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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)***,efficiently restoring PTEN gene expression in cancer cells is critical to improving the responding rate to ICB ***,we screened an adeno-associated virus(AAV)capsid for efficient PTEN gene delivery into B16F10 tumor *** 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 ***,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 *** 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 *** 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

JW-1-283 inhibits melanoma tumor growth via stabilization of the p53 pathway

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Genes & Diseases 2024年第3期11卷 18-21页

作者： Yang Xie Ruida Hou Kelli LHartman Jianxiong Jiang Zhongzhi Wu Wei Li drug Discovery center College of PharmacyUniversity of Tennessee Health Science CenterMemphisTN38163USA

Melanoma is a lethal skin malignancy and the fifth most diagnosed cancer in the United States.1 Currently,for unresectable melanoma,the recommended treatment options include checkpoint inhibitor immunotherapy targeting programmed cell death 1(PD-1),and inhibitors targeting the mitogen-activated protein kinase(MAPK)***,the response rate may vary among the patients,and therefore demanding the development of novel treatment *** suppressor TP53has been suggested as one of the critical regulators mediating the aggressiveness and progression of melanoma.

关键词： melanoma suppressor death

Multicomponent remote C(sp^(2))–H bond addition by Ru catalysis:An efficient access to the alkylarylation of 2H-imidazoles

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Chinese Chemical Letters 2024年第10期35卷 257-261页

作者： Yi Luo Lin Dong 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

Sequential C–H bond addition with two different coupling partners is a powerful method for the rapid and modular construction of complex molecules based on simple starting ***,an efficient ruthenium-catalysed multicomponent long-range C–H functionalization of 2H-imidazoles was *** protocol showed good substrate suitability and yielded alkyl arylation products with potential biological activity.

关键词： Remote C-H functionalization Multi-component reaction Ruthenium catalysis 2H-Imidazoles

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

Enzyme-activatable disk-shaped nanocarriers augment tumor permeability for breast cancer combination therapy

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Nano Research 2024年第7期17卷 6400-6410页

作者： Hanming Zhang Honglin Gao Yicong Zhang Yikun Han Qing Lin Tao Gong Xun Sun Zhirong Zhang Ling Zhang Shiqi Huang 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

Unique physiopathological characteristics of tumor tissues impose obstacles to the sufficient penetration of traditional nanomedicines,resulting in undesirable drug delivery efficacy and therapeutic ***,we constructed TRAIL-[NDHCPT]^(GAC),a synergistic hydroxycamptothecin(HCPT)and tumor necrosis factor-related apoptosis-inducing ligand(TRAIL)protein co-loaded disk-shaped nanocarrier withγ-glutamyl transpeptidase *** the novel nanodisks extravasated into the tumor interstitium,theγ-glutamyl transpeptidase overexpressed on the tumor cell membranes cleaved theγ-glutamyl portions of the nanodisk surface to produce positively charged amino *** a result,the cationic nanodisks possessed stronger tumor infiltration ability through transcytosis than anionic *** and TRAIL exerted synergistic antitumor effects with better overall therapeutic *** TRAIL-[ND-HCPT]^(GAC)system performed significantly better than free HCPT and remarkably prolonged the survival of breast tumor-bearing mice with no significant toxicity.

关键词： tumor penetration combination therapy charge reversal γ-glutamyl transpeptidase nanodisk

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 ***,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 *** aroyl fluoride reacts with the NHC catalyst,leading to the formation of an acyl azolium *** acyl azolium ion can then be reduced by the photoredox catalyst,generating the corresponding ketyl radical *** 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

Bacterial and cancerous cell membrane fused liposome coordinates with PD-L1 inhibitor for cancer immunotherapy

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Nano Research 2024年第9期17卷 8389-8401页

作者： Xianjin Luo Chenglong Li Zhaofei Guo Hairui Wang Penghui He Yuanhao Zhao Yi Lin Chunting He Yingying Hou Yongshun Zhang Guangsheng Du 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 610064China Pharmaceutical Biotechnology Department of PharmacyLMU MunichButenandt Strasse 5-13Munich 81377Germany Department of Biomedical Engineering College of Future TechnologyPeking UniversityBeijing 100871China

Although tumor cell membranes with broad-spectrum antigens have been explored for cancer vaccines for decades,their relatively poor capacity to stimulate immune responses,especially cellular immune responses,has limited their ***,we presented a novel bacterial and cancerous cell membrane fusogenic liposome for co-delivering cell membrane-derived antigens and ***,a programmed death-ligand 1(PD-L1)inhibitor,JQ-1,was incorporated into the formulation to tackle the up-regulated PD-L1 expression of antigen-presenting cells(APCs)upon vaccination,thereby augmenting its anti-tumor *** fusogenic liposomes demonstrated significantly improved cellular uptake by APCs and effectively suppressed PD-L1 expression in bone marrow-derived dendritic cells(BMDCs)in *** subcutaneous vaccination,the nano-vaccines efficiently drained to the tumor-draining lymph nodes(TDLNs),and significantly inhibited PD-L1 expression of both dendritic cells(DCs)and macrophages within the TDLNs and *** a result,the liposomal vaccine induced robust innate and cellular immune responses and inhibited tumor growth in a colorectal carcinoma-burden mouse *** summary,the fabricated cell membrane-based fusogenic liposomes offer a safe,effective,and easily applicable strategy for tumor immunotherapy and hold potential for personalized cancer immunotherapy.

关键词： fusogenic liposome tumor cell membrane adjuvant programmed death-ligand 1(PD-L1)inhibitor tumor draining lymph nodes

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 ***,less invasive or toxic therapies such as photothermal therapy(PTT)and chemodynamic therapy(CDT)generally failed to show satisfactory *** multimodal therapies with proper safety profiles may provide better solutions for ***,a simple nanocomposite that synergistically combines CDT,PTT,and chemotherapy for osteosarcoma treatment was *** 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 *** 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 ***,the composite is simple to produce,enabling the fine-tuning of dosages to suit different ***,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

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 ***,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 *** 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 *** 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)*** combination synergistically facilitated chemoimmunotherapy efficacy by remodeling the immunosuppressive *** work presents a promising strategy to increase anti-tumor efficiency of chemotherapeutic agents.

关键词： Quercetin Nanoparticle Responsiveness Chemoimmunotherapy Tumor immune microenvironment