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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)***,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

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Combination losartan with hyaluronic acid modified diethyldithiocarbamate loaded hollow copper sulfide nanoparticles for the treatment of breast cancer and metastasis

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Chinese Chemical Letters 2024年第3期35卷 406-414页

作者： Haili Hu Weiwei Zhang Lei Lei Fan Tong Huilin Zhang Yiwei Zhang Wenqin Yang Yilu Tang Ruyi Lin Xue Xia Jiamei Li Shiyong Song Huile Gao key laboratory of drug Targeting and drug delivery Systems West China School of PharmacySichuan UniversityChengdu 610041China School of Pharmacy Henan UniversityKaifeng 475004China Department of Public Health Chengdu Medical CollegeChengdu 610500China

The application of photothermal therapy(PTT)is greatly limited by the low accumulation of photothermal agents,uneven photothermal distribution,and heat endurance of cancer *** still,despite PTT enhances immunogenicity,the anti-tumor immune efficacy is still unsatisfactory due to the inefficient immunogenic cell death(ICD)induction and poor infiltration of immune *** solve the above problems of PTT,we developed hyaluronic acid(HA)modified hollow copper sulfide nanoparticles encapsulating diethyldithiocarbamate(DDTC)to construct a breast tumor targeting and near infrared(NIR)photo-responsive drug delivery system(D-HCuS@HA),which further combined with losartan to improve the accumulation and penetration in the tumor *** irradiation,D-HCuS@HA realized enhanced PTT and released cytotoxic Cu(DDTC)_(2)to eliminate heat endurance tumor cells,thereby enhancing antitumor effect and inducing effective ***,the combination with losartan could remodel the tumor microenvironment,allowing more T cells to infiltrate into the tumor,and significantly inhibiting the occurrence and development of metastatic *** vitro/vivo results revealed the great potential of D-HCuS@HA combined with losartan,which provides a new paradigm for anti-tumor and anti-metastases.

关键词： Targeted drug delivery system Hollow copper sulfide nanoparticles Photothermal therapy Hyaluronic acid Breast cancer Anti-metastasis

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Click chemistry and natural products

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Chinese Journal of Natural Medicines 2024年第2期22卷 97-99页

作者： ZHANG Chen WU Jianbing ZHANG Yihua HUANG Zhangjian State key laboratory of Natural Medicines Jiangsu Key Laboratory of Drug Discovery for Metabolic DiseasesCenter of Drug DiscoveryChina Pharmaceutical UniversityNanjing 210009China State key laboratory of Pathogenesis Prevention and Treatment of High Incidence Diseases in Central AsiaXinjiang Key Laboratory of Natural Medicines Active Components and Drug Release TechnologySchool of PharmacyXinjiang Medical UniversityUrumqi 830054China

The 2022 Nobel Prize in Chemistry was awarded to American scientists Carolyn Bertozzi,*** Sharpless,and Danish scientist Morten *** for their contributions to the development of click chemistry and bioorthogonal chemi... 详细信息

关键词： Click chemistry Natural product Target identification drug discovery

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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 ***,multifunctional melanin-like metal ion chelators and neuroinflammation regulators(named PDA@K)were constructed for targeted treatment of *** 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 Aβ*** 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 *** engineered PDA@K effectively mitigated Aβaggregate and alleviated neuroinflammation.

关键词： oxidative aggregation chelating

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A Dynamic Covalent Bonding-based Nanoplatform for Intracellular Co-delivery of Protein drugs and Chemotherapeutics with Enhanced Anti-Cancer Effect

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Chinese Journal of Polymer Science 2024年第5期42卷 559-569,I0005页

作者： Sai-Nan Liu Jia-Hui Meng Li-Yun Cui Hua Chen Lin-Qi Shi Ru-Jiang Ma key laboratory of Functional Polymer Materials of Ministry of Education Institute of Polymer ChemistryTianjin Key Laboratory of Functional Polymer MaterialsState Key Laboratory of Medicinal Chemical BiologyFrontiers Science Center for New Organic MatterCollege of ChemistryNankai UniversityTianjin300071China Haihe laboratory of Sustainable Chemical Transformations Tianjin300192China

