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Novel Pt(IV) complex OAP2 induces STING activation and pyroptosis via mitochondrial membrane remodeling for synergistic chemo-immunotherapy

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Acta Pharmaceutica Sinica B 2024年第4期14卷 1742-1758页

作者： Renming Fan Ruizhuo Lin Shuo Zhang Aohua Deng Yongrui Hai Junyan Zhuang Yang Liu Maosheng Cheng Gaofei Wei Institute of Medical Research Northwestern Polytechnical UniversityXi'an 710072China Research&Development Institute of Northwestern Polytechnical University in Shenzhen Shenzhen 518057China Key Laboratory of Structure-Based Drug Design and Discovery Ministry of EducationSchool of Pharmaceutical EngineeringShenyang Pharmaceutical UniversityShenyang 110016China

Mitochondrial membrane remodeling can trigger the release of mitochondrial DNA (mtDNA), leading to the activation of cellular oxidative stress and immune responses. While the role of mitochondrial membrane remodeling in promoting inflammation in hepatocytes is well-established, its effects on tumors have remained unclear. In this study, we designed a novel Pt(IV) complex, OAP2, which is composed of oxaliplatin (Oxa) and acetaminophen (APAP), to enhance its anti-tumor effects and amplify the immune response. Our findings demonstrate that OAP2 induces nuclear DNA damage, resulting in the production of nuclear DNA. Additionally, OAP2 downregulates the expression of mitochondrial Sam50, to promote mitochondrial membrane remodeling and trigger mtDNA secretion, leading to double-stranded DNA accumulation and ultimately synergistically activating the intracellular cGAS-STING pathway. The mitochondrial membrane remodeling induced by OAP2 overcomes the limitations of Oxa in activating the STING pathway and simultaneously promotes gasdermin-D-mediated cell pyroptosis. OAP2 also promotes dendritic cell maturation and enhances the quantity and efficacy of cytotoxic T cells, thereby inhibiting cancer cell proliferation and metastasis. Briefly, our study introduces the first novel small-molecule inhibitor that regulates mitochondrial membrane remodeling for active immunotherapy in anti-tumor research, which may provide a creative idea for targeting organelle in anti-tumor therapy.

关键词： Anti-tumor drug Prodrug Platinum chemo-immunotherapy Mitochondrial membrane modeling STING Pyroptosis mtDNA

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Nanomedicine integrating the lipidic derivative of 5-fluorouracil,miriplatin and PD-L1 si RNA for enhancing tumor therapy

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Chinese Chemical Letters 2024年第6期35卷 385-391页

作者： An Lu Yuhao Guo Yi Yan Lin Zhai Xiangyu Wang Weiran Cao Zijie Li Zhixia Zhao Yujie Shi Yuanjun Zhu Xiaoyan Liu Huining He Zhiyu Wang Jian-Cheng Wang Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems State Key Laboratory of Natural and Biomimetic DrugsSchool of Pharmaceutical SciencesPeking UniversityBeijing 100191China Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics School of PharmacyTianjin Medical UniversityTianjin 300070China Department of Immuno-oncology The Fourth Hospital of Hebei Medical UniversityShijiazhuang 050011China Department of Pharmacy Clinical Trial Research CenterChina-Japan Friendship HospitalBeijing 100029China Laboratory of innovative formulations and pharmaceutical excipients Ningbo Institute of Marine MedicinePeking UniversityNingbo 315832China

Immunosuppressive microenvironments present critical problems in clinical chemotherapy.To regulate the tumor immune microenvironment for enhancing antitumor effect,a combination of immune checkpoint inhibitors(ICIs)with chemotherapeutics has been applied clinically.In this study,miriplatin(MiPt),the lipidic derivative of 5-fluorouracil(Fu-OA),as well as the programmed death ligand 1(PD-L1)target si RNA(siPD-L1)were integrated into Lip-Pt/Fu@siPD-L1 nanoparticles(NPs)for chemo-immunotherapy.In vitro results showed that Lip-Pt/Fu@siPD-L1 NPs could exhibit effective siRNA gene silencing and promote the phagocytosis of tumor cells by macrophages.Furthermore,in vivo results revealed that LipPt/Fu@siPD-L1 NPs showed significantly higher anti-tumor efficiency than that of the physical mixing of Mi Pt,5-fluorouracil,and Lip@siPD-L1 NPs(delivery of siPD-L1 by liposomes).The best anti-tumor efficiency of Lip-Pt/Fu@siPD-L1 NPs resulted from the synergistic immunotherapeutic effects of Mi Pt and siPD-L1 based on the inhibition of CD47 expression and the downregulation of PD-L1 in tumor cells,which elicited a robust anti-tumor immune response through the activation of macrophage phagocytosis and immune checkpoint inhibition.The Lip-Pt/Fu@siPD-L1 NPs provide a potential strategy for tumor chemo-immunotherapy.

