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Nanoparticles (NPs)-mediated Siglec15 silencing and macrophage repolarization for enhanced cancer immunotherapy

Acta Pharmaceutica Sinica B 2023年第12期13卷 5048-5059页

作者： Xiaodi Liu Qi Zhang Yixia Liang Shiyu Xiong Yan Cai Jincheng Cao Yanni Xu Xiaolin Xu Ye Wu Qiang Lu Xiaoding Xu Baoming Luo Department of Ultrasound Laboratory of Ultrasound Imaging and DrugWest China HospitalSichuan UniversityChengdu 610041China Department of Ultrasound Sun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangzhou 510120China Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation Sun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangzhou 510120China Department of Ultrasound Central People's Hospital of ZhanjiangZhanjiang 524045China

cell infiltration and proliferation in tumor tissues are the main factors that significantly affect the therapeutic outcomes of cancer *** evidence has shown that interferon-gamma(IFN)could enhance CXCL9 secretion from macrophages to recruit T cells,but Siglec15 expressed on TAMs can attenuate T cell ***,targeted regulation of macrophage function could be a promising strategy to enhance cancer immunotherapy via concurrently promoting the infiltration and proliferation of T cells in tumor *** herein developed reductionresponsive nanoparticles(NPs)made with poly(disulfide amide)(PDSA)and lipid-poly(ethylene glycol)(lipid-PEG)for systemic delivery of Siglec15 siRNA(siSiglec15)and IFN for enhanced cancer *** intravenous administration,these cargo-loaded could highly accumulate in the tumor tissues and be efficiently internalized by tumor-associated macrophages(TAMs).With the highly concentrated glutathione(GSH)in the cytoplasm to destroy the nanostructure,the loaded IFN and si-Siglec15 could be rapidly released,which could respectively repolarize macrophage phenotype to enhance CXCL9 secretion for T cell infiltration and silence Siglec15 expression to promote T cell proliferation,leading to significant inhibition of hepatocellular carcinoma(HCC)growth when combining with the immune checkpoint *** strategy developed herein could be used as an effective tool to enhance cancer immunotherapy.

关键词： Nanoparticles Tumor-associated macrophages Macrophage repolarization T cell infiltration T cell proliferation cancer immunotherapy Siglec15 Hepatocellular carcinoma

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Applying artificial intelligence for cancer immunotherapy

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Acta Pharmaceutica Sinica B 2021年第11期11卷 3393-3405页

作者： Zhijie Xu Xiang Wang Shuangshuang Zeng Xinxin Ren Yuanliang Yan Zhicheng Gong Department of Pathology Xiangya HospitalCentral South UniversityChangsha 410008China Department of Pharmacy Xiangya HospitalCentral South UniversityChangsha 410008China Institute for Rational and Safe Medication Practices National Clinical Research Center for Geriatric DisordersXiangya HospitalCentral South UniversityChangsha 410008China Center for Molecular Medicine Xiangya HospitalKey Laboratory of Molecular Radiation Oncology of Hunan ProvinceCentral South UniversityChangsha 410008China

Artificial intelligence(AI)is a general term that refers to the use of a machine to imitate intelligent behavior for performing complex tasks with minimal human intervention,such as machine learning;this technology is revolutionizing and reshaping *** has considerable potential to perfect health-care systems in areas such as diagnostics,risk analysis,health information administration,lifestyle supervision,and virtual health *** terms of immunotherapy,AI has been applied to the prediction of immunotherapy responses based on immune signatures,medical imaging and histological *** features could also be highly useful in the management of cancer immunotherapy given their ever-increasing performance in improving diagnostic accuracy,optimizing treatment planning,predicting outcomes of care and reducing human resource *** this review,we present the details of AI and the current progression and state of the art in employing AI for cancer ***,we discuss the challenges,opportunities and corresponding strategies in applying the technology for widespread clinical ***,we summarize the impact of AI on cancer immunotherapy and provide our perspectives about underlying applications of AI in the future.

