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Immunostimulatory gene therapy combined with checkpoint blockade reshapes tumor microenvironment and enhances ovarian cancer immunotherapy

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Acta Pharmaceutica Sinica B 2024年第2期14卷 854-868页

作者： Yunzhu Lin Xiang Wang Shi He Zhongxin Duan Yunchu Zhang Xiaodong Sun Yuzhu Hu Yuanyuan Zhang Zhiyong Qian Xiang Gao Zhirong Zhang Key Laboratory of Drug Targeting and Drug Delivery Systems Ministry of EducationWest China School of PharmacySichuan UniversityChengdu 610041China Department of Pharmacy Evidence-based Pharmacy CenterWest China Second University HospitalKey Laboratory of Birth Defects and Related Diseases of Women and ChildrenSichuan UniversityChengdu 610041China Department of Neurosurgery and institute of Neurosurgery State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalWest China Medical SchoolSichuan University and Collaborative Innovation Center for BiotherapyChengdu 610041China Department of Radiation Oncology State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalWest China Medical SchoolSichuan University and Collaborative Innovation Center for BiotherapyChengdu 610041China West China School of Basic Medical Sciences&Forensic Medicine Sichuan UniversityChengdu 610041China

Immune evasion has made ovarian cancer notorious for its refractory features, making the development of immunotherapy highly appealing to ovarian cancer treatment. The immune-stimulating cytokine IL-12 exhibits excellent antitumor activities. However, IL-12 can induce IFN-γ release and subsequently upregulate PDL-1 expression on tumor cells. Therefore, the tumor-targeting folate-modified delivery system F-DPC is constructed for concurrent delivery of IL-12 encoding gene and small molecular PDL-1 inhibitor(i PDL-1) to reduce immune escape and boost anti-tumor immunity. The physicochemical characteristics, gene transfection efficiency of the F-DPC nanoparticles in ovarian cancer cells are analyzed. The immune-modulation effects of combination therapy on different immune cells are also studied. Results show that compared with non-folate-modified vector, folate-modified F-DPC can improve the targeting of ovarian cancer and enhance the transfection efficiency of p IL-12. The underlying anti-tumor mechanisms include the regulation of T cells proliferation and activation, NK activation,macrophage polarization and DC maturation. The F-DPC/p IL-12/i PDL-1 complexes have shown outstanding antitumor effects and low toxicity in peritoneal model of ovarian cancer in mice. Taken together, our work provides new insights into ovarian cancer immunotherapy. Novel F-DPC/p IL-12/i PDL-1 complexes are revealed to exert prominent anti-tumor effect by modulating tumor immune microenvironment and preventing immune escape and might be a promising treatment option for ovarian cancer treatment.

关键词： IL-12encodinggene Checkpointblocker Nanoparticles Targeted delivery Tumormicroenvironment Immune escape Ovarian cancer Immunotherapy

Programmable double-unlock nanocomplex self-supplies phenylalanine ammonia-lyase for precise phenylalanine deprivation of tumors

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Chinese Chemical Letters 2024年第8期35卷 455-459页

作者： Chunqing Ou Meijia Xiao Xinyue Zheng Xianzhou Huang Suleixin Yang Yingying Leng Xiaowei Liu Xiuqi Liang Linjiang Song Yanjie You Shaohua Yao Changyang Gong Department of biotherapy Cancer Center and State Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu 610041China State Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical SciencesUniversity of MacaoAvenida da UniversidadeTaipaMacao 999087China School of Medical and Life Sciences Chengdu University of Traditional Chinese MedicineChengdu 611137China Department of Gastroenterology People’s Hospital of Ningxia Hui Autonomous RegionYinchuan 750002China

Essential amino acids(EAAs)deprivation is a potential antitumor approach because EAAs are critical for tumor *** efficiently inhibit tumor growth,continuous deprivation of EAAs is required,how-ever,continuous deprivation without precise control will introduce toxicity to normal ***,a programmable double-unlock nanocomplex(ROCK)was prepared,which could self-supply phenylalanine ammonia-lyase(PAL)to tumor cells for phenylalanine(Phe)*** was double-locked in physiological conditions when administered *** ROCK actively targeted to tumor cells by integrinαvβ3/5 and CD44,ROCK was firstly unlocked by cleavage of protease on tumor cell membrane,exposing CendR and R8 to enhance ***,hyaluronic acid was digested by hyaluronidase overexpressed in endo/lysosome of tumor cells,in which ROCK was secondly unlocked,resulting in pro-moting endo/lysosome escape and PAL plasmid(pPAL)*** pPAL could sustainably express PAL in host tumor cells until the self-supplied PAL precisely and successfully deprived Phe,thereby block-ing the protein synthesis and killing tumor cells ***,our precise Phe deprivation strategy effectively inhibited tumor growth with no observable toxicity to normal cells,providing new insights to efficiently remove intratumoral nutrition for cancer therapy.