Efficient intracellular delivery of protein drugs is critical for protein *** combination of protein drugs with chemotherapeutics represents a promising strategy in enhancing anti-cancer ***,co-delivery systems for efficient delivery of these two kinds of drugs are still lacking because of their different ***,we show a well-designed delivery system based on dynamic covalent bond for efficient intracellular co-delivery of ribonuclease A(RNase A)and doxorubicin(DOX).Two polymers,PEG-b-P(Asp-co-AspDA)and PAE-b-P(Asp-co-AspPBA),and two 2-acetylphenylboronic acid(2-APBA)-functionalized drugs,2-APBA-RNase A and 2-APBA-DOX,self-assemble into mixed-shell nanoparticles(RNase A/DOX@MNPs)via dynamic phenylboronic acid(PBA)-catechol bond between PBA and dopamine(DA)*** PBA-catechol bond endows the nanoparticles with high stability and excellent stimulus-responsive drug release *** the slight acidic environment at tumor tissue,RNase A/DOX@MNPs are positively charged,promoting their *** cellular uptake into endosome,further protonation of PAE chains leads to the rupture of endosomes because of the proton sponge effect and the cleavage of PBA-catechol bond promotes the release of two *** cytoplasm,the high level of GSH removed the modification of 2-APBA on *** restored RNase A and DOX show a synergistic and enhanced antic-cancer *** system may be a promising platform for intracellular co-delivery of protein drugs and chemotherapeutics.

关键词： drug co-delivery Combination therapy Dynamic covalent bond

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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 *** 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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Gas-generating polymersomes-based amplified photoimmunotherapy for abscopal effect and tumor metastasis inhibition

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Chinese Chemical Letters 2024年第6期35卷 456-461页

作者： Chenlu Huang Xinyu Yang Qingyu Yu Linhua Zhang Dunwan Zhu tianjin key laboratory of Biomedical Materials Key Laboratory of Biomaterials and Nanotechnology for Cancer ImmunotherapyInstitute of Biomedical EngineeringChinese Academy of Medical Sciences&Peking Union Medical CollegeTianjin 300192China

Due to the heterogeneity of tumors,single phototherapy cannot completely ablate tumors and inhibit tumor *** overcome these,we formulated targeted and multifunctional polymersomes ABC@ICGIMQ-LHRH(AIRL)that encapsulated Toll-like receptor(TLR)7/8 agonist imiquimod(IMQ)and photosensitizer indocyanine green(ICG)in the hydrophobic layer as well as bubble-generator NH_(4)HCO_(3) in the hydrophilic cavity to inhibit the growth of primary and distant tumors,and prevent tumor metastasis through synergistic *** AIRL polymersomes exhibited uniform and stable size,and high drug encapsulation efficiency,acid/reduction/laser responsiveness,excellent photothermal conversion efficiency,effective reactive oxygen species generation,high tumor *** could be effectively internalized by dendritic cells(DCs),achieve lysosome escape and enhance DCs *** synergistic photoimmunotherapy via AIRL polymersomes remarkably promoted the differentiation and activation of T cells,elevated strong systemic immune response to eradicate primary tumors and inhibit the growth of distant ***,the endurable immunological memory prevented tumor metastasis,which provided a promising nanoplatform for the combination therapy of cancer.

关键词： Polymersomes Phototherapy Immunotherapy TLR 7/8 agonist Gas-generating

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Selective type II TRK inhibitors overcome xDFG mutation mediated acquired resistance to the second-generation inhibitors selitrectinib and repotrectinib

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Acta Pharmaceutica Sinica B 2024年第2期14卷 517-532页

作者： Shuang Xiang Xiaoyun Lu International Cooperative laboratory of Traditional Chinese Medicine Modernization and Innovative drug Discovery of Chinese Ministry of Education(MOE) Guangdong Provincial Key Laboratory of New Drug Design and EvaluationGuangzhou City Key Laboratory of Precision Chemical Drug DevelopmentSchool of PharmacyJinan UniversityGuangzhou 510632China

Neurotrophic receptor kinase(NTRK) fusions are actionable oncogenic drivers of multiple pediatric and adult solid tumors,and tropomyosin receptor kinase(TRK) has been considered as an attractive therapeutic target for "pan-cancer" harboring these ***,two generations TRK inhibitors have been *** representative second-generation inhibitors selitrectinib and repotrectinib were designed to overcome clinic acquired resistance of the first-generation inhibitors larotrectinib or entrectinib resulted from solvent-front and gatekeeper on-target ***,xDFG(TRKAG667C/A/S,homologous TRKCG696C/A/S) and some double mutations still confer resistance to selitrectinib and repotrectinib,and overcoming these resistances represents a major unmet clinical *** this review,we summarize the acquired resistance mechanism of the first-and second-generation TRK inhibitors,and firstly put forward the emerging selective type Ⅱ TRK inhibitors to overcome xDFG mutations mediated ***,we concluded our perspectives on new challenges and future directions in this field.