关键词： Artificial intelligence cancer immunotherapy Machine learning Diagnostics

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Bacterial extracellular vesicle applications in cancer immunotherapy

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Bioactive Materials 2023年第4期22卷 551-566页

作者： Kanika Suri Anisha D’Souza Di Huang Aashray Bhavsar Mansoor Amiji Department of Bioengineering College of EngineeringNortheastern UniversityBostonMA02115USA Department of Pharmaceutical Sciences School of PharmacyNortheastern UniversityBostonMA02115USA Massachusetts Eye and Ear Infirmary Harvard Medical SchoolBostonMA20115USA Department of Chemical Engineering College of EngineeringNortheastern UniversityBostonMA02115USA

cancer therapy is undergoing a paradigm shift toward immunotherapy focusing on various approaches to activate the host immune *** research to identify appropriate immune cells and activate anti-tumor immunity continues to expand,scientists are looking at microbial sources given their inherent ability to elicit an immune *** extracellular vesicles(BEVs)are actively studied to control systemic humoral and cellular immune responses instead of using whole microorganisms or other types of extracellular vesicles(EVs).BEVs also provide the opportunity as versatile drug delivery *** mammalian EVs,BEVs have already made it to the clinic with the meningococcal vaccine(Bexsero®).However,there are still many unanswered questions in the use of BEVs,especially for chronic systemically administered *** this review,we address the opportunities and challenges in the use of BEVs for cancer immunotherapy and provide an outlook towards development of BEV products that can ultimately translate to the clinic.

关键词： cancer immunotherapy Bacterial extracellular vesicles Membrane vesicles Outer membrane vesicles Mammalian extracellular vesicles

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A novel cyclic peptide targeting LAG-3 for cancer immunotherapy by activating antigenspecific CD8^+ T cell responses

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Acta Pharmaceutica Sinica B 2020年第6期10卷 1047-1060页

作者： Wenjie Zhai Xiuman Zhou Hongfei Wang Wanqiong Li Guanyu Chen Xinghua Sui Guodong Li Yuanming Qi Yanfeng Gao School of Life Sciences Zhengzhou UniversityZhengzhou 450001China School of Pharmaceutical Sciences(Shenzhen) Sun Yat-sen UniversityGuangzhou 510006China

PD-1 and CTLA-4 antibodies offer great hope for cancer ***,many patients are incapable of responding to PD-1 and CTLA-4 blockade and show low response rates due to insufficient immune *** combination of checkpoint blockers has been proposed to increase the response ***,antibody drugs have disadvantages such as inclined to cause immune-related adverse events and infiltration *** this study,we developed a cyclic peptide C25 by using Ph.D.-C7C phage display technology targeting *** a result,C25 showed a relative high affinity with human LAG-3 protein and could effectively interfere the binding between LAG-3 and HLA-DR(MHC-II).Additionally,C25 could significantly stimulate CD8^+T cell activation in human *** results also demonstrated that C25 could inhibit tumor growth of CT26,B16 and B 16-OVA bearing mice,and the infiltration of CD8^+T cells was significantly increased while FOXP3^+Tregs significantly decreased in the tumor ***,the secretion of IFN-γby CD8^+T cells in spleen,draining lymph nodes and especially in the tumors was ***,we exploited T cells depletion models to study the anti-tumor mechanisms for C25 peptide,and the results combined with MTT assay confirmed that C25 exerted anti-tumor effects via CD8+T cells but not direct *** conclusion,cyclic peptide C25 provides a rationale for targeting the immune checkpoint,by blockade of LAG-3/HLA-DR interaction in order to enhance anti-tumor immunity,and C25 may provide an alternative for cancer immunotherapy besides antibody drugs.