关键词： Programmable double-unlock Essential amino acids deprivation Phenylalanine ammonia-lyase Self-supply Gene therapy

A folic acid-decorated nanoparticles loaded JQ1 for oral squamous cell carcinoma therapy

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Chinese Chemical Letters 2024年第3期35卷 332-336页

作者： Dequan Zeng Zhongkai Ma Xin Zan Ting Luo Xiang Wang Xiang Gao Xianghui Fu School of Health Management Xihua UniversityChengdu 610039China State Key Laboratory of Oral Diseases National Clinical Research Center for Oral DiseasesWest China College of StomatologySichuan UniversityChengdu 610041China Department of Neurosurgery and institute of Neurosurgery State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalWest China Medical SchoolSichuan University and Collaborative Innovation Center for BiotherapyChengdu 610041China Breast Disease Center Cancer CenterWest China HospitalSichuan UniversityChengdu 610041China

Oral squamous cell carcinoma(OSCC)is known as one of the most malignant tumors with high recurrence and fatality *** poor tumor-targeting ability of traditional chemotherapeutic drugs has been a grand challenge for anti-OSCC *** that,a large quantity of tumor associated macrophages in OSCC tissues further diminish the anti-tumor effects of these ***,we produced a therapeutic nano drug delivery system(FA-PEG-PLA-JQ1)through encapsulating JQ1[a small-molecule inhibitor of bromodomain containing protein 4(BRD4)]into the folic acid(FA)-modified nanoparticle(PEG-PLA),which could prolong the half-life of JQ1 and target the tumor *** then,JQ1 released from this nanoparticle could prevent OSCC growth inducing tumor cell apoptosis,inhibiting tumor angiogenesis and the polarization of M2 type *** conclusion,our date demonstrated the therapeutic benefits of FA-PEG-PLA-JQ1 against OSCC in vivo or in vitro,which could be a novel treatment strategy for OSCC in coming days.

关键词： Folic acid Nanoparticles JQ1 Oral squamous cell carcinoma Macrophages

Expression of cyclin-dependent kinase 9 is positively correlated with the autophagy level in colon cancer

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World Journal of Gastrointestinal Oncology 2024年第2期16卷 314-330页

作者： Lei Zheng Jia Lu Da-Lu Kong Department of Colorectal Cancer Surgery National Clinical Research Center for CancerKey Laboratory of Cancer Immunology and Biotherapy of TianjinTianjin Key Laboratory of Digestive CancerKey Laboratory of Cancer Prevention and Therapy of TianjinTianjin’s Clinical Research Center for CancerTianjin Medical University Cancer Institute and HospitalTianjin 300060China Department of Infection Management National Clinical Research Center for CancerKey Laboratory of Cancer Immunology and Biotherapy of TianjinTianjin Key Laboratory of Digestive CancerKey Laboratory of Cancer Prevention and Therapy of TianjinTianjin’s Clinical Research Center for CancerTianjin Medical University Cancer Institute and HospitalTianjin 300060China

BACKGROUND Cyclin-dependent kinase 9(CDK9)expression and autophagy in colorectal cancer(CRC)tissues has not been widely ***9,a key regulator of transcription,may influence the occurrence and progression of *** expression of auto-phagy-related genes BECN1 and drug resistance factor ABCG2 may also play a role in *** normal physiological conditions,autophagy can inhibit tumorigenesis,but once a tumor forms,autophagy may promote tumor ***,understanding the relationship between autophagy and cancer,partic-ularly how autophagy promotes tumor growth after its formation,is a key motivation for this *** To investigate the relationship between CDK9 expression and autophagy in CRC,assess differences in autophagy between left and right colon cancer,and analyze the associations of autophagy-related genes with clinical features and *** We collected tumor tissues and paracarcinoma tissues from colon cancer patients with liver metastasis to observe the level of autophagy in tissues with high levels of CDK9 and low levels of *** also collected primary tissue from left and right colon cancer patients with liver metastasis to compare the autophagy levels and the expression of BECN1 and ABCG2 in the tumor and paracarcinoma *** The incidence of autophagy and the expression of BECN1 and ABCG2 were different in left and right colon cancer,and autophagy might be involved in the occurrence of chemotherapy *** analysis of the rela-tionship between the expression of autophagy-related genes CDK9,ABCG2,and BECN1 and the clinical features and prognosis of colorectal cancer showed that the high expression of CDK9 indicated a poor prognosis in colorectal *** This study laid the foundation for further research on the combination of CDK9 inhibitors and autophagy inhibitors in the treatment of patients with CRC.

