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Branched glycopolymer prodrug-derived nanoassembly combined with a STING agonist activates an immuno-supportive status to boost anti-PD-L1 antibody therapy

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Acta Pharmaceutica Sinica B 2024年第5期14卷 2194-2209页

作者： Zhilin Li Qianfeng Zhang Zhiqian Li Long Ren Dayi Pan qiyong gong Zhongwei Gu Hao Cai Kui Luo Department of Radiology Huaxi MR Research Center(HMRRC)Clinical Research Center for BreastDepartment of Breast SurgeryDepartment of Thoracic Surgery and Institute of Thoracic OncologyFrontiers Science Center for Disease-Related Molecular NetworkState Key Laboratory of BiotherapyWest China Hospital Sichuan UniversityChengdu 610041China Functional and Molecular Imaging Key Laboratory of Sichuan Province and Research Unit of PsychoradiologyChinese Academy of Medical SciencesChengdu 610041China Department of Radiology West China Xiamen Hospital of Sichuan UniversityXiamen 361021China Key Laboratory of Medicinal Chemistry for Natural Resource Ministry of EducationYunnan Key Laboratory of Research and Development for Natural ProductsSchool of PharmacyYunnan UniversityKunming 650500China

Despite the great potential of anti-PD-L1 antibodies for immunotherapy,their low response rate due to an immunosuppressive tumor microenvironment has hampered their application.To address this issue,we constructed a cell membrane-coated nanosystem(mB4S)to reverse an immunosuppressive microenvironment to an immuno-supportive one for strengthening the anti-tumor effect.In this system,Epirubicin(EPI)as an immunogenic cell death(ICD)inducer was coupled to a branched glycopolymer via hydrazone bonds and diABZI as a stimulator of interferon genes(STING)agonist was encapsulated into mB4S.After internalization of mB4S,EPI was acidic-responsively released to induce ICD,which was characterized by an increased level of calreticulin(CRT)exposure and enhanced ATP secretion.Meanwhile,diABZI effectively activated the STING pathway.Treatment with mB4S in combination with an anti-PD-L1 antibody elicited potent immune responses by increasing the ratio of matured dendritic cells(DCs)and CD8+T cells,promoting cytokines secretion,up-regulating M1-like tumor-associated macrophages(TAMs)and down-regulating immunosuppressive myeloid-derived suppressor cells(MDSCs).Therefore,this nanosystem for co-delivery of an ICD inducer and a STING agonist achieved promotion of DCs maturation and CD8+T cells infiltration,creating an immuno-supportive microenvironment,thus potentiating the therapy effect of the anti-PD-L1 antibody in both 4T1 breast and CT26 colon tumor mice.

关键词： Glycopolymer Polymer prodrug Immunogenic cell death Nanoassembly Epirubicin STING pathway Immuno-supportive microenvironment Immunotherapy

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Cerebral fractional amplitude of low-frequency fluctuations may predict headache intensity improvement following acupuncture treatment in migraine patients

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Journal of Traditional Chinese Medicine 2020年第6期40卷 1041-1051页

作者： Li Zhengjie Zhou Jun Cheng Shirui Lan Lei Sun Ruirui Liu Mailan Yang Jie Gao Yujie Guo Taipin gong qiyong Zeng Fang Liang Fanrong Acupuncture&Tuina School/The Third Teaching Hospital Chengdu University of Traditional Chinese MedicineChengdu 610000China Acupuncture&Tuina School Hunan University of Chinese MedicineChangsha 410000China Huaxi Magnetic Resonance Research Center West China Hospital of Sichuan UniversityChengdu 610000China

