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

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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Anti-osteosarcoma trimodal synergistic therapy using NiFe-LDH and MXene nanocomposite for enhanced biocompatibility and efficacy

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Acta Pharmaceutica Sinica B 2024年第3期14卷 1329-1344页

作者： Yani Xu Lan Yang Min Li Haozhou Shu Na Jia Yunzhen Gao Rongying Shi Xiaojia Yang Zhirong Zhang Ling Zhang key laboratory of drug-targeting and drug delivery system of the education ministry West China School of PharmacySichuan UniversityChengdu 610041China Med-X Center for Materials College of Polymer Science and EngineeringSichuan UniversityChengdu 610065China

Osteosarcoma is usually resistant to immunotherapy and,thus primarily relies on surgical resection and high-dosage chemotherapy.Unfortunately,less invasive or toxic therapies such as photothermal therapy(PTT)and chemodynamic therapy(CDT)generally failed to show satisfactory outcomes.Adequate multimodal therapies with proper safety profiles may provide better solutions for osteosarcoma.Herein,a simple nanocomposite that synergistically combines CDT,PTT,and chemotherapy for osteosarcoma treatment was fabricated.In this composite,small 2D Ni Fe-LDH flakes were processed into 3D hollow nanospheres via template methods to encapsulate 5-Fluorouracil(5-FU)with high loading capacity.The nanospheres were then adsorbed onto larger 2D Ti3C2MXene monolayers and finally shielded by bovine serum albumin(BSA)to form 5-FU@Ni Fe-LDH/Ti3C2/BSA nanoplatforms(5NiTiB).Both in vitro and in vivo data demonstrated that the 5-FU induced chemotherapy,Ni Fe-LDH driven chemodynamic effects,and MXene-based photothermal killing collectively exhibited a synergistic“all-in-one”anti-tumor effect.5NiTiB improved tumor suppression rate from<5%by 5-FU alone to~80.1%.This nanotherapeutic platform achieved higher therapeutic efficacy with a lower agent dose,thereby minimizing side effects.Moreover,the composite is simple to produce,enabling the fine-tuning of dosages to suit different requirements.Thus,the platform is versatile and efficient,with potential for further development.

关键词： Osteosarcoma NiFe-LDH MXene Chemodynamic therapy Photothermal therapy Chemotherapy 5-Fluorouracil Nanocomposite

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Rhodium-catalyzed Doyle-Kirmse rearrangement reactions of sulfoxoniun ylides

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Chinese Chemical Letters 2024年第4期35卷 363-366页

作者： Ying-Di Hao Zhi-Qian Lin Xiao-Yu Guo Jiao Liang Can-Kun Luo Qian-Tao Wang Li Guo Yong Wu key laboratory of drug-targeting and drug delivery system of the education ministry and Department of Medicinal Chemistry Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial TechnologyWest China School of PharmacySichuan UniversityChengdu 610041China

Doyle-Kirmse rearrangement reactions have received continuous attention as an important method for constructing complex chemical structures. Herein, we disclosed an efficient rhodium-catalyzed DoyleKirmse rearrangement reaction, which can simultaneously construct C–C bonds and C–X(X = S/Se) bonds using sulfoxonium ylides as starting materials to obtain sulfur-or selenium-containing compounds. This strategy is characterized by the safer and greener carbene precursor, high yields and broad substrate scope, possessing a wide range of application.

关键词： Sulfoxonium ylides Rhodium(Ⅱ)-catalyzed Carbene Rearrangement reactions One-pot process

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A pH/ROS dual-responsive system for effective chemoimmunotherapy against melanoma via remodeling tumor immune microenvironment

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Acta Pharmaceutica Sinica B 2024年第5期14卷 2263-2280页

作者： Leilei Wang Shanshan He Rong Liu Yuan Xue Yuan Quan Rongying Shi Xueying Yang Qing Lin Xun Sun Zhirong Zhang Ling Zhang key laboratory of drug-targeting and drug delivery system of the education ministry West China School of PharmacySichuan UniversityChengdu 610041China Med-X Center for Materials College of Polymer Science and EngineeringSichuan UniversityChengdu 610065China

