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Combination of AAV-delivered tumor suppressor PTEN with anti-PD-1 loaded depot gel for enhanced antitumor immunity

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Acta Pharmaceutica Sinica B 2024年第1期14卷 350-364页

作者： Yongshun Zhang Lan Yang Yangsen Ou Rui Hu Guangsheng Du Shuang Luo Fuhua Wu Hairui Wang Zhiqiang Xie Yu Zhang Chunting He Cheng Ma Tao Gong Ling Zhang Zhirong Zhang Xun Sun key laboratory of drug-targeting and drug delivery system of the education ministry and sichuan Province Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial TechnologyWest China School of PharmacySichuan UniversityChengdu 610041China Med-X center for Materials College of Polymer Science and EngineeringSichuan UniversityChengdu 610065China

Recent clinical studies have shown that mutation of phosphatase and tensin homolog deleted on chromosome 10(PTEN)gene in cancer cells may be associated with immunosuppressive tumor microenvironment(TME)and poor response to immune checkpoint blockade(ICB)therapy.Therefore,efficiently restoring PTEN gene expression in cancer cells is critical to improving the responding rate to ICB therapy.Here,we screened an adeno-associated virus(AAV)capsid for efficient PTEN gene delivery into B16F10 tumor cells.We demonstrated that intratumorally injected AAV6-PTEN successfully restored the tumor cell PTEN gene expression and effectively inhibited tumor progression by inducing tumor cell immunogenic cell death(ICD)and increasing immune cell infiltration.Moreover,we developed an anti-PD-1 loaded phospholipid-based phase separation gel(PPSG),which formed an in situ depot and sustainably release anti-PD-1 drugs within 42 days in vivo.In order to effectively inhibit the recurrence of melanoma,we further applied a triple therapy based on AAV6-PTEN,PPSG^(@anti-PD-1)and CpG,and showed that this triple therapy strategy enhanced the synergistic antitumor immune effect and also induced robust immune memory,which completely rejected tumor recurrence.We anticipate that this triple therapy could be used as a new tumor combination therapy with stronger immune activation capacity and tumor inhibition efficacy.

关键词： Triple therapy Adeno-associated virus PTEN PPSG@anti-PD-1 CpG Immunogenic cell death Antitumor immune response Immune memory

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Cooperative NHC/Photoredox Catalysis:Three-Component Reaction of Aroyl Fluorides,Styrenes and Oxalates

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Chinese Journal of Chemistry 2024年第5期42卷 511-515页

作者： Zheng Lin Guanghui Lv Jianghong Liu Jiangyan Tang Binsong Mu Jian Chen Tianle Huang Zhongzhen Yang Yong Wu key laboratory of drug-targeting and drug delivery system of the education ministry and sichuan Province Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial TechnologyWest China School of PharmacySichuan UniversityChengduSichuan610041 China Department of Pharmacy Hubei Provincial Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem CellsTaihe HospitalHubei University of MedicineShiyanHubei442000 China

Cooperative NHC/photoredox catalysis has emerged as an important research field in recent years.Herein,this article describes the use of cesium salt derivatives of tert-alcohols as alkyl radical precursors in a three-component reaction with styrene and aromatic acyl fluorides to synthesizeα-arylalkyl aryl ketones.The aroyl fluoride reacts with the NHC catalyst,leading to the formation of an acyl azolium ion.This acyl azolium ion can then be reduced by the photoredox catalyst,generating the corresponding ketyl radical anion.The C-radical generated from oxalate oxidation undergoes an addition reaction with the styrene derivative,followed by cross-coupling of the addition radical with the ketone radical,which is fragmented by NHC to give the target ketone.