OBJECTIVE:To explore how baseline resting-state cerebral function predicts clinical outcomes of acupuncture treatment for migraine.METHODS:One hundred migraine patients and 46 healthy subjects were recruited.Patients were randomized into the acupuncture,sham acupuncture,and waiting list groups.Resting-state functional magnetic resonance imaging data were collected at baseline and after 1 month of longitudinal acupuncture treatments.Fractional amplitude of low-frequency fluctuations(f ALFF)calculations were applied to explore the associations between baseline f ALFF and changes in clinical variables in the acupuncture treatment group and the waiting list group.RESULTS:Compared with healthy subjects,migraine patients had lower f ALFF in the left rostral ventromedial medulla,right thalamus,left amygdala,and right angular gyrus.Regression analyses revealed that baseline f ALFF values in the left middle frontal gyrus,left superior temporal gyrus,and middle temporal gyrus were positively associated with headache intensity changes in the acupuncture treatment group,while baseline f ALFF values in the bilateral lingual gyrus and cuneus were negatively associated with headache intensity changes in this group.CONCLUSION:The baseline f ALFF values of brain regions associated with cognitive pain modulation,but not migraine severity,may predict future headache intensity improvement levels in migraine patients receiving acupuncture treatment.

关键词： Acupuncture Migraine disorders Treatment outcome Magnetic resonance imaging

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Amphiphilic dextran/magnetite nanocomposites as magnetic resonance imaging probes

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Chinese Science Bulletin 2009年第17期54卷 2925-2933页

作者： WANG QiaoYing SU HongYing XIA ChunChao SUN JiaYu LIU Chen WANG ZhiYong gong qiyong SONG Bin GAO FaBao AI Hua GU ZhongWei National Engineering Research Center for Biomaterials Sichuan University Chengdu 610064 China Department of Radiology West China Hospital Sichuan University Chengdu 610041 China

Superparamagnetic iron oxide (SPIO) nanoparticles are effective contrast agents for enhancement of magnetic resonance imaging at the tissue, cellular or even molecular levels. High quality SPIO nanoparticles can be synthesized in the organic phase but need to be transferred into water before any biomedical applications. In this study, amphiphilic poly(ε-caprolactone) grafted dextran (Dex-g-PCL) was used as carriers for particle encapsulation and stabilization in the aqueous phase. Multiple SPIO nanoparticles were self-assembled together with the help of Dex-g-PCL during phase transfer from chloroform to water, and diameters of Dex-g-PCL/SPIO nanocomposites were (64 ± 22) nm through dynamic light scattering measurement. These nanocomposites were superparamagnetic at 300 K with saturated magnetization of 88 emu/g Fe. In the magnetic field of 1.5 T, Dex-g-PCL/SPIO nanocomposites had a T2 relaxivity of 363 Fe mL·mol-1·s-1. This unique nanocomposite brought significant mouse liver contrast with signal intensity changes of -60% at 5 min after intravenous administration. However, uptake of Dex-g-PCL/SPIO nanocomposites in liver reticuloendothelial cells (Kupffer cells) did not immediately happen at shorter time points (<4 h) as verified by histology studies, and it was evident that more iron staining would be located in Kupffer cells 24 h after contrast agent administration. After 24 h and 10 d, the signal intensities (SI) gradually recovered, and SI changes were -44% and -31%, respectively. From our observation, the time window for enhanced-MRI could last at least 12 days and totally recovered after 16 days. This novel sensitive MRI contrast agent may find potential applications in discovering small liver lesions such as early tumor diagnosis.

关键词：纳米复合材料磁共振成像磁铁矿葡聚糖探针

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Near-infrared fluorescent amphiphilic polycation wrapped magnetite nanoparticles as multimodality probes

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Chinese Science Bulletin 2012年第31期57卷 4012-4018页

作者： WANG Dan SU HongYing LIU yanHong WU ChangQiang XIA ChunChao SUN JiaYu GAO FaBao gong qiyong SONG Bin AI Hua National Engineering Research Center for Biomaterials Sichuan UniversityChengdu 610064China Department of Radiology West China HospitalSichuan University Chengdu 610041China