关键词： NTRK fusions TRK kinase Clinical resistance xDFG mutations Selective type II inhibitors

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Boosting synergism of chemo- and immunotherapies via switching paclitaxel-induced apoptosis to mevalonate metabolism-triggered ferroptosis by bisphosphonate coordination lipid nanogranules

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Acta Pharmaceutica Sinica B 2024年第2期14卷 836-853页

作者： Ge Song Minghui Li Shumin Fan Mengmeng Qin Bin Shao Wenbing Dai Hua Zhang Xueqing Wang Bing He Qiang Zhang Beijing key laboratory of Molecular Pharmaceutics and New drug delivery Systems School of Pharmaceutical SciencesPeking UniversityBeijing 100191China State key laboratory of Natural and Biomimetic drugs School of Pharmaceutical SciencesPeking UniversityBeijing 100191China Department of Medical Oncology Key Laboratory of Carcinogenesis and Translational Research(Ministry of Education)Peking University Cancer HospitalBeijing 100142China

Conventional chemotherapy based on cytotoxic drugs is facing tough challenges recently following the advances of monoclonal antibodies and molecularly targeted *** is critical to inspire new potential to remodel the value of this classical therapeutic ***,we fabricate bisphosphonate coordination lipid nanogranules(BC-LNPs)and load paclitaxel(PTX)to boost the chemo-and immuno-therapeutic synergism of cytotoxic *** in BC-LNPs@PTX,a bisphosphonate to block mevalonate metabolism,works as both the structure and drug constituent in nanogranules,where alendronate coordinated with calcium ions to form the particle *** synergy of alendronate enhances the efficacy of paclitaxel,suppresses tumor metastasis,and alters the cytotoxic *** from the paclitaxel-induced apoptosis,the involvement of alendronate inhibits the mevalonate metabolism,changes the mitochondrial morphology,disturbs the redox homeostasis,and causes theaccumulation of mitochondrial ROS and lethal lipid peroxides(LPO).These factors finally trigger the ferroptosis of tumor cells,an immunogenic cell death mode,which remodels the suppressive tumor immune microenvironment and synergizes with ***,by switching paclitaxel-induced apoptosis to mevalonate metabolism-triggered ferroptosis,BC-LNPs@PTX provides new insight into the development of cytotoxic drugs and highlights the potential of metabolism regulation in cancer therapy.

关键词： Bisphosphonate coordinationlipid nanogranules Ferroptosis Mevalonatemetabolism Mitochondrial metabolism Nano-systematic biology

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Inhalable metal–organic framework-mediated cuproptosis combined with PD-L1 checkpoint blockade for lung metastasis synergistic immunotherapy

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Acta Pharmaceutica Sinica B 2024年第5期14卷 2281-2297页

作者： Chongzheng Yan Ying Liu Guozhi Zhao Huatian Yang Huaiyou Lv Genju Li Yuhan Li Yaqing Fu Fengqin Sun Yafei Feng Yizhe Li Zhongxi Zhao Department of Pharmaceutics Key Laboratory of Chemical Biology of Ministry of EducationSchool of Pharmaceutical SciencesCheelloo College of MedicineShandong UniversityJinan 250012China key University laboratory of Pharmaceutics&drug delivery Systems of Shandong Province School of Pharmaceutical SciencesCheeloo College of MedicineShandong UniversityJinan 250012China

Cuproptosis shows enormous application prospects in lung metastasis ***,the glycolysis,Cu^(+)efflux mechanisms,and insufficient lung drug accumulation severely restrict cuproptosis ***,an inhalable poly(2-(N-oxide-N,N-diethylamino)ethyl methacrylate)(OPDEA)-coated copper-based metal–organic framework encapsulating pyruvate dehydrogenase kinase 1 siRNA(siPDK)is constructed for mediating cuproptosis and subsequently promoting lung metastasis immunotherapy,namely *** inhalation,OMP shows highly efficient lung accumulation and long-term retention,ascribing to the OPDEA-mediated pulmonary mucosa *** tumor cells,OMP is degraded to release Cu2+under acidic condition,which will be reduced to toxic Cu^(+)to induce cuproptosis under glutathione(GSH)***,siPDK released from OMP inhibits intracellular glycolysis and adenosine-5ʹ-triphosphate(ATP)production,then blocking the Cu^(+)efflux protein ATP7B,thereby rendering tumor cells more sensitive to OMP-mediated ***,OMP-mediated cuproptosis triggers immunogenic cell death(ICD)to promote dendritic cells(DCs)maturation and CD8^(+)T cells ***,OMP-induced cuproptosis up-regulates membrane-associated programmed cell death-ligand 1(PD-L1)expression and induces soluble PD-L1 secretion,and thus synergizes with anti-PD-L1 antibodies(aPD-L1)to reprogram immunosuppressive tumor microenvironment,finally yielding improved immunotherapy ***,OMP may serve as an efficient inhalable nanoplatform and afford preferable efficacy against lung metastasis through inducing cuproptosis and combining with aPD-L1.

关键词： Cuproptosis Immunogenic cell death PD-L1 checkpoint blockade Copper-based metal-organic framework Immunotherapy Tumor microenvironment Transmucosal deliveryLung metastasis

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