关键词： Three-component Photoredox NHC Aryl ketones Iridium Radical C—C coupling Amides

Metochalcone induces senescence-associated secretory phenotype via JAK2/STAT3 pathway in breast cancer

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Oncology research 2024年第5期32卷 943-953页

作者： JIANBO ZHOU FENG WAN BIN XIAO XIN LI CHENG PENG FU PENG Department of Pharmacology West China School of PharmacySichuan UniversityChengduChina State key laboratory of Southwestern Chinese Medicine Resources Chengdu University of Traditional Chinese MedicineChengduChina key laboratory of drug-targeting and drug delivery system of the education ministry Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial TechnologySichuan UniversityChengduChina Chengdu No.1 Pharmaceutical Co. Ltd.PengzhouChina Chengdu Push Bio-technology Co. Ltd.ChengduChina

Breast and lung cancers are the leading causes of mortality and most frequently diagnosed cancers in women and men,respectively,worldwide.Although the antitumor activity of chalcones has been extensively studied,the molecular mechanisms of isoliquiritigenin analog 2',4',4-trihydroxychalcone(metochalcone;TEC)against carcinomas remain less well understood.In this study,we found that TEC inhibited cell proliferation of breast cancer BT549 cells and lung cancer A549 cells in a concentration-dependent manner.TEC induced cell cycle arrest in the S-phase,cell migration inhibition in vitro,and reduced tumor growth in vivo.Moreover,transcriptomic analysis revealed that TEC modulated the activity of the JAK2/STAT3 and P53 pathways.TEC triggered the senescence-associated secretory phenotype(SASP)by repressing the JAK2/STAT3 axis.The mechanism of metochalcone against breast cancer depended on the induction of SASP via deactivation of the JAK2/STAT3 pathway,highlighting the potential of chalcone in senescence-inducing therapy against carcinomas.

关键词： Metochalcone Breast cancer Lung cancer SASP JAK2/STAT3

Pathological BBB Crossing Melanin-Like Nanoparticles as Metal-Ion Chelators and Neuroinflammation Regulators against Alzheimer’s Disease

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research 2024年第1期6卷 687-706页

作者： Qianqian Huang Chaoqing Jiang Xue Xia Yufan Wang Chenxing Yan Xiaorong Wang Ting Lei Xiaotong Yang Wenqin Yang Guo Cheng Huile Gao key laboratory of drug-targeting and drug delivery system of the education ministry West China School of PharmacySichuan UniversityChengdu 610041P.R.China laboratory of Molecular Translational Medicine Center for Translational MedicineKey Laboratory of Birth Defects and Related Diseases of Women and Children(Sichuan University)Ministry of EducationDepartment of PediatricsWest China Second University HospitalSichuan UniversityChengdu 610041P.R.China

Inflammatory responses,manifested in excessive oxidative stress and microglia overactivation,together with metal ion-triggered amyloid-beta(Aβ)deposition,are critical hallmarks of Alzheimer’s disease(AD).The intricate pathogenesis causes severe impairment of neurons,which,in turn,exacerbates Aβaggregation and facilitates AD progression.Herein,multifunctional melanin-like metal ion chelators and neuroinflammation regulators(named PDA@K)were constructed for targeted treatment of AD.In this platform,intrinsically bioactive material polydopamine nanoparticles(PDA)with potent metal ion chelating and ROS scavenging effects were decorated with the KLVFF peptide,endowing the system with the capacity of enhanced pathological blood–brain barrier(BBB)crossing and lesion site accumulation via Aβhitchhiking.In vitro and in vivo experiment revealed that PDA@K had high affinity toward Aβand were able to hitch a ride on Aβto achieve increased pathological BBB crossing.The engineered PDA@K effectively mitigated Aβaggregate and alleviated neuroinflammation.

关键词： oxidative aggregation chelating

Rh(Ⅱ)catalyzed efficient sigmatropic rearrangement reaction of pyridotriazoles and sulfides

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Green Synthesis and Catalysis

Green Synthesis and Catalysis 2024年第2期5卷 77-79页

作者： Yuting Chen Guanghui Lv Zhiyang Li Meiling Ye Tianle Huang Li Hai Yong Wu key laboratory of drug-targeting and drug delivery system of the education ministry and sichuan Province Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial TechnologyWest China School of PharmacySichuan UniversityChengdu610041China Department of Pharmacy Taihe HospitalHubei University of MedicineShiyan442000China

The[2,3]-and[1,2]-sigmatropic rearrangement reactions between pyridotriazoles and sulfides catalyzed by rhodium(II)were investigated.The utilization of pyridotriazoles as the carbene precursors in this kind of reaction efficiently constructed the C(sp3)-S and C(sp3)-Se bond with broad substrate scope and great functional group tolerance.