Construction of multifunctional/multimodality nanoparticles for cancer diagnosis and therapy has become an attractive area of investigation. In this report, we designed a multimodality nanoprobe for cell labeling, and can be detectable by both magnetic resonance and near infrared (NIR) fluorescence imaging. Multiple hydrophobic superparamagnetic iron oxide (SPIO) nanocrystals are self-assembled into nanocomposites in water phase with the help of partially alkylated hyperbranched polycation, polyethylenimine (PEI), which already conjugated with the indocyanine dye Cy5.5 and can be used for cell imaging under NIR fluorescence imaging. The amphiphilic PEI/SPIO nanocomposites have a strong T 2 relaxivity. The iron uptake process in MCF-7/Adr displays a time dependent behavior. Confocal laser scanning microscopy reveals that the nanoprobes are internalized into the cytoplasm of MCF-7/Adr after 24 h labeling. Both MR and NIR fluorescence imaging showed strong image contrast against unlabeled cells. Under a clinical MRI scanner, labeled cells in gelatin phantom present much darker images than controlled ones. The T2 relaxation rate of the labeled cells is 98.2 s 1 , significantly higher than that of the control ones of 2.3 s 1 . This study provides an important alternative to label MCF-7/Adr at optimized low dosages with high efficiency, and may be useful to label other biologically important cells and track their behaviors in vivo.

关键词：荧光成像纳米粒子聚阳离子近红外多模态磁铁矿两亲性超顺磁性氧化铁

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Shared and distinct abnormalities of brain magnetization transfer ratio in schizophrenia and major depressive disorder:a comparative voxel-based meta-analysis

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Chinese Medical Journal 2023年第23期136卷 2824-2833页

作者： Huan Lan Xueling Suo Chao Zuo Weishi Ni Song Wang Graham JKemp qiyong gong Department of Radiology Huaxi MR Research Center(HMRRC)West China Hospital of Sichuan UniversityChengduSichuan 610041China Department of Radiology West China Xiamen Hospital of Sichuan UniversityXiamenFujian 361000China Research Unit of Psychoradiology Chinese Academy of Medical SciencesChengduSichuan 610041China Department of Radiology Shengjing Hospital of China Medical UniversityShenyangLiaoning 110004China Functional and Molecular Imaging Key Laboratory of Sichuan Province West China Hospital of Sichuan UniversityChengduSichuan 610041China Liverpool Magnetic Resonance Imaging Centre(LiMRIC)and Institute of Life Course and Medical Sciences University of LiverpoolLiverpool L693BXUnited Kingdom

Background:Patients with schizophrenia(SCZ)and major depressive disorder(MDD)share significant clinical overlap,although it remains unknown to what extent this overlap reflects shared neural profiles.To identify the shared and specific abnormalities in SCZ and MDD,we performed a whole-brain voxel-based meta-analysis using magnetization transfer imaging,a technique that characterizes the macromolecular structural integrity of brain tissue in terms of the magnetization transfer ratio(MTR).Methods:A systematic search based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was conducted in PubMed,EMBASE,International Scientific Index(ISI)Web of Science,and MEDLINE for relevant studies up to March 2022.Two researchers independently screened the articles.Rigorous scrutiny and data extraction were performed for the studies that met the inclusion criteria.Voxel-wise meta-analyses were conducted using anisotropic effect size-signed differential mapping with a unified template.Meta-regression was used to explore the potential effects of demographic and clinical characteristics.Results:A total of 15 studies with 17 datasets describing 365 SCZ patients,224 MDD patients,and 550 healthy controls(HCs)were identified.The conjunction analysis showed that both disorders shared higher MTR than HC in the left cerebellum(P=0.0006)and left fusiform gyrus(P=0.0004).Additionally,SCZ patients showed disorder-specific lower MTR in the anterior cingulate/paracingulate gyrus,right superior temporal gyrus,and right superior frontal gyrus,and higher MTR in the left thalamus,precuneus/cuneus,posterior cingulate gyrus,and paracentral lobule;and MDD patients showed higher MTR in the left middle occipital region.Meta-regression showed no statistical significance in either group.Conclusions:The results revealed a structural neural basis shared between SCZ and MDD patients,emphasizing the importance of shared neural substrates across psychopathology.Meanwhile,distinct disease-specific characteristics could have implic

