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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

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A nonenzymatic electrochemical sensor for the detection of hydrogen peroxide in vitro and in vivo fibrosis models

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Chinese Chemical Letters 2024年第3期35卷 394-398页

作者： Hongyao Liu Yan Yu Taixiong Xue Cailing Gan Yuting Xie Doudou Wang Peilin Li zhiyong qian Tinghong Ye Department of Gastroenterology and Hepatology Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer and Frontiers Science Center for Disease-Related Molecular NetworkState Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu 610041China Department of Biotherapy Cancer Center and State Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu 610041China

Fibrosis occurs due to the excessive deposition of extracellular matrix caused by cell injury.After various types of tissue injury,the dysregulation of the internal response can eventually lead to the destruction of organ structure and dysfunction.There is increasing evidence that oxidative stress,which is characterized by excessive production of hydrogen peroxide(H_(2)O_(2)),is an important cause of fibrosis.Therefore,we synthesized a biosensitive and efficient electrochemical H_(2)O_(2)sensor based on PtNi nanoparticle-doped N-reduced graphene oxide(PtNi-N-rGO)to detect H_(2)O_(2)released from transforming growth factorβ1(TGFβ1)-induced myofibroblast.In addition,the sensor could easily detect changes in H_(2)O_(2)in the lung and bronchoalveolar lavage fluid(BALF)of mice with pulmonary fibrosis.Furthermore,the sensor could also detect H_(2)O_(2)in activated hepatic stellate cells and the liver of carbon tetrachloride(CCl_(4))-induced liver fibrosis.Moreover,the alterations in H_(2)O_(2)detected by the sensor were consistent with nicotinamide adenine dinucleotide phosphate oxidase 4(NOX4)protein expression and the staining results of pathological sections.Taken together,these results highlight the use of H_(2)O_(2)sensors for the rapid detection of fibrosis and facilitate the rapid evaluation of antifibrotic drug candidates.

关键词： Fibrosis H_(2)O_(2) Electrochemical sensor NOX4 Nintedanib

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Drug delivery systems for colorectal cancer chemotherapy

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Chinese Chemical Letters 2024年第2期35卷 163-175页

作者： Wen Chen Kun Shi Yan Yu Peipei Yang Zhongwu Bei Dong Mo Liping Yuan Meng Pan Yu Chen zhiyong qian Department of Biotherapy Cancer Center and State Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu 610041China

Colorectal cancer causes the third most common type of malignant tumors with high morbidity and mortality.Chemotherapy is currently one of the most effective and common treatments for colorectal cancer.However,the poor water solubility of some chemotherapeutics,untargeted drug delivery,and the undesirable systemic side effects of conventional treatment remain the major issues for colorectal cancer chemotherapy.Fortunately,drug delivery systems(DDS)based on biomaterials have been widely investigated and found to be capable of resolving those issues with good performance.Therefore,the main goal of this review is to summarize and discuss the progress and potential advantages of different DDS for colorectal cancer chemotherapy.We not only reviewed the nanocarriers used to improve the solubility of chemotherapeutics,including liposomes,micelles,and nanoparticles,but also discussed targeted DDS based on specific ligand-receptor recognition and tumor microenvironmental stimulus responses.Furthermore,locally administered systems based on hydrogels and microspheres,which have been shown to increase drug accumulation at the tumor site while decreasing systemic toxicity,were also emphasized.DDS provides a good option for improving the efficacy of chemotherapy in the treatment of colorectal cancer.

关键词： Colorectal cancer Chemotherapy Drug delivery systems Solubility Targeted Local administration

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Editorial of Special Column on A New Era of Nanobiomaterial-based Drug Delivery

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Acta Pharmaceutica Sinica B 2022年第9期12卷 3453-3455页

作者： Haijun Yu zhiyong qian Center of Pharmaceutics Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China State Key Laboratory of Biotherapy and Cancer Center West China HospitalSichuan UniversityCollaborative Innovation Center of BiotherapyChengdu 610041China

In the present era of nano/biomaterials,nanosized drug delivery systems(NDDS)have been extensively contributed to the advancement of nanomedicine1.Fundamental research is carried out on a diverse range of nano-biomaterials,such as liposomes,dendrimers,micelles and so on.However,nanobiomaterial-based delivery systems yet need to be further optimized to achieve convincing therapeutic performance2.