关键词： Pyridotriazole Sulfide -Sigmatropic rearrangement -Sigmatropic rearrangement Rhodium catalysis

Mild construction of N-fused polycyclic compounds via Rh(Ⅲ)/EosinY co-catalyze C—H activation

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Green Synthesis and Catalysis

Green Synthesis and Catalysis 2024年第2期5卷 108-111页

作者： Zhouping Wu Guanghui Lv Zheng Lin Jiangyan Tang Jian Chen Jianghong Liu Li Hai Yong Wu key laboratory of drug-targeting and drug delivery system of the education ministry and sichuan Province Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial TechnologyWest China School of PharmacySichuan UniversityChengdu 610041China Department of Pharmacy Taihe HospitalHubei University of MedicineNo.32 South Renmin RoadShiyan 442000China

The construction of N-fused polycyclic compounds at room temperature via the combination of transition-metal catalyst and photocatalyst has been reported.This novel work has successfully realized LED irradiated C—H activation of iodonium ylides.The strategy shows wide substrate scope and ideal functional group tolerance.Our work would be useful for the construction of various heterocyclic compounds.

关键词： N-fused polycyclic compounds C—H activation Rh(Ⅲ)catalyst and photocatalyst Iodonium ylides Energy transfer process

Insights and implications of sexual dimorphism in osteoporosis

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Bone research 2024年第1期12卷 20-49页

作者： Yuan-Yuan Zhang Na Xie Xiao-Dong Sun Edouard C.Nice Yih-Cherng Liou Canhua Huang Huili Zhu Zhisen Shen key laboratory of drug-targeting and drug delivery system of the education ministry and sichuan Province Sichuan Research Center for Drug Precision Industrial TechnologyWest China School of PharmacySichuan UniversityChengdu 610041China West China School of Basic Medical Sciences&Forensic Medicine Sichuan UniversityChengdu 610041China Department of Biochemistry and Molecular Biology Monash UniversityClaytonVIC 3800Australia Department of Biological Sciences Faculty of ScienceNational University of SingaporeSingapore 117543Republic of Singapore Department of Biotherapy Cancer Center and State Key Laboratory of BiotherapyWest China Hospitaland West China School of Basic Medical Sciences&Forensic MedicineSichuan UniversityChengdu 610041China key laboratory of Birth Defects and Related Diseases of Women and Children of ministry of education Department of Reproductive MedicineWest China Second University Hospital of Sichuan UniversityChengduChina Department of Otorhinolaryngology and Head and Neck Surgery The Affiliated Lihuili HospitalNingbo University315040 NingboZhejiangChina

Osteoporosis,a metabolic bone disease characterized by low bone mineral density and deterioration of bone microarchitecture,has led to a high risk of fatal osteoporotic fractures worldwide.Accumulating evidence has revealed that sexual dimorphism is a notable feature of osteoporosis,with sex-specific differences in epidemiology and pathogenesis.Specifically,females are more susceptible than males to osteoporosis,while males are more prone to disability or death from the disease.To date,sex chromosome abnormalities and steroid hormones have been proven to contribute greatly to sexual dimorphism in osteoporosis by regulating the functions of bone cells.Understanding the sex-specific differences in osteoporosis and its related complications is essential for improving treatment strategies tailored to women and men.This literature review focuses on the mechanisms underlying sexual dimorphism in osteoporosis,mainly in a population of aging patients,chronic glucocorticoid administration,and diabetes.Moreover,we highlight the implications of sexual dimorphism for developing therapeutics and preventive strategies and screening approaches tailored to women and men.Additionally,the challenges in translating bench research to bedside treatments and future directions to overcome these obstacles will be discussed.