关键词： LAG-3 Phage display Cyclic peptide Immune checkpoint blockade CD8^+T cell cancer immunotherapy

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Identification and optimization of peptide inhibitors to block VISTA/PSGL-1 interaction for cancer immunotherapy

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Acta Pharmaceutica Sinica B 2023年第11期13卷 4511-4522页

作者： Xiaoshuang Niu Menghan Wu Guodong Li Xiuman Zhou Wenpeng Cao Wenjie Zhai Aijun Wu Xiaowen Zhou Shengzhe Jin Guanyu Chen Yanying Li Jiangfeng Du Yahong Wu Lu Qiu Wenshan Zhao Yanfeng Gao School of Life Sciences Zhengzhou UniversityZhengzhou 450001China School of Pharmaceutical Sciences(Shenzhen) Shenzhen Campus of Sun Yat-sen UniversityShenzhen 518107China International Joint Laboratory for Protein and Peptide Drugs of Henan Province Zhengzhou UniversityZhengzhou 450001China

Developing new therapeutic agents for cancer immunotherapy is highly demanding due to the low response ratio of PD-1/PD-L1 blockade in cancer ***,we discovered that the novel immune checkpoint VISTA is highly expressed on a variety of tumor-infiltrating immune cells,especially myeloid derived suppressor cells(MDSCs)and CD8^(+)T ***,peptide C1 with binding affinity to VISTA was developed by phage displayed bio-panning technique,and its mutant peptide VS3 was obtained by molecular docking based *** VS3 could bind VISTA with high affinity and block its interaction with ligand PSGL-1 under acidic condition,and elicit anti-tumor activity in *** peptide DVS3-Pal was further designed by D-amino acid substitution and fatty acid modification,which exhibited strong proteolytic stability and significant anti-tumor activity through enhancing CD8^(+)T cell function and decreasing MDSCs *** is the first study to develop peptides to block VISTA/PSGL-1 interaction,which could act as promising candidates for cancer immunotherapy.

关键词： Immune checkpoint VISTA PSGL-1 Phage displayed biopanning Peptide cancer immunotherapy MDSC T cell

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Photosensitive pro-drug nanoassemblies harboring a chemotherapeutic dormancy function potentiates cancer immunotherapy

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Acta Pharmaceutica Sinica B 2023年第2期13卷 879-896页

作者： Jianjun Cheng Haitian Zhao Bin Li Hua Zhang Qianyu Zhao Shiyao Fu Ying Han Weihong Lu Jiahua Shi Xin Yang School of Medicine and Health Harbin Institute of TechnologyHarbin 150001China Academician Workstation Jiangxi University of Chinese MedicineNanchang 330004China School of Chemistry and Chemical Engineering Harbin Institute of TechnologyHarbin 150001China Chongqing Research Institute Harbin Institute of TechnologyChongqing 401135China National and Local Joint Engineering Laboratory for Synthesis Transformation and Separation of Extreme Environmental NutrientsHarbin 150001China Key Laboratory of Natural Medicine and Immune-Engineering of Henan Province Henan UniversityKaifeng 475004China

immunotherapy combined with effective therapeutics such as chemotherapy and photodynamic therapy have been shown to be a successful strategy to activate anti-tumor immune responses for improved anticancer ***,developing multifunctional biodegradable,biocompatible,low-toxic but highly efficient,and clinically available transformed nano-immunostimulants remains a challenge and is in great ***,we report and design of a novel carrier-free photo-chemotherapeutic nano-prodrug COS-BA/Ce6 NPs by combining three multifunctional components-a self-assembled natural small molecule betulinic acid(BA),a water-soluble chitosan oligosaccharide(COS),and a low toxic photosensitizer chlorin e6(Ce6)-to augment the antitumor efficacy of the immune adjuvant anti-PD-L1-mediated cancer *** show that the designed nanodrugs harbored a smart and distinctive“dormancy”characteristic in chemotherapeutic effect with desired lower cytotoxicity,and multiple favorable therapeutic features including improved^(1)O_(2)generation induced by the reduced energy gap of Ce6,pH-responsiveness,good biodegradability,and biocompatibility,ensuring a highly efficient,synergistic ***,when combined with anti-PD-L1 therapy,both nano-coassembly based chemotherapy and chemotherapy/photodynamic therapy(PDT)could effectively activate antitumor immunity when treating primary or distant tumors,opening up potentially attractive possibilities for clinical immunotherapy.

