancer types and a broadened group of subjects should be carried to solidify the TCR repertoire’s position as an immunotherapy biomarker.

关键词： diagnosis diversity immunotherapy rearrangement repertoire sequencing solid tumor T-cell receptors

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INVESTIGATION ON EFFECT OF DRUG DOSING REGIMENTS ON DRUG DELIVERY IN solid tumor VIA LUMPED PARAMETER MODELING AND ANIMAL EXPERIMENTS

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Journal of Hydrodynamics 2009年第1期21卷 20-25页

作者： GAO Ci-xiu XU Shi-xiong JIANG Yu-ping TU Jiang-long Department of Mechanics and Engineering Science Fudan University Shanghai 200433 China Huashan Hospital attached to Fudan University Shanghai 200040 China Jiangxi Medical School Nanchang 330006 China

This work aims to investigate the effects of dosing regiments on drug delivery in solid tumors and to validate them with experiments on rats. The lumped parameter models of pharmacokinetics and of drug delivery in tumor were developed to simulate time courses of average drug concentration （Ct） of tumor interstitium in two types of dosing regiments （i.e., single-shot and triple-shot ones）. The two regiments were performed via antitumor drug, hydroxycamptothecin （HCPT）, on rats, to measure the drug concentration in the tumor. The simulations of the drug concentration in the tumor of the two dosing regiments were conducted and compared with the experimental data on rats. The coefficients in the models were investigated. It is concluded that the triple-shot method is more effective than that of single-shot injection. The present lumped-parameter model is quantitatively competent for drug delivery in solid tumor.

关键词： solid tumor dosing regiments lumped parameter model experiment on rats

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Bifurcation Analysis for a Free Boundary Problem Modeling Growth of solid tumor with Inhibitors

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Communications in Mathematical Research 2017年第1期33卷 85-96页

作者： Wang Ze-jia Xu Jian-lei Li Jing-hua College of Mathematics and Information Science Jiangxi Normal UniversityNanchang 330022

This paper is concerned with the bifurcation analysis for a free boundary problem modeling the growth of solid tumor with inhibitors.In this problem,surface tension coefficient plays the role of bifurcation parameter,it is proved that there exists a sequence of the nonradially stationary solutions bifurcate from the radially symmetric stationary solutions.Our results indicate that the tumor grown in vivo may have various shapes.In particular,a tumor with an inhibitor is associated with the growth of protrusions.

关键词： free boundary problem bifurcation analysis solid tumor

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Co-delivery of nigericin and decitabine using hexahistidine-metal nanocarriers for pyroptosis-induced immunotherapeutics

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Acta Pharmaceutica Sinica B 2022年第12期12卷 4458-4471页

作者： Qiang Niu Yu Liu Yujing Zheng Ziwei Tang Yuna Qian Ruogu Qi Jianliang Shen Ping Zhao School of Chemistry and Chemical Engineering Guangdong Pharmaceutical UniversityGuangzhou 510006China State Key Laboratory of Ophthalmology Optometry and Vision ScienceSchool of Ophthalmology and OptometrySchool of Biomedical EngineeringWenzhou Medical UniversityWenzhou 325027China Wenzhou Institute University of Chinese Academy of SciencesWenzhou 325001China School of Medicine&Holistic Integrative Medicine Nanjing University of Chinese MedicineNanjing 210023China

Pyroptosis provides a new window for relieving the tumor immunosuppressive microenvironment(TIM)and promoting systemic immune responses for tumor treatments.However,gasdermin D(GSDMD),a key protein in the pyroptosis process mediated by caspase-1,is low expressed in the majority of tumor cells and small-molecule inhibitors of DNA methylation suffer from nonspecific or single-function defects.To address these issues,hexahistidine(His6)-metal assembly(HmA)was employed as the drug delivery vector to load nigericin(Nig)and decitabine(DAC)affording a dual-drug delivery system(Nig^(+)DAC)@HmA.The(Nig^(+)DAC)@HmA nanoparticles are efficiently internalized by cells through endocytosis,easily escape from the lysosome,and are highly distributed in the tumor sites.DAC up-regulates the expression of GSDMD which is then cleaved by the nucleotide-binding oligomerization domain-like receptor protein 3(NLRP3)inflammasome and caspase-1 protein activated by Nig.Effective cancer cell pyroptosis is thus achieved and induces a significant systemic antitumor immunity for impressive tumor suppression with negligible side effects in vivo.Our results suggest that such an easy-to-manipulate self-assembled nano-system(Nig^(+)DAC)@HmA provides a new anticancer path by enhancing pyroptosis through reinforced inflammation.

关键词： Self-assembled nanoparticle Pyroptosis NLRP3 GSDMD Inflammation IL-8 Immunotherapy responses solid tumor

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Characterization of a novel bispecific antibody targeting tissue factor-positive tumors with T cell engagement

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Acta Pharmaceutica Sinica B 2022年第4期12卷 1928-1942页

作者： Zhidi Pan Jie Chen Xiaodong Xiao Yueqing Xie Hua Jiang Baohong Zhang Huili Lu Yunsheng Yuan Lei Han Yuexian Zhou Huifang Zong Lei Wang Rui Sun Jianwei Zhu Engineering Research Center of Cell&Therapeutic Antibody MOESchool of PharmacyShanghai Jiao Tong UniversityShanghai 200240China Jecho Laboratories Inc.FrederickMD 21704USA Jecho Biopharmaceuticals Co. Ltd.Tianjin 300467China

T cell engaging bispecific antibody(TCB)is an effective immunotherapy for cancer treatment.Through co-targeting CD3 and tumor-associated antigen(TAA),TCB can redirect CD3+T cells to eliminate tumor cells regardless of the specificity of T cell receptor.Tissue factor(TF)is a TAA that involved in tumor progression.Here,we designed and characterized a novel TCB targeting TF(TF-TCB)for the treatment of TF-positive tumors.In vitro,robust T cell activation,tumor cell lysis and T cell proliferation were induced by TF-TCB.The tumor cell lysis activity was dependent upon both CD3 and TF binding moieties of the TF-TCB,and was related to TF expression level of tumor cells.In vivo,in both tumor cell/human peripheral blood mononuclear cells(PBMC)co-grafting model and established tumor models with poor T cell infiltration,tumor growth was strongly inhibited by TF-TCB.T cell infiltration into tumors was induced during the treatment.Furthermore,efficacy of TF-TCB was further improved by combination with immune checkpoint inhibitors.For the first time,our results validated the feasibility of using TF as a target for TCB and highlighted the potential for TF-TCB to demonstrate efficacy in solid tumor treatment.

关键词： T cell engaging bispecific antibody Immunotherapy Tissue factor solid tumor Pancreatic cancer Lung cancer PD-1 antibody

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Minimal residual disease in solid tumors:an overview

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Frontiers of Medicine 2023年第4期17卷 649-674页

作者： Yarui Ma Jingbo Gan Yinlei Bai Dandan Cao Yuchen Jiao State Key Laboratory of Molecular Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China Genetron Health(Beijing)Co.Ltd. Beijing 102206China

Minimal residual disease(MRD)is termed as the small numbers of remnant tumor cells in a subset of patients with tumors.Liquid biopsy is increasingly used for the detection of MRD,illustrating the potential of MRD detection to provide more accurate management for cancer patients.As new techniques and algorithms have enhanced the performance of MRD detection,the approach is becoming more widely and routinely used to predict the prognosis and monitor the relapse of cancer patients.In fact,MRD detection has been shown to achieve better performance than imaging methods.On this basis,rigorous investigation of MRD detection as an integral method for guiding clinical treatment has made important advances.This review summarizes the development of MRD biomarkers,techniques,and strategies for the detection of cancer,and emphasizes the application of MRD detection in solid tumors,particularly for the guidance of clinical treatment.

关键词： MRD solid tumor CTC ctDNA

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