关键词： biomaterials biomaterial advancement

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An injectable conductive hydrogel restores electrical transmission at myocardial infarct site to preserve cardiac function and enhance repair

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生物活性材料(英文) 2023年第2期20卷 339-354页

作者： Linghong Zhang Tao Li Yan Yu Kun Shi Zhongwu Bei Yongjun qian zhiyong qian State Key Laboratory of Biotherapy State Key Laboratory and Collaborative Innovation Center of BiotherapyWest China HospitalSichuan UniversityChengdu610041SichuanPR China Department of Cardiovascular Surgery West China HospitalSichuan UniversityChengdu610041SichuanPR China

Myocardial infarction(MI)leads to massive cardiomyocyte death and deposition of collagen fibers.This fibrous tissue disrupts electrical signaling in the myocardium,leading to cardiac systolic and diastolic dysfunction,as well as arrhythmias.Conductive hydrogels are a promising therapeutic strategy for MI.Here,we prepared a highly water-soluble conductive material(GP)by grafting polypyrrole(PPy)onto non-conductive gelatin.This component was added to the gel system formed by the Schiff base reaction between oxidized xanthan gum(OXG)and gelatin to construct an injectable conductive hydrogel.The prepared self-healing OGGP3(3 wt%GP)hydrogel had good biocompatibility,elastic modulus,and electrical conductivity that matched the natural heart.The prepared biomaterials were injected into the rat myocardial scar tissue 2 days after MI.We found that the cardiac function of the rats treated with OGGP3 was improved,making it more difficult to induce arrhythmias.The electrical resistivity of myocardial fibrous tissue was reduced,and the conduction velocity of myocardial tissue was increased.Histological analysis showed reduced infarct size,increased left ventricular wall thickness,increased vessel density,and decreased inflammatory response in the infarcted area.Our findings clearly demonstrate that the OGGP3 hydrogel attenuates ventricular remodeling and inhibits infarct dilation,thus showing its potential for the treatment of MI.

关键词： Myocardial infarction Injectable hydrogel Conductivity Cardiac function

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Extensible and swellable hydrogel-forming microneedles for deep point-of-care sampling and drug deployment

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Chinese Chemical Letters 2023年第6期34卷 90-100页

作者： Yuan Liu Ting Huang zhiyong qian Wei Chen Department of Pharmacology School of Basic MedicineTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China Hubei Key Laboratory for Drug Target Research and Pharmacodynamic Evaluation Huazhong University of Science and TechnologyWuhan 430030China State Key Laboratory of Biotherapy and Cancer Center West China HospitalSichuan UniversityCollaborative Innovation Center for BiotherapyChengdu 610041China

Microneedles are considered to be an effective,convenient,non-invasive,biosafety and compliant medical technology for vaccinations,biomarker testing,medical aesthetics and other related fields.Nonetheless,further clinical and commercial translation of regular microneedles is hampered by challenges in manufacturability,cost variability,insufficient comfort,contamination and so on.Recent innovations in functional biomaterials and chemical engineering technologies have been applied to develop extensible and swellable hydrogel-forming microneedles,achieving precise and controlled drug delivery and localized sampling from the target tissues.In this review,we systematically summarize the latest development of the extensible and swellable hydrogel-forming microneedles,including deep point-of-care testing,drug deployment,wound healing and mucoadhesion improvement.In addition,further analysis of the challenges and prospects for clinical application of current strategies is well presented.It is believed that the combined efforts of engineering,material,pharmaceutical and clinical research will contribute to the future success of this clinical and commercial translation.

关键词： Dynamic shape alteration Hydrogel-forming microneedles Controlled drug released Biomarker detection Interaction tunability

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Newly developed gas-assisted sonodynamic therapy in cancer treatment

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药学学报:英文版 2023年第7期13卷 2926-2954页

作者： Meng Pan Danrong Hu Liping Yuan Yan Yu Yicong Li zhiyong qian State Key Laboratory of Biotherapy and Cancer Center West China HospitalSichuan UniversityCollaborative Innovation Center of BiotherapyChengdu 610041China Rehabilitation Medicine Center and Institute of Rehabilitation Medicine Key Laboratory of Rehabilitation Medicine in Sichuan ProvinceWest China HospitalSichuan UniversityChengdu 610041China

Sonodynamic therapy(SDT) is an emerging noninvasive treatment modality that utilizes lowfrequency and low-intensity ultrasound(US) to trigger sensitizers to kill tumor cells with reactive oxygen species(ROS).Although SDT has attracted much attention for its properties including high tumor specificity and deep tissue penetration,its anticancer efficacy is still far from satisfactory.As a result,new strategies such as gas-assisted therapy have been proposed to further promote the effectiveness of SDT.In this review,the mechanisms of SDT and gas-assisted SDT are first summarized.Then,the applications of gas-assisted SDT for cancer therapy are introduced and categorized by gas types.Next,therapeutic systems for SDT that can realize real-time imaging are further presented.Finally,the challenges and perspectives of gas-assisted SDT for future clinical applications are discussed.