关键词： Magnetization transfer imaging Major depressive disorder Meta-analysis Neuroimaging Psychoradiology Schizophrenia

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GSH-sensitive polymeric prodrug: Synthesis and loading with photosensitizers as nanoscale chemo-photodynamic anti-cancer nanomedicine

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Acta Pharmaceutica Sinica B 2022年第1期12卷 424-436页

作者： Lei Luo Yiming Qi Hong Zhong Shinan Jiang Hu Zhang Hao Cai Yahui Wu Zhongwei Gu qiyong gong Kui Luo Huaxi MR Research Center(HMRRC) Department of RadiologyFunctional and Molecular Imaging Key Laboratory of Sichuan ProvinceNational Clinical Research Center for GeriatricsWest China HospitalSichuan UniversityChengdu 610041China College of Pharmaceutical Sciences Southwest UniversityChongqing 400716China Research Unit of Psychoradiology Chinese Academy of Medical SciencesChengdu 610041China Amgen Bioprocessing Centre Keck Graduate InstituteClaremontCA 91711USA

Precisely delivering combinational therapeutic agents has become a crucial challenge for anti-tumor treatment. In this study, a novel redox-responsive polymeric prodrug(molecular weight,MW: 93.5 k Da) was produced by reversible addition-fragmentation chain transfer(RAFT) polymerization. The amphiphilic block polymer-doxorubicin(DOX) prodrug was employed to deliver a hydrophobic photosensitizer(PS), chlorin e6(Ce6), and the as-prepared nanoscale system [NPs(Ce6)] was investigated as a chemo-photodynamic anti-cancer agent. The glutathione(GSH)-cleavable disulfide bond was inserted into the backbone of the polymer for biodegradation inside tumor cells, and DOX conjugated onto the polymer with a disulfide bond was successfully released intracellularly. NPs(Ce6) released DOX and Ce6 with their original molecular structures and degraded into segments with low MWs of 41.2 k Da in the presence of GSH. NPs(Ce6) showed a chemo-photodynamic therapeutic effect to kill 4 T1 murine breast cancer cells, which was confirmed from a collapsed cell morphology, a lifted level in the intracellular reactive oxygen species, a reduced viability and induced apoptosis. Moreover, ex vivo fluorescence images indicated that NPs(Ce6) retained in the tumor, and exhibited a remarkable in vivo anticancer efficacy. The combinational therapy showed a significantly increased tumor growth inhibition(TGI,58.53%). Therefore, the redox-responsive, amphiphilic block polymeric prodrug could have a great potential as a chemo-photodynamic anti-cancer agent.

关键词： Stimuli responsiveness Polymeric prodrug Photodynamic therapy Combinational therapy Nanomedicine

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A tumor cell membrane-coated self-amplified nanosystem as a nanovaccine to boost the therapeutic effect of anti-PD-L1 antibody

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Bioactive Materials 2023年第3期21卷 299-312页

作者： Zhilin Li Hao Cai Zhiqian Li Long Ren Xuelei Ma Hongyan Zhu qiyong gong Hu Zhang Zhongwei Gu Kui Luo Laboratory of Stem Cell Biology Department of RadiologyHuaxi MR Research Centner(HMRRC)Department of BiotherapyCancer CenterNational Clinical Research Center for GeriatricsFrontiers Science Center for Disease-related Molecular NetworkState Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu610041China Amgen Bioprocessing Centre Keck Graduate InstituteClaremontCA91711USA Functional and Molecular Imaging Key Laboratory of Sichuan Province And Research Unit of PsychoradiologyChinese Academy of Medical SciencesChengdu610041China