关键词： chemo-immunotherapy Immune checkpoint inhibition Gene silencing Miriplatin Macrophage phagocytosis Nanotechnology

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Enhancing cancer chemo-immunotherapy by biomimetic nanogel with tumor targeting capacity and rapid drug-releasing in tumor microenvironment

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Acta Pharmaceutica Sinica B 2022年第5期12卷 2550-2567页

作者： Lihuan Shang Xue Jiang Ting Yang Hongbo Xu Qi Xie Mei Hu Conglian Yang Li Kong Zhiping Zhang Tongji School of Pharmacy Huazhong University of Science and TechnologyWuhan 430030China Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation Medical Research CenterSun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangzhou 510120China National Engineering Research Center for Nanomedicine Huazhong University of Science and TechnologyWuhan 430030China Hubei Engineering Research Centre for Novel Drug Delivery System Huazhong University of Science and TechnologyWuhan 430030China

In the development of chemo-immunotherapy, many efforts have been focusing on designing suitable carriers to realize the co-delivery of chemotherapeutic and immunotherapeutic with different physicochemical properties and mechanisms of action. Besides, rapid drug release at the tumor site with minimal drug degradation is also essential to facilitate the antitumor effect in a short time. Here, we reported a cancer cell membrane-coated pH-responsive nanogel(NG@M) to co-deliver chemotherapeutic paclitaxel(PTX) and immunotherapeutic agent interleukin-2(IL-2) under mild conditions for combinational treatment of triple-negative breast cancer. In the designed nanogels, the synthetic copolymer PDEA-co-HP-β-cyclodextrin-co-Pluronic F127 and charge reversible polymer dimethylmaleic anhydride-modified polyethyleneimine endowed nanogels with excellent drug-loading capacity and rapid responsive drug-releasing behavior under acidic tumor microenvironment. Benefited from tumor homologous targeting capacity, NG@M exhibited 4.59-fold higher accumulation at the homologous tumor site than heterologous cancer cell membrane-coated NG. Rapidly released PTX and IL-2 enhanced the maturation of dendritic cells and quickly activated the antitumor immune response in situ, followed by prompted infiltration of immune effector cells. By the combined chemo-immunotherapy, enhanced antitumor effect and efficient pulmonary metastasis inhibition were achieved with a prolonged median survival rate(39 days).

关键词： chemo-immunotherapy Nanogel pH-responsive Cancer cell membrane Biomimetic

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Immunogenic cell death effects induced by doxorubicin improved chemo-immunotherapy via restoration of granzyme B activity

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Nano Research 2023年第12期16卷 13250-13258页

作者： Tao Huang Xiaofan Sun Yingqiu Qi Xi Yang Linyao Fan Mengdie Chen Yale Yue Hong Ge Yiye Li Guangjun Nie Huan Min Xianfu Sun Department of Breast Disease The Affiliated Cancer Hospital of Zhengzhou University&Henan Cancer HospitalHenan Institute of Advanced TechnologyZhengzhou UniversityZhengzhou 450008China Department of Pharmacology School of Basic Medical SciencesZhengzhou UniversityZhengzhou 450001China Department of Radiation Oncology The Affiliated Cancer Hospital of Zhengzhou University&Henan Cancer HospitalZhengzhou 450003China CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety&CAS Center for Excellence in Nanoscience National Center for Nanoscience and TechnologyBeijing 100190China

chemotherapy remains one of the irreplaceable treatments for cancer therapy.The use of immunogenic cell death(ICD)-inducing chemotherapeutic drugs offers a practical strategy for killing cancer cells,simultaneously eliciting an antitumor immune response by promoting the recruitment of cytotoxic immune cells and production of granzyme B(GrB).However,numerous malignant cancers adaptively acquired the capacity of secreting serpinb9(Sb9),a physiological inhibitor of GrB,which can reversibly inhibit the biological activity of GrB.To circumvent this dilemma,in this study,an integrated tailor-made nanomedicine composed of tumor-targeting peptide(Arg-Gly-Asp,RGD)decorated liposome,doxorubicin(DOX,an effective ICD inducer),and the compound 3034(an inhibitor of Sb9),is developed(termed as D3RL)for breast cancer chemo-immunotherapy.In vitro and in vivo studies show that D3RL can directly kill tumor cells and trigger the host immune response by inducing ICD.Meanwhile,D3RL can competitively relieve the inhibition of Sb9 to GrB.The restored GrB can not only effectively induce tumor immunotherapy,but also degrade matrix components in the tumor microenvironment,consequently improving the infiltration of immune cells and the penetration of nanomedicines,which in return enhance the combined antitumor effect.Taken together,this work develops an integrated therapeutic solution for targeted production and restoration of GrB to achieve a combined chemo-immunotherapy for breast cancer.

关键词： immunogenic cell death granzyme B serpinb9 chemo-immunotherapy nanomedicine

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Recent advances in organic and polymeric carriers for local tumor chemo-immunotherapy

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Science China(Technological Sciences) 2022年第5期65卷 1011-1028页

作者： BAI YiTing WANG TianRan ZHANG SongLing CHEN XueSi HE ChaoLiang Department of Obstetrics and Gynecology The First Hospital of Jilin UniversityChangchun130021China CAS Key Laboratory of Polymer Ecomaterials Changchun Institute of Applied ChemistryChinese Academy of SciencesChangchun130022China

Combination therapy involves the simultaneous administration of compounds with varying mechanisms of action that can improve the efficacy of antitumor therapy and reduce toxicity.The most widely used combination regimen is chemotherapy combined with focused immunotherapy.This is implemented to induce the apoptosis of tumor cells and can activate immune responses,improving the clearance rate of primary lesions and maintaining the resistance to postoperative tumor recurrence and metastasis.Advances in micro/nanotechnology,nanomedicine and biomaterials have contributed to the development of enhanced local drug co-delivery systems for cancer treatment,improving tumor targeting and ameliorating severe systemic complications.Carrier materials can achieve the local long-term controllable release of multiple drugs,which not only avoids rapid drug diffusion from the pathological site,but can achieve synergistic effects at lower drug concentrations.Polymeric carriers display excellent biocompatibility and biodegradability;especially,some of them also have anti-tumor effects.The aim of this article was to review recent progress in the use of organic and polymeric materials for local tumor chemo-immunotherapy,which can be used as carriers for chemotherapeutic drugs,immune adjuvants and genes,including amphiphilic nanoparticles,nanocapsules,nano-disks,nano-polyplex particles,hydrogels and implantable materials.

关键词： chemo-immunotherapy nanocarrier hydrogel anticancer therapy biomedical polymer

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CaCO3-Assisted Preparation of pH-Responsive Immune-Modulating Nanoparticles for Augmented chemo-immunotherapy

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Nano-Micro Letters 2021年第2期13卷 144-161页

作者： Yujie Zhu Zhijuan Yang Ziliang Dong Yimou Gong Yu Hao Longlong Tian Xianzhu Yang Zhuang Liu Liangzhu Feng Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices Institute of Functional Nano and Soft Materials(FUNSOM)Soochow UniversitySuzhou 215123JiangsuPeople’s Republic of China Institutes for Life Sciences School of MedicineSouth China University of TechnologyGuangzhou 510006GuangdongPeople’s Republic of China

Due to the negative roles of tumor microenvironment(TME)in compromising therapeutic responses of various cancer therapies,it is expected that modulation of TME may be able to enhance the therapeutic responses during cancer treatment.Herein,we develop a concise strategy to prepare pH-responsive nanoparticles via the CaCO3-assisted double emulsion method,thereby enabling effective co-encapsulation of both doxorubicin(DOX),an immunogenic cell death(ICD)inducer,and alkylated NLG919(aNLG919),an inhibitor of indoleamine 2,3-dioxygenase 1(IDO1).The obtained DOX/aNLG919-loaded CaCO3 nanoparticles(DNCaNPs)are able to cause effective ICD of cancer cells and at the same time restrict the production of immunosuppressive kynurenine by inhibiting IDO1.Upon intravenous injection,such DNCaNPs show efficient tumor accumulation,improved tumor penetration of therapeutics and neutralization of acidic TME.As a result,those DNCaNPs can elicit effective anti-tumor immune responses featured in increased density of tumor-infiltrating CD8+cytotoxic T cells as well as depletion of immunosuppressive regulatory T cells(Tregs),thus effectively suppressing the growth of subcutaneous CT26 and orthotopic 4T1 tumors on the Balb/c mice through combined chemotherapy&immunotherapy.This study presents a compendious strategy for construction of pH-responsive nanoparticles,endowing significantly enhanced chemo-immunotherapy of cancer by overcoming the immunosuppressive TME.

关键词： CaCO3-assisted double emulsion pH-responsiveness Neutralization of acidic TME Immunosuppressive tumor microenvironment modulation chemo-immunotherapy

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Long survival after immunotherapy plus paclitaxel in advanced intrahepatic cholangiocarcinoma: A case report and review of literature

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World Journal of Clinical Cases 2022年第32期10卷 11889-11897页

作者： Meng-Ye He Fei-Fei Yan Kai-Li Cen Peng Shen Department of Medical Oncology First Affiliated HospitalZhejiang University School of MedicineHangzhou 310000Zhejiang ProvinceChina

BACKGROUND Intrahepatic cholangiocarcinoma(iCCA)is the second most common primary hepatic malignancy worldwide.However,currently available systemic therapies are of limited effectiveness,and the median overall survival of patients treated with first-line standard chemotherapy is less than one year.Immune checkpoint inhibitors have been used to treat solid tumors.Clinical studies recently explored the combination of chemotherapy and immunotherapy for CCA.However,the clinical significance of predictive biomarkers for chemo-immunotherapy in CCA remains unclear.It is also worth exploring whether a combination of chemotherapeutic agents can increase the sensitivity of CCA immunotherapy.CASE SUMMARY This study reports a case of advanced iCCA in which clinical complete remission had been achieved using a programmed death 1(PD-1)inhibitor and paclitaxel without known predictive biomarkers,but with BRCA1,KRAS,and NTRK3 mutations after rapid progression to first-line chemotherapy,and has remained in clinical complete remission for more than two years.This case suggests that chemo-immunotherapy is a potential therapeutic option for patients with iCCA and few known predictive biomarkers for immunotherapies as well as synergistic effect of the combination of paclitaxel and PD-1 monoclonal antibody.CONCLUSION The combination of paclitaxel and PD-1 monoclonal antibodyr can be explored in patients with advanced iCCA.

关键词： Intrahepatic cholangiocarcinoma Programmed cell death protein-1 inhibitor Paclitaxel chemo-immunotherapy Predictive biomarker Case report

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KRAS-G12D mutation drives immune suppression and the primary resistance of anti-PD-1/PD-L1 immunotherapy in non-small cell lung cancer

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Cancer Communications 2022年第9期42卷 828-847页

作者： Chengming Liu Sufei Zheng Zhanyu Wang Sihui Wang Xinfeng Wang Lu Yang Haiyan Xu Zheng Cao Xiaoli Feng Qi Xue Yan Wang Nan Sun Jie He Department of Thoracic Surgery National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021P.R.China State Key Laboratory of Molecular Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021P.R.China Department of Medical Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021P.R.China Department of Comprehensive Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021P.R.China Department of Pathology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021P.R.China

Background:Although immune checkpoint inhibitors(ICIs)against programmed cell death protein 1(PD-1)and its ligand PD-L1 have demonstrated potency towards treating patients with non-small cell lung carcinoma(NSCLC),the potential association between Kirsten rat sarcoma viral oncogene homolog(KRAS)oncogene substitutions and the efficacy of ICIs remains unclear.In this study,we aimed to find point mutations in the KRAS gene resistant to ICIs and elucidate resistance mechanism.Methods:The association between KRAS variant status and the efficacy of ICIs was explored with a clinical cohort(n=74),and confirmed with a mouse model.In addition,the tumor immune microenvironment(TIME)of KRASmutant NSCLC,such as CD8+tumor-infiltrating lymphocytes(TILs)and PD-L1 level,was investigated.Cell lines expressing classic KRAS substitutions were used to explore signaling pathway activation involved in the formation of TIME.Furthermore,interventions that improved TIME were developed to increase responsiveness to ICIs.Results:We observed the inferior efficacy of ICIs in KRAS-G12D-mutant NSCLC.Based upon transcriptome data and immunostaining results from KRAS-mutant NSCLC,KRAS-G12D point mutation negatively correlated with PD-L1 level and secretion of chemokines CXCL10/CXCL11 that led to a decrease in CD8+TILs,which in turn yielded an immunosuppressive TIME.The analysis of cell lines overexpressing classic KRAS substitutions further revealed that KRAS-G12D mutation suppressed PD-L1 level via the P70S6K/PI3K/AKT axis and reduced CXCL10/CXCL11 levels by down-regulating high mobility group protein A2(HMGA2)level.Notably,paclitaxel,a chemotherapeutic agent,upregulated HMGA2 level,and in turn,stimulated the secretion of CXCL10/CXCL11.Moreover,PD-L1 blockade combined with paclitaxel significantly suppressed tumor growth compared with PD-L1 inhibitor monotherapy in a mouse model with KRAS-G12D-mutant lung adenocarcinoma.Further analyses revealed that the combined treatment significantly enhanced the recruitment of CD8+TILs via the up-regulation

关键词： KRAS-G12D non-small cell lung carcinoma immunotherapy PD-L1 tumor-infiltrating lymphocyte chemo-immunotherapy

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Follicular lymphoma:the diminishing role of chemotherapy

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Journal of Cancer Metastasis and Treatment 2022年第1期8卷 393-411页

作者： Beatrice Casadei Laura Nanni Ginevra Lolli Pier Luigi Zinzani IRCCS Azienda Ospedaliero-Universitaria di Bologna Istituto di Ematologia“Seràgnoli”Bologna 40138Italy Dipartimento di Medicina Specialistica Diagnostica e SperimentaleUniversitàdi BolognaBologna 40138Italy

Follicular lymphoma(FL)is the most common indolent non-Hodgkin lymphoma,accounting for 70%of cases in Western countries.Despite this unique name,FL is an extremely heterogeneous disease,both clinically and biologically.The basis of FL heterogeneity lies in the different biological pathways which can be activated,because of the variety of gene mutations that can occur.Today,there is a growing interest in the knowledge of these activated pathways,which is also testified by the presence of a new model that incorporates FL mutations to define patient’s prognosis(m7-FLIPI).These evaluations are also appealing because of the recent possibility of using“targeted therapies”.Targeted therapies are new tools,currently applicable in the setting of relapse/refractory(R/R)disease,where we can find a great variety of“chemo-free”combinations.As in other hematologic malignancies,“cellular therapy”enriches FL drug scenario,including T-cell dependent bispecific antibodies and chimeric antigen receptor(CAR)T-cell.Since FL heterogeneity is the basis of the difference in therapeutic efficacy and disease course among patients,the hope for the future is to understand FL biology more deeply,to better comprehend how to obtain more representative samples and pre-treatment prognostic information in order to individualize the treatment strategy as early as frontline therapy.

关键词： Follicular lymphoma POD24 target therapies chemo-immunotherapy biological heterogeneity

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主动穿细胞转运的定向纳米载体用于化学-免疫治疗抑制肿瘤生长及转移

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Science China Materials 2022年第5期65卷 1391-1402页

作者：张敏王文莉马贺于冰丛海林申有青 Institute of Biomedical Materials and Engineering College of Materials Science and EngineeringQingdao UniversityQingdao 266071China State Key Laboratory of Bio-Fibers and Eco-Textiles College of Chemistry and Chemical EngineeringQingdao UniversityQingdao 266071China Center for Bionanoengineering and Key Laboratory of Biomass Chemical Engineering of Ministry of Education College of Chemical and Biological EngineeringZhejiang UniversityHangzhou 310027China

目前免疫治疗已经显示出了极大的肿瘤治疗潜力,然而纳米载体较低的转运能力以及肿瘤免疫响应性低等问题严重阻碍了免疫治疗的临床应用.为了解决这些问题,本课题研制了一种具有主动穿细胞转运能力的定向纳米载体用于化疗增强的免疫治疗.... 详细信息

目前免疫治疗已经显示出了极大的肿瘤治疗潜力,然而纳米载体较低的转运能力以及肿瘤免疫响应性低等问题严重阻碍了免疫治疗的临床应用.为了解决这些问题,本课题研制了一种具有主动穿细胞转运能力的定向纳米载体用于化疗增强的免疫治疗.当该纳米载药系统到达肿瘤部位,金属基质蛋白酶2响应的纳米外壳崩解,释放出带有正电荷的纳米内核.正电荷促使纳米内核产生吸附介导的胞吞,进而促进纳米载药系统的跨血管内皮细胞运输和跨细胞药物递送,并最终将药物递送到远端肿瘤细胞中. PD-L1抗体和化疗药物分别被载于纳米载体的外壳和内核中进行精准递送,从而达到对具有不同治疗靶点的药物同步递送、定向释药的目的.肿瘤微环境中释放的PD-L1抗体作用于T细胞表面的特异性受体,阻断了T细胞与肿瘤细胞的结合.正电荷纳米内核同步运载奥沙利铂和吲哚美辛进入深层肿瘤细胞,在整个肿瘤组织中引发免疫原性死亡、逆转免疫抑制作用,招募大量的T细胞并最终增强免疫治疗疗效.本研究中所构建的纳米载药体系不仅能够抑制原位瘤生长,还能够阻止肿瘤的转移.这为化疗增强的免疫治疗提供了一种新的纳米递送方案,提高了免疫治疗在免疫响应率低的肿瘤中的疗效.

关键词： active transcellular drug delivery site-oriented drug release chemo-immunotherapy immunosuppressive effect reversion tumor metastasis inhibition

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