关键词： Autophagy Tumorigenesis Tumor tissue Paracarcinoma tissue Expression Left/right colon cancer

Recent progresses of exosome-liposome fusions in drug delivery

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Chinese Chemical Letters 2024年第2期35卷 107-117页

作者： Lulu Zheng Bo Hu Deyao Zhao Wenjing Liu Qing Liu Yuanyu Huang Shaobo Ruan School of Life Science Advanced Research Institute of Multidisciplinary ScienceSchool of Medical TechnologyKey Laboratory of Molecular Medicine and BiotherapyKey Laboratory of Medical Molecule Science and Pharmaceutics EngineeringBeijing Institute of TechnologyBeijing 100081China Department of Radiation Oncology The First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450000China Beijing Key Laboratory of Drug Resistance Tuberculosis Research Beijing Tuberculosis and Thoracic Tumor Research Instituteand Beijing Chest HospitalCapital Medical UniversityBeijing 101149China

Exosomes are membrane-bound nanoscale extracellular vesicles,which produced by almost all *** to the excellent biocompatibility,long circulation time as well as low immunogenicity,exosomes as naturally-derived drug delivery carriers have experienced explosive growth over the past ***,issues such as insufficient loading efficiency,heterogeneous delivery efficiency,uncontrollable targeting ability,and low production limit their wide ***,the emerging exosome-liposome fusion strategy has become a potential approach to solve such ***,this review mainly focuses on the currently developed exosome-liposome fusion strategy and their application in drug delivery as well as disease *** review aims to shed light on the advantages of fusion strategy in drug delivery and provides a better understanding for more rational *** current challenge and future perspective regarding their clinical translation and application will also be discussed.

关键词： Exosome Liposome Membrane fusion Drug delivery Disease treatment

A novel deep generative model for mRNA vaccine development: Designing 5′ UTRs with N1-methyl-pseudouridine modification

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Acta Pharmaceutica Sinica B 2024年第4期14卷 1814-1826页

作者： Xiaoshan Tang Miaozhe Huo Yuting Chen Hai Huang Shugang Qin Jiaqi Luo Zeyi Qin Xin Jiang Yongmei Liu Xing Duan Ruohan Wang Lingxi Chen Hao Li Na Fan Zhongshan He Xi He Bairong Shen Shuai Cheng Li Xiangrong Song institute of Systems Genetics Department of Critical Care MedicineFrontiers Science Center for Disease-related Molecular NetworkState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengdu 610000China Department of Computer Science City University of Hong KongHong Kong 99907China Department of Biology Brandeis UniversityBostonMA 02453USA

Efficient translation mediated by the 5'untranslated region(5'UTR)is essential for the robust efficacy of mRNA ***,the N1-methyl-pseudouridine(m1)modification of mRNA can impact the translation efficiency of the 5'*** discovered that the optimal 5'UTR for m1y-modified mRNA(m1y-5'UTR)differs significantly from its unmodified counterpart,high-lighting the need for a specialized tool for designing mly-5'UTRs rather than directly utilizing high-expression endogenous gene 5'*** response,we developed a novel machine learning-based tool,Smart5UTR,which employs a deep generative model to identify superior m1y-5'UTRs in *** tailored loss function and network architecture enable Smart5UTR to overcome limitations inherent in existing *** a result,Smart5UTR can successfully design superior 5'UTRs,greatly benefiting mRNA vaccine ***,Smart5UTR-designed superior 5'UTRs significantly enhanced antibody titers induced by COVID-19 mRNA vaccines against the Delta and Omicron variants of SARS-CoV-2,surpassing the performance of vaccines using high-expression endogenous gene 5'UTRs.