关键词： cancer immunotherapy Nano-immunostimulants Chemotherapeutic dormancy Pro-drug Self-assembly Natural small molecule Betulinic acid Photodynamic therapy

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Self-assembled FeS-based cascade bioreactor with enhanced tumor penetration and synergistic treatments to trigger robust cancer immunotherapy

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Acta Pharmaceutica Sinica B 2021年第10期11卷 3244-3261页

作者： Hao Ren Jiahui Yong Qingqing Yang Zhen Yang Zhangya Liu Yan Xu Hao Wang Xing Jiang Wenjun Miao Xueming Li School of Pharmaceutical Science Nanjing Tech UniversityNanjing 211816China School of Nursing Nanjing University of Chinese MedicineNanjing 210023China

Major challenges for cancer treatment are how to effectively eliminate primary tumor and sufficiently induce immunogenic cell death(ICD)to provoke a robust immune response for metastasis ***,a self-assembled cascade bioreactor was developed to improve cancer treatment with enhanced tumor penetration and synergistic therapy of starvation,chemodynamic(CDT)and photothermal *** Fe S-GOx nanodots were synthesized with glucose oxidase(GOx)as template and induced by paclitaxel(PTX)to form self-assembling Fe S-GOx@PTX(FGP)via hydrophobic *** accumulated at tumor sites,FGP disassembles to smaller Fe S-GOx for enhanced deep tumor *** maintains high enzymatic activity to catalyze glucose with assistant of oxygen to generate hydrogen peroxide(H2O2)as starvation *** reaction involving the regenerated H_(2)O_(2) in turn produced more hydroxyl radicals for enhanced *** near-infrared laser at 808 nm,FGPs displayed pronounced tumor inhibition in vitro and in vivo by the combination *** consequent increased exposure to calreticulin amplified ICD and promoted dendritic cells *** combination with anti-CTLA4 checkpoint blockade,FGP can absolutely eliminate primary tumor and avidly inhibit distant tumors due to the enhanced intratumoral infiltration of cytotoxic T *** work presents a promising strategy for primary tumor and metastasis inhibition.

关键词： Fe S-based cascade bioreactor Glucose oxidase Tumor penetration Synergistic therapy ICD amplifier cancer immunotherapy Metastasis inhibition

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Acid-activatible micelleplex delivering siRNA-PD-L1 for improved cancer immunotherapy of CDK4/6 inhibition

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Chinese Chemical Letters 2021年第6期32卷 1929-1936页

作者： Jing Gao Hanwu Zhang Fengqi Zhou Bo Hou Meiwan Chen Zhigang Xie Haijun Yu State Key Laboratory of Drug Research&Center of Pharmaceutics Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China Department of Medical Ultrasound Shanghai Tenth People's HospitalUltrasound Research and Education InstituteTongji University School of MedicineTongji University Cancer CenterShanghai 200072China Peking University Shenzhen Institute Shenzhen 518055China State Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical SciencesUniversity of MacaoMacao 999078China State Key Laboratory of Polymer Physics and Chemistry Changchun Institute of Applied ChemistryChinese Academy of SciencesChangchun 130022China

Cyclin-dependent kinases 4 and 6 inhibitors(CDK4/6i)have been demonstrated to trigger antitumor immunity for tumor ***,the therapeutic performance of CDK4/6i-meadiated cancer immunotherapy was impaired by the immunosuppressive tumor microenvironment(ITM)due to overexpression of programmed death ligand 1(PD-L1)on the surface of cancer cell *** improve the immunotherapeutic performance of CDK4/6i,we herein developed endosomal acidactivatable micelleplex for si RNA delivery and PD-L1 knockdown in the tumor cells in vitro and in *** further demonstrated that the combination of PD-L1 knockdown and CDK4/6 inhibition facilitated intratumoral infiltration of cytotoxic T lymphocytes(CTLs),and elicited protective immune response and efficiently suppressed tumor growth in *** study revealed the importance of molecular design of the micelleplex for highly efficient si RNA delivery,which might provide a novel insight for RNAi-based cancer immunotherapy.