关键词： Sonodynamic therapy Gas therapy Cancer therapy US imaging Sonotheranostics

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An injectable conductive hydrogel with dual responsive release of rosmarinic acid improves cardiac function and promotes repair after myocardial infarction

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Bioactive Materials 2023年第11期29卷 132-150页

作者： Linghong Zhang Zhongwu Bei Tao Li zhiyong qian Department of Biotherapy Cancer Center and State Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu610041China Department of Pediatric Cardiac Surgery West China the Second HospitalSichuan UniversityChengdu610041China

Myocardial infarction (MI) causes irreversible damage to the heart muscle, seriously threatening the lives of patients. Injectable hydrogels have attracted extensive attention in the treatment of MI. By promoting the coupling of mechanical and electrical signals between cardiomyocytes, combined with synergistic therapeutic strategies targeting the pathological processes of inflammation, proliferation, and fibrotic remodeling after MI, it is expected to improve the therapeutic effect. In this study, a pH/ROS dual-responsive injectable hydrogel was developed by modifying xanthan gum and gelatin with reversible imine bond and boronic ester bond double crosslinking. By encapsulating polydopamine-rosmarinic acid nanoparticles to achieve on-demand drug release in response to the microenvironment of MI, thereby exerting anti-inflammatory, anti-apoptotic, and anti-fibrosis effects. By adding conductive composites to improve the conductivity and mechanical strength of the hydrogel, restore electrical signal transmission in the infarct area, promote synchronous contraction of cardiomyocytes, avoid induced arrhythmias, and induce angiogenesis. Furthermore, the multifunctional hydrogel promoted the expression of cardiac-specific markers to restore cardiac function after MI. The in vivo and in vitro results demonstrate the effectiveness of this synergistic comprehensive treatment strategy in MI treatment, showing great application potential to promote the repair of infarcted hearts.

关键词： Myocardial infarction Responsive hydrogel Rosmarinic acid Conductivity Combined treatment

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Nanovaccines for cancer immunotherapy:Current knowledge and future perspectives

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中国化学快报:英文版 2023年第8期34卷 57-68页

作者： Yiming Wu Zhe Zhang Yuquan Wei zhiyong qian Xiawei Wei Laboratory of Aging Research and Cancer Drug Target State Key Laboratory of Biotherapy and Cancer CenterNational Clinical Research Center for GeriatricsWest China HospitalSichuan UniversityChengdu 610041China

Cancer immunotherapy harnesses the immune system to attack tumors and has received extensive attention in recent years.Cancer vaccines as an important branch of immunotherapy are designed for delivering tumor antigens to antigen-presenting cells(APCs)to stimulate a strong immune response to against tumors,representing a potentially therapeutic and prophylactic effect with the long-term anticancer benefits.Nevertheless,the disappointing outcomes of their clinical use might be attributed to dilemma in antigen selection,immunogenicity,lymph nodes(LNs)targeting ability,lysosomal escape ability,immune evasion,etc.Nanotechnology,aiming to overcome these barriers,has been utilized in cancer vaccine development for decades.Numerous preclinical and clinical studies demonstrate positive results in nanomaterials-based cancer vaccines with considerable improvement in the vaccine efficacy.In this review,we systematically introduced the characteristics of nanovaccines and highlighted the different types of nanomaterials used for cancer vaccine design.In addition,the opportunities and challenges of the emerging nanotechnology-based cancer vaccines were discussed.

关键词： Cancer immunotherapy Cancer vaccines Nanoparticles Antitumor immune response Clinical transformation

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Nanoparticles targeting tumor-associated macrophages:A novel anti-tumor therapy

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Nano Research 2022年第3期15卷 2177-2195页

作者： Siyuan Chen Furong Qin Manni Wang Yuquan Wei zhiyong qian Xiawei Wei Laboratory of Aging Research and Cancer Drug Target State Key Laboratory of BiotherapyNational Clinical Research Center for GeriatricsWest China HospitalSichuan UniversityChengdu 610041China

The immunosuppressive tumor microenvironment(TME)is crucial in the occurrence of tumorigenesis,metastasis,and drug resistance.Among all stromal cells,tumor-associated macrophages(TAMs)are recognized as vital components causing the TME to be favorable for cancer cells and are also main targets in cancer immunotherapy.To date,nanoparticle(NP)-based drug delivery systems,as new technology platforms,have exhibited considerable advantages,such as targeted drug delivery at tumor sites,enhanced drug transport efficiency,and controllable drug release profiles,which provide new approaches for cancer therapy.Regarding TAM-targeting nanoparticles,various therapeutic strategies have been developed by varying their design,namely,by blocking TAM recruitment,promoting TAM transformation,and directly diminishing existing TAMs.In the current review,we provide a brief overview of the role of TAMs in the tumor microenvironment and their functions and highlight strategies for TAM targeting.Moreover,the applications of nanoparticles in targeting TAMs to improve cancer therapeutic efficiency are summarized.

关键词： tumors immunotherapy tumor-associated macrophages nanoparticles

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