关键词： mRNA vaccine Machine learning 5'UTR mRNA design Sequence design N1-Methyl-pseudouridine COVID-19 SARS-CoV-2

Long non-coding RNA MALAT1 in hematological malignancies and its clinical applications

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Chinese Medical Journal 2024年第10期137卷 1151-1159页

作者： Chunlan Zhang Yun Qin Yu Wu Heng Xu Yang Shu Department of Hematology West China HospitalSichuan UniversityChengduSichuan 610041China Department of Radiology West China HospitalSichuan UniversityChengduSichuan 610041China Department of Laboratory Medicine/Research Center of Clinical Laboratory Medicine West China HospitalSichuan UniversityChengduSichuan 610041China Department of biotherapy State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengduSichuan 610041China institute of General Surgery West China HospitalSichuan UniversityChengduSichuan 610041China Department of General Surgery Gastric Cancer Center and Laboratory of Gastric CancerWest China HospitalSichuan UniversityChengduSichuan 610041China

Metastasis-associated lung adenocarcinoma transcript 1(MALAT1)is a well-established oncogenic long non-coding RNA,the higher expression of which is strongly correlated with cancer events such as tumorigenesis,progression,metastasis,drug resistance,and treatment outcome in solid ***,a series of studies has highlighted its potential role in hematological malignancies in terms of these *** to solid cancers,MALAT1 can regulate various target genes via sponging and epigenetic mechanisms,but the miRNAs sponged by MALAT1 differ from those identified in solid *** this review,we systematically describe the role and underlying mechanisms of MALAT1 in multiple types of hematological malignancies,including regulation of cell proliferation,metastasis,stress response,and ***,MALAT1 expression is related to poor treatment outcome and drug resistance,therefore exhibiting potential prognostic value in multiple myeloma,lymphoma,and ***,we discuss the evaluation of MALAT1 as a novel therapeutic target against cancer in preclinical studies.

关键词： Long non-coding RNA Hematological malignancies Tumorigenesis Metastasis Drug resistance Prognostic biomarker

Expanding the horizons of targeted protein degradation:A non-small molecule perspective

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Acta Pharmaceutica Sinica B 2024年第6期14卷 2402-2427页

作者： Xiaowei Huang Fengbo Wu Jing Ye Lian Wang Xiaoyun Wang Xiang Li Gu He Department of Pharmacy and Department of Dermatology&Venerology West China HospitalSichuan UniversityChengdu 610041China Department of Urology West China HospitalSichuan UniversityChengdu 610041China Laboratory of Dermatology Clinical Institute of Inflammation and ImmunologyFrontiers Science Center for Disease-Related Molecular Network and State Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu 610041China

Targeted protein degradation(TPD)represented by proteolysis targeting chimeras(PROTACs)marks a significant stride in drug discovery.A plethora of innovative technologies inspired by PROTAC have not only revolutionized the landscape of TPD but have the potential to unlock functionalities beyond ***-small-molecule-based approaches play an irreplaceable role in this field.A wide variety of agents spanning a broad chemical spectrum,including peptides,nucleic acids,antibodies,and even vaccines,which not only prove instrumental in overcoming the constraints of conventional small molecule entities but also provided rapidly renewing *** we summarize the burgeoning non-small molecule technological platforms inspired by PROTACs,including three major trajectories,to provide insights for the design strategies based on novel paradigms.

关键词： Targeted protein degradation Proteolysis targeting chimera Endocytosis Autophagy Proximity-inducing modality Post-translational modification

Development of small molecule drugs targeting immune checkpoints

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Cancer Biology & Medicine 2024年第5期21卷 382-399页

作者： Luoyi Chen Xinchen Zhao Xiaowei Liu Yujie Ouyang Chuan Xu Ying Shi Department of Oncology Sichuan Academy of Medical SciencesSichuan Provincial People’s HospitalSchool of MedicineUniversity of Electronic Science and Technology of ChinaChengdu 610054China institute for Breast Health Medicine State Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu 610041China Acupuncture and Massage College Chengdu University of Traditional Chinese MedicineChengdu 611137China

Immune checkpoint inhibitors(ICIs)are used to relieve and refuel anti-tumor immunity by blocking the interaction,transcription,and translation of co-inhibitory immune checkpoints or degrading co-inhibitory immune *** of small molecule drugs or biological materials,especially antibody-based ICIs,are actively being studied and antibodies are currently widely ***,such as anti-tumor efficacy,poor membrane permeability,and unneglected tolerance issues of antibody-based ICIs,remain evident but are thought to be overcome by small molecule *** structural studies have broadened the scope of candidate immune checkpoint molecules,as well as innovative chemical *** way of comparison,small molecule drug-based ICIs represent superior oral bioavailability and favorable pharmacokinetic *** ongoing clinical trials are exploring the synergetic effect of ICIs and other therapeutic strategies based on multiple ICI functions,including immune regulation,anti-angiogenesis,and cell cycle *** this review we summarized the current progression of small molecule ICIs and the mechanism underlying immune checkpoint proteins,which will lay the foundation for further exploration.

关键词： Immune checkpoints small molecule drugs programmed death protein 1 CD47 signal-regulatory proteinα