To improve the response rate of immune checkpoint inhibitors such as anti-PD-L1 antibody in immunosup-pressive cancers like triple-negative breast cancer(TNBC),induction of immunogenic cell death(ICD)at tumor sites can increase the antigenicity and adjuvanticity to activate the immune microenvironment so that tumors become sensitive to the intervention of immune checkpoint inhibitors.Herein,a self-amplified biomimetic nanosystem,mEHGZ,was constructed by encapsulation of epirubicin(EPI),glucose oxidase(Gox)and hemin in ZIF-8 nanoparticles and coating of the nanoparticles with calreticulin(CRT)over-expressed tumor cell mem-brane.EPI acts as an ICD inducer,Gox and hemin medicate the cascade generation of reactive oxygen species(ROS)to strengthen the ICD effect,and CRT-rich membrane as“eat me”signal promote presentation of the released antigens by dendritic cells(DCs)to invoke the tumor-immunity cycle.The biomimetic delivery system displays an amplified ICD effect via Gox oxidation,hydroxyl radical generation and glutathione(GSH)depletion.The induced potent ICD effect promotes DCs maturation and cytotoxic T lymphocytes(CTLs)infiltration,reversing an immunosuppressive tumor microenvironment to an immunoresponsive one.Treatment with the nanosystem in combination with anti-PD-L1 antibody results in distinctive inhibition of tumor growth and lung metastasis,supporting that a potent ICD effect can significantly boost the therapeutic efficacy of the anti-PD-L1 antibody.This self-amplified biomimetic nanoplatform offers a promising means of raising the response rate of immune checkpoint inhibitors.

关键词： Cell membrane Biomimetic nanosystem Immunogenic cell death Immunotherapy anti-PD-L1 antibody

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Pre-coronavirus disease 2019 brain structure might be associated with social anxiety alterations during the pandemic

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Chinese Medical Journal 2023年第13期136卷 1621-1623页

作者： Xun Zhang Qingyuan Li Xun Yang Nanfang Pan Xueling Suo Min He Song Wang Graham JKemp qiyong gong Huaxi Magnetic Resonance Research Center(HMRRC) Department of RadiologyWest China Hospital of Sichuan UniversityChengduSichuan 610041China Functional and Molecular Imaging Key Laboratory of Sichuan Province West China Hospital of Sichuan UniversityChengduSichuan 610041China Research Unit of Psychoradiology Chinese Academy of Medical SciencesChengduSichuan 610041China Department of Interventional Therapy Cancer Hospital of Chinese Academy of Medical Sciences and Peking Union Medical CollegeNational Cancer CenterNational Clinical Research Center for CancerBeijing 100021China School of Public Affairs Chongqing UniversityChongqing 400044China Liverpool Magnetic Resonance Imaging Centre(LiMRIC)and Institute of Life Course and Medical Sciences University of LiverpoolLiverpool L693BXUK Department of Radiology West China Xiamen Hospital of Sichuan UniversityXiamenFujian 361000China

To the Editor:As the novel coronavirus disease 2019(COVID-19)pandemic rapidly spreads around the world,it has resulted in unprecedented economic loss,social turmoil,and detrimental effects on public mental health.In particular,the implementation of disease control measures such as nationwide lockdowns,social distancing,school closures,and home quarantine has given rise to a wide range of social anxiety(SA)around the world,from nonclinical manifestations to clinical social anxiety disorder(SAD).[1]Given the potentially severe impairments from SA and the limited mental health care resources,it is vital to identify whether there are vulnerability/risk neuropsychological factors contributing to the progression of SA during the pandemic.

关键词： alterations nationwide closure

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Polymeric dual-modal imaging nanoprobe with two-photon aggregation-induced emission for fluorescence imaging and gadolinium-chelation for magnetic resonance imaging

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Bioactive Materials 2023年第1期19卷 538-549页

作者： Xueyang Xiao Hao Cai Qiaorong Huang Bing Wang Xiaoming Wang Qiang Luo Yinggang Li Hu Zhang qiyong gong Xuelei Ma Zhongwei Gu Kui Luo Department of Radiology Department of BiotherapyHuaxi MR Research Center(HMRRC)Laboratory of Stem Cell BiologyCancer CenterDepartment of UltrasoundNational Clinical Research Center for GeriatricsFrontiers Science Center for Disease-Related Molecular NetworkState Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu610041China Functional and Molecular Imaging Key Laboratory of Sichuan Province Research Unit of PsychoradiologyChinese Academy of Medical SciencesChengdu610041China Amgen Bioprocessing Centre Keck Graduate InstituteCA91711USA

