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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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Multitarget Thiol-Activated Tetrapyridyl Gold(Ⅲ)Complexes for Hypoxic Cancer Therapy

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CCS Chemistry 2024年第3期6卷 783-797页

作者： Xue-Quan Zhou Selda Abyar Imma Carbo-Bague Lan Wang Sebastian Türck Maxime ASiegler Uttara Basu Ingo Ott Rongfang Liu Adriaan PIJzerman Sylvestre Bonnet Institute of Biopharmaceutical and Health Engineering Tsinghua Shenzhen International Graduate School(SIGS)Tsinghua UniversityShenzhen 518055 Leiden Institute of Chemistry Leiden University2333 CC Leiden Department of Chemistry Simon Fraser UniversityBurnabyBritish Columbia V5A 1S6 Institute of Medicinal and Pharmaceutical Chemistry Technische Universität Braunschweig38106 Braunschweig Department of Chemistry Johns Hopkins UniversityBaltimoreMaryland 21218 Division of Drug Discovery&Safety Leiden Academic Centre for Drug ResearchLeiden University2333 CC Leiden

Gold complexes have emerged as promising anticancer metallodrugs due to their efficient thioredoxin reductase(TrxR)inhibition,which disturbs the redox balance of cancer cells.However,in this model,the role of the ligand(s)coordinated to gold is often overlooked.In this work,we present a series of tetrapyridyl Au(Ⅲ)complexes that exhibit thiol-induced release of a Au(Ⅰ)ion and a tetrapyridyl ligand.The formation of a free Au(Ⅰ)center is responsible for the expected TrxR inhibition.Additionally,the released ligand,which was visible in cells due to its intense blue fluorescence,showed excellent binding properties to the hERG potassium channel.Moreover,these ligands ended up in the lysosomes,resulting in significant lysosome damage.Altogether,the Au(Ⅲ)complexes presented in this work showed broad-spectrum anticancer properties,both in hypoxic 2D monolayers and 3D tumor spheroids.We suggest that the interaction of the released Au(Ⅰ)center and the tetrapyridyl ligand with two different protein targets may combine into prodrugs that overcome hypoxia-induced drug deactivation.

关键词： anticancer Au(Ⅲ)complexes enzyme inhibtion potassium channel affinity lysosome damage cell imaging prodrug

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Engineering prodrug nanomicelles as pyroptosis inducer for codelivery of PI3K/mTOR and CDK inhibitors to enhance antitumor immunity

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Acta Pharmaceutica Sinica B 2022年第7期12卷 3139-3155页

作者： Qichao Yang Xianbin Ma Yao Xiao Tian Zhang Leilei Yang Shaochen Yang Mengyun Liang Shuo Wang Zhizhong Wu Zhigang Xu Zhijun Sun The State Key Laboratory Breeding Base of Basic Science of Stomatology(Hubei-MOST)&Key Laboratory of Oral Biomedicine Ministry of Education School&Hospital of StomatologyWuhan UniversityWuhan 430079China Key Laboratory of Luminescence Analysis and Molecular Sensing(Southwest University) Ministry of EducationSchool of Materials and Energy&Chongqing Engineering Research Center for Micro-Nano Biomedical Materials and DevicesSouthwest UniversityChongqing 400715China

Aberrant activation of oncogenic signaling pathways in tumors can promote resistance to the antitumor immune response.However,single blockade of these pathways is usually ineffective because of the complex crosstalk and feedback among oncogenic signaling pathways.The enhanced toxicity of free small molecule inhibitor combinations is considered an insurmountable barrier to their clinical applications.To circumvent this issue,we rationally designed an effective tumor microenvironment-activatable prodrug nanomicelle(PNM)for cancer therapy.PNM was engineered by integrating the PI3K/m TOR inhibitor PF-04691502(PF)and the broad spectrum CDK inhibitor flavopiridol(Flav)into a single nanoplatform,which showed tumor-specific accumulation,activation and deep penetration in response to the high glutathione(GSH)tumoral microenvironment.The codelivery of PF and Flav could trigger gasdermin E(GSDME)-based immunogenic pyroptosis of tumor cells to elicit a robust antitumor immune response.Furthermore,the combination of PNM-induced immunogenic pyroptosis with antiprogrammed cell death-1(a PD-1)immunotherapy further boosted the antitumor effect and prolonged the survival time of mice.Collectively,these results indicated that the pyroptosis-induced nanoplatform codelivery of PI3K/m TOR and CDK inhibitors can reprogram the immunosuppressive tumor microenvironment and efficiently improve checkpoint blockade cancer immunotherapy.

关键词： Pyroptosis prodrug Stimuli-responsive Immunotherapy Targeted therapy Tumor microenvironment

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Bioresponsive immune-booster-based prodrug nanogel for cancer immunotherapy

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Acta Pharmaceutica Sinica B 2022年第1期12卷 451-466页

作者： Xianbin Ma Shaochen Yang Tian Zhang Shuo Wang Qichao Yang Yao Xiao Xiaoxiao Shi Peng Xue Yuejun Kang Gang Liu Zhi-Jun Sun Zhigang Xu Key Laboratory of Luminescence Analysis and Molecular Sensing(Southwest University) Ministry of EducationSchool of Materials and Energy&Chongqing Engineering Research Center for Micro-Nano Biomedical Materials and DevicesSouthwest UniversityChongqing 400715China The State Key Laboratory Breeding Base of Basic Science of Stomatology(Hubei-MOST)&Key Laboratory of Oral Biomedicine Ministry of EducationSchool and Hospital of StomatologyWuhan UniversityWuhan 430079China State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics&Center for Molecular Imaging and Translational Medicine School of Public HealthXiamen UniversityXiamen 361102China

The combination of chemotherapy and immunotherapy motivates a potent immune system by triggering immunogenic cell death(ICD), showing great potential in inhibiting tumor growth and improving the immunosuppressive tumor microenvironment(ITM). However, the therapeutic effectiveness has been restricted by inferior drug bioavailability. Herein, we reported a universal bioresponsive doxorubicin(DOX)-based nanogel to achieve tumor-specific co-delivery of drugs. DOX