关键词： osteoporosis epidemiology overcome

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Evolving landscape of treatments targeting the microenvironment of liver metastases in non-small cell lung cancer

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中华医学杂志(英文版) 2024年第9期137卷 1019-1032页

作者： Zhu Lingling Yu Xianzhe Tang Xiaojun Hu Chenggong Wu Lei Liu Yanyang Zhou Qinghua Lung Cancer center Lung Cancer Institute West China Hospital Sichuan University Chengdu Sichuan China key laboratory of drug targeting and drug delivery systems Ministry of Education West China School of Pharmacy College of Polymer Science and Engineering Sichuan University Chengdu Sichuan China Department of Gastrointestinal Surgery Chengdu Second People’s Hospital Chengdu Sichuan China Department of Critical Care Medicine West China Hospital Sichuan University Chengdu Sichuan China Core Facility of West China Hospital Sichuan University Chengdu Sichuan China Department of Medical Oncology Cancer Center West China Hospital Sichuan University Chengdu Sichuan China

Liver metastases (LMs) are common in lung cancer. Despite substantial advances in diagnosis and treatment, the survival rate of patients with LM remains low as the immune-suppressive microenvironment of the liver allows tumor cells to evade the immune system. The impact of LMs on the outcomes of immune checkpoint inhibitors in patients with solid tumors has been the main focus of recent translational and clinical research. Growing evidence indicates that the hepatic microenvironment delivers paracrine and autocrine signals from non-parenchymal and parenchymal cells. Overall, these microenvironments create pre- and post-metastatic conditions for the progression of LMs. Herein, we reviewed the epidemiology, physiology, pathology and immunology, of LMs associated with non-small cell lung cancer and the role and potential targets of the liver microenvironment in LM in each phase of metastasis. Additionally, we reviewed the current treatment strategies and challenges that should be overcome in preclinical and clinical investigations. These approaches target liver elements as the basis for future clinical trials, including combinatorial interventions reported to resolve hepatic immune suppression, such as immunotherapy plus chemotherapy, immunotherapy plus radiotherapy, immunotherapy plus anti-angiogenesis therapy, and surgical resection.

关键词： Non-small cell lung cancer Liver metastasis Combination therapy Immune checkpoint inhibitors Immune tolerance Immunotherapy

Ceria nanoparticles: biomedical applications and toxicity

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2024年第5期25卷 361-388页

作者： Xiaoxuan FU Peng LI Xi CHEN Yuanyuan MA Rong WANG Wenxuan JI Jiakuo GU Bowen SHENG Yizhou WANG Zhuhong ZHANG School of Pharmacy Key Laboratory of Molecular Pharmacology and Drug Evaluation(Yantai University)Ministry of EducationCollaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of ShandongYantai UniversityYantai 264005China Department of Nephrology Yantai Yuhuangding HospitalQingdao UniversityYantai 264005China Institute of Crop Science College of Agriculture and BiotechnologyZhejiang UniversityHangzhou 310058China

Ceria nanoparticles(CeO_(2) NPs)have become popular materials in biomedical and industrial fields due to their potential applications in anti-oxidation,cancer therapy,photocatalytic degradation of pollutants,sensors,etc.Many methods,including gas phase,solid phase,liquid phase,and the newly proposed green synthesis method,have been reported for the synthesis of CeO_(2) NPs.Due to the wide application of CeO_(2) NPs,concerns about their adverse impacts on human health have been raised.This review covers recent studies on the biomedical applications of CeO_(2) NPs,including their use in the treatment of various diseases(e.g.,Alzheimer's disease,ischemic stroke,retinal damage,chronic inflammation,and cancer).CeO_(2) NP toxicity is discussed in terms of the different systems of the human body(e.g.,cytotoxicity,genotoxicity,respiratory toxicity,neurotoxicity,and hepatotoxicity).This comprehensive review covers both fundamental discoveries and exploratory progress in CeO_(2) NP research that may lead to practical developments in the future.

关键词： Ceria nanoparticle Synthetic method Biomedical application Oxidative stress Toxicity