Nanoprobes that offer both fluorescence imaging(FI)and magnetic resonance imaging(MRI)can provide supplementary information and hold synergistic advantages.However,synthesis of such dual-modality imaging probes that simultaneously exhibit tunability of functional groups,high stability,great biocompatibility and desired dual-modality imaging results remains challenging.In this study,we used an amphiphilic block polymer from(ethylene glycol)methyl ether methacrylate(OEGMA)and N-(2-hydroxypropyl)methacrylamide(HPMA)derivatives as a carrier to conjugate a MR contrast agent,Gd-DOTA,and a two-photon fluorophore with an aggregation-induced emission(AIE)effect,TPBP,to construct a MR/two-photon fluorescence dual-modality contrast agent,Gd-DOTA-TPBP.Incorporation of gadolinium in the hydrophilic chain segment of the OEGMA-based carrier resulted in a high r_(1)value for Gd-DOTA-TPBP,revealing a great MR imaging resolution.The contrast agent specifically accumulated in the tumor region,allowing a long enhancement duration for vascular and tumor contrast-enhanced MR imaging.Meanwhile,coupling TPBP with AIE properties to the hydrophobic chain segment of the carrier not only improved its water solubility and reduced its cytotoxicity,but also significantly enhanced its imaging performance in an aqueous phase.Gd-DOTA-TPBP was also demonstrated to act as an excellent fluorescence probe for two-photon-excited bioimaging with higher resolution and greater sensitivity than MRI.Since high-resolution,complementary MRI/FI dual-modal images were acquired at both cellular and tissue levels in tumor-bearing mice after application of Gd-DOTA-TPBP,it has great potential in the early phase of disease diagnosis.

关键词： RAFT polymerization Amphiphilic block polymers Magnetic resonance/fluorescence dual-modal imaging Tumor/vascular imaging Two-photon AIE fluorescent contrast agent

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Translational application of neuroimaging in major depressive disorder:a review of psychoradiological studies

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Frontiers of Medicine 2021年第4期15卷 528-540页

作者： Ziqi Chen Xiaoqi Huang qiyong gong Bharat B.Biswal Huaxi MR Research Center(HMRRC) Department of RadiologyWest China Hospital of Sichuan UniversityChengdu 610041China Research Unit of Psychoradiology.Chinese Academy of Medical Sciences Chengdu 610041China Functional and Molecular Imaging Key Laboratory of Sichuan Province Chengdu 610041China Department of Biomedical Engineering New Jersey Institute of TechnologyNewarkNJ 07102USA The Clinical Hospital of Chengdu Brain Science Institute MOE Key Lab for NeuroinformationUniversity of Electronic Science and Technology of ChinaChengdu 610054China

Major depressive disorder(MDD)causes great decrements in health and quality of life with increments in healthcare costs,but the causes and pathogenesis of depression remain largely unknown,which greatly prevent its early detection and effective treatment.With the advancement of neuroimaging approaches,numerous functional and structural alterations in the brain have been detected in MDD and more recently attempts have been made to apply these findings to clinical practice.In this review,we provide an updated summary of the progress in translational application of psychoradiological findings in MDD with a specified focus on potential clinical usage.The foreseeable clinical applications for different MRI modalities were introduced according to their role in disorder classification,subtyping,and prediction.While evidence of cerebral structural and functional changes associated with MDD classification and subtyping was heterogeneous and/or sparse,the ACC and hippocampus have been consistently suggested to be important biomarkers in predicting treatment selection and treatment response.These findings underlined the potential utility of brain biomarkers for clinical practice.

关键词： psychoradiology major depressive disorder MRI biomarker

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