Chemotherapeutics can induce immunogenic cell death(ICD)in tumor cells,offering new possibilities for cancer therapy.However,the efficiency of the immune response generated is insufficient due to the inhibitory nature of the tumor microenvironment(TME).Here,we developed a pH/reactive oxygen species(ROS)dual-response system to enhance chemoimmunotherapy for melanoma.The system productively accumulated in tumors by specific binding of phenylboronic acid(PBA)to sialic acids(SA).The nanoparticles(NPs)rapidly swelled and released quercetin(QUE)and doxorubicin(DOX)upon the stimulation of tumor microenvironment(TME).The in vitro and in vivo results consistently demonstrated that the NPs improved anti-tumor efficacy and prolonged survival of mice,significantly enhancing the effects of the combination.Our study revealed DOX was an ICD inducer,stimulating immune responses and promoting maturation of dendritic cells(DCs).Additionally,QUE served as a TME regulator by inhibiting the cyclooxygenase-2(COX2)-prostaglandin E2(PGE2)axis,which influenced various immune cells,including increasing cytotoxic T cells(CLTs)infiltration,promoting M1 macrophage polarization,and reducing regulatory T cells(Tregs)infiltration.The combination synergistically facilitated chemoimmunotherapy efficacy by remodeling the immunosuppressive microenvironment.This work presents a promising strategy to increase anti-tumor efficiency of chemotherapeutic agents.

关键词： Quercetin Nanoparticle Responsiveness Chemoimmunotherapy Tumor immune microenvironment

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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

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Macrocyclic peptides:up-and-coming weapons to combat antimicrobial resistance

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Signal Transduction and Targeted Therapy 2024年第5期9卷 1786-1787页

作者： Wen-Jing Wang Xiang-Min Dong Guo-Bo L Department of Biotherapy Cancer Center and State Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengduSichuanChina key laboratory of drug targeting and drug delivery system of ministry of education Department of Medicinal ChemistryWest China School of PharmacySichuan UniversityChengduSichuanChina

Recently,two companion papers published in Nature reported a first-in-class tethered macrocyclic peptide antibiotic targeting carbapenem-resistant A.baumannii(CRAB)and unveiled their unique antibacterial mechanism,whi... 详细信息

关键词： outer macrocyclic Macrocyclic

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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

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Dual-responsive supramolecular photodynamic nanomedicine with activatable immunomodulation for enhanced antitumor therapy

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Acta Pharmaceutica Sinica B 2024年第2期14卷 765-780页

作者： Siqin He Lulu Wang Dongxu Wu Fan Tong Huan Zhao Hanmei Li Tao Gong Huile Gao Yang Zhou key laboratory of Tropical Biological Resources of ministry of education School of Pharmaceutical SciencesHainan UniversityHaikou 570200China key laboratory of drug-targeting and drug delivery system West China School of PharmacySichuan UniversityChengdu 610041China Revvity Inc. WalthamMA 02451USA School of Food and Biological Engineering Chengdu UniversityChengdu 610106China

A major challenge facing photodynamic therapy(PDT) is that the activity of the immuneinduced infiltrating CD8^(+)T cells is subject to the regulatory T lymphocytes(Tregs), leaving the tumor at risk of recurrence and metastasis after the initial ablation. To augment the antitumor response and reprogram the immunosuppressive tumor microenvironment(TME), a supramolecular photodynamic nanoparticle(DACss) is constructed by the host-guest interaction between demethylcantharidin-conjugated β-cyclodextrin(DMC-CD) and amantadine-terminated disulfide-conjugated FFVLGGGC peptide with chlorin e6 decoration(Ad-ss-pep-Ce6) to achieve intelligent delivery of photosensitizer and immunomodulator for breast cancer treatment. The acid-labile β-carboxamide bond of DMC-CD is hydrolyzed in response to the acidic TME, resulting in the localized release of DMC and subsequent inhibition of Tregs.The guest molecule Ad-ss-pep-Ce6 can be cleaved by a high level of intracellular GSH, reducing photosensitizer toxicity and increasing photosensitizer retention in the tumor. With a significant increase in the CTL/Treg ratio, the combination of Ce6-based PDT and DMC-mediated immunomodulation adequately achieved spatiotemporal regulation and remodeling of the TME, as well as improved primary tumor and in situ lung metastasis suppression with the aid of PD-1 antibody.

关键词： Photodynamic therapy Immunosuppressive microenvironment Immunomodulator Dual-responsive Supramolecularassembly Checkpointblockade

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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

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

Green Synthesis and Catalysis

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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

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