关键词： cancer immunotherapy siRNA delivery Acid-activatible micelleplex CDK4/6 inhibitor PD-L1 knockdown

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PD-1/PD-L1 pathway blockade works as an effective and practical therapy for cancer immunotherapy

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cancer Biology & Medicine 2018年第2期15卷 116-123页

作者： Long Jia Qi Zhang Rongxin Zhang Laboratory of Immunology and Inflammation Department of Immunology and Research Center of Basic Medical SciencesKey Laboratory of Immune Microenvironments and Diseases of Educational MinistryTianjin Medical University Institute of Integrative Medicines for Acute Abdominal Diseases Tianjin Nankai Hospital Guangdong Province Key Laboratory for Biotechnology Drug Candidates School of Life Sciences and BiopharmaceuticsGuangdong Pharmaceutical University

cancer immunotherapy has greatly advanced in recent years,and PD-1/PD-L1 blocking therapy has become a major pillar of *** clinical trials of PD-1/PD-L1 blocking therapies in cancer treatments have benefited many patients,which promoted the Food and Drug Administration(FDA)approval of PD-1/PD-L1 blocking *** this review,we provide a detailed introduction of five PD-1/PD-L1 blocking drugs,with indications and studies,as a valuable reference for doctors and medical ***,the characteristics of PD-1/PD-L1 blocking therapies,including their universality and sustainability,are discussed in this ***,we also discuss and predict the possibility of PD-L1 as an indication marker of PD-1/PD-L1 blocking therapy for pan-cancer treatment,and the current status of combination therapies.

关键词： PD-1 PD-L1 cancer immunotherapy

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Nanomedicines modulating tumor immunosuppressive cells to enhance cancer immunotherapy

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Acta Pharmaceutica Sinica B 2020年第11期10卷 2054-2074页

作者： Yuefei Zhu Xiangrong Yu Soracha D.Thamphiwatana Ying Zheng Zhiqing Pang Department of Biomedical Engineering Columbia UniversityNew YorkNY 10027USA Key Laboratory of Smart Drug Delivery School of PharmacyFudan UniversityMinistry of EducationShanghai 201203China Department of Medical Imaging Zhuhai People’s HospitalZhuhai Hospital Affiliated with Jinan UniversityZhuhai 519000China Department of Biomedical Engineering Faculty of EngineeringMahidol UniversityNakhon Pathom 73170Thailand State Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical SciencesUniversity of MacaoMacao 999078China

cancer immunotherapy has veered the paradigm of cancer *** recent advances in immunotherapy for improved antitumor efficacy,the complicated tumor microenvironment(TME)is highly immunosuppressive,yielding both astounding and unsatisfactory clinical *** this regard,clinical outcomes of currently available immunotherapy are confined to the varied immune systems owing in large part to the lack of understanding of the complexity and diversity of the immune context of the *** advanced designs of nanomedicines could still not fully surmount the delivery barriers of the *** immunosuppressive TME may even dampen the efficacy of antitumor ***,some nanotechnology-related strategies have been inaugurated to modulate the immunosuppressive cells within the tumor immune microenvironment(TIME)for robust immunotherapeutic *** this review,we will highlight the current understanding of the immunosuppressive TIME and identify disparate subclasses of TIME that possess an impact on immunotherapy,especially those unique classes associated with the immunosuppressive *** immunoregulatory cell types inside the immunosuppressive TIME will be delineated along with the existing and potential approaches for immunosuppressive cell *** introducing the various strategies,we will ultimately outline both the novel therapeutic targets and the potential issues that affect the efficacy of TIME-based nanomedicines.

关键词： cancer immunotherapy Nanomedicine Tumor immunosuppressive microenvironment Drug delivery

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