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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 ***,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 *** 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 *** exposed to the second-wave of laser irradiation,the synergistic chemo-photo-immunotherapy can be *** 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 ***,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 *** 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

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

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 *** 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 ***,TCR repertoire analysis occupied an important position in T-cell regarding ***,next-generation sequencing technology allows the simultaneous detection of TCR sequences with high throughput,and several evaluation indexes facilitate the measure of TCR *** on this new methodology,discoveries are made across a range of tumor *** 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 *** 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 *** delineation of the T-cell repertoire can further the understanding of the immune system response to ***,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 *** results of some studies are even *** this article,we reviewed TCR rearrangement mechanisms and analysis *** progress of TCR sequencing technology in tumor research is also *** 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

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 *** 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 *** results indicate that the tumor grown in vivo may have various *** particular,a tumor with an inhibitor is associated with the growth of protrusions.

关键词： free boundary problem bifurcation analysis solid tumor

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 〉3

关键词： Anthracyclines Cardiotoxicity Children Echocardiography solid tumor

Bioorthognal Equipping CAR-T Cells with Hyaluronidase and Checkpoint Blocking Antibody for Enhanced solid tumor Immunotherapy

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Bioorthognal Equipping CAR-T Cells with Hyaluronidase and Ch...

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

第十四届全国免疫学学术大会

作者： Yangyang Zhao Yansong Dong Shuhan Yang Youyong Yuan Zhexiong Lian South China University of Technology

Adoptive cellular therapy utilizing Chimeric antigen receptor-redirected T(CAR-T) cells has shown striking therapeutic effects on hematological malignancies. In contrast, the efficacy of treating solid tumors with CAR-T cell therapies is still poor, which is largely due to inefficient penetration into solid tumors and immunosuppressive tumor microenvironment. Herein, we engineered hyaluronidase(HAase) and the checkpoint blocking antibody α-PDL1 on the surface of CAR-T cells via highly efficient and biocompatible bioorthogonal click chemistry to improve the therapeutic effects of CAR-T cells on solid tumors. The modified HAase degrades hyaluronic acid and destroys the tumor extracellular matrix, allowing CAR-T cells penetrate deeply into solid tumors, as evidenced by in vitro infiltration experiments and in vivo biodistribution studies. In addition, in vitro cytotoxicity studies showed stronger antitumor activity of α-PDL1-decorated CAR-T cells than traditional CAR-T cells. Importantly, HAase-and α-PDL1-engineered CAR-T cells showed better therapeutic efficacy on A20 solid tumors, and did not cause significant systemic toxicity. In this work, we provided a simple, efficient, and biologically safe chemical strategy to engineer traditional CAR-T cells for enhanced therapeutic efficacy on solid tumors, which can be extended to other adoptive cellular immunotherapies and holds great potential for clinical application.

关键词： Bioorthogonal reaction Chimeric antigen receptor T cell Immunotherapy solid tumor

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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 ***,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 ***-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 ***,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 ***,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

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 ***,we present disulfide-based nanoparticles that actively penetrate deep tumors in vivo through a thiol-mediated transportation *** 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 ***,FA-DBNPs exhibit GSH concentration-dependent depolymerization characterization,indicating that the GSH level in tumor tissues regulates the penetration depth of *** from these advantages,FA-DBNPs showed potent anti-tumor activity in mouse models,leading to the significant regression of *** 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

M1-polarized macrophage-derived cellular nanovesicle-coated lipid nanoparticles for enhanced cancer treatment through hybridization of gene therapy and cancer immunotherapy

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Acta Pharmaceutica Sinica B 2024年第7期14卷 3169-3183页

作者： Ha Eun Shin Jun-Hyeok Han Seungyong Shin Ga-Hyun Bae Boram Son Tae-Hyung Kim Hee Ho Park Chun Gwon Park Wooram Park Department of Integrative Biotechnology Sungkyunkwan University(SKKU)SuwonGyeonggi 16419Republic of Korea Deparment of Inteligent Precision Healthcare Convergence SKKUSuwonGyeonggi 16419Republic of Korea Department of MetaBioHealth SKKU Institute for ConvergenceSKKUSuwonGyeonggi 16419Republic of Korea Department of Bioengineering Hanyang UniversitySeoul 04763Republic of Korea Department of Integrative Engineering Chung-Ang UniversitySeoul 06974Republic of Korea Department of Biomedical Engineering SKKUSuwonGyeonggi 16419Republic of Korea Korea Institute of Science and Technology(KIST) Seoul 02792Republic of Korea

Optimum genetic delivery for modulating target genes to diseased tissue is a major obstacle for profitable gene *** nanoparticles(LNPs),considered a prospective vehicle for nucleic acid delivery,have demonstrated efficacy in human use during the COVID-19 *** study introduces a novel biomaterial-based platform,M1-polarized macrophage-derived cellular nanovesicle-coated LNPs(M1-C-LNPs),specifically engineered for a combined gene-immunotherapy approach against solid *** dual-function system of M1-C-LNPs encapsulates Bcl2-targeting siRNA within LNPs and immune-modulating cytokines within M1 macrophage-derived cellular nanovesicles(M1-NVs),effectively facilitating apoptosis in cancer cells without impacting T and NK cells,which activate the intratumoral immune response to promote granule-mediating killing for solid tumor *** retention within tumor was observed upon intratumoral administration of M1-C-LNPs,owing to the presence of adhesion molecules on M1-NVs,thereby contributing to superior tumor growth *** findings represent a promising strategy for the development of targeted and effective nanoparticle-based cancer genetic-immunotherapy,with significant implications for advancing biomaterial use in cancer therapeutics.

关键词： Genetic-immunotherapy M1 macrophage-derived cellular nanovesicles Lipid nanoparticles(LNPs) Gene therapy siRNA Cancer immunotherapy solid tumor tumor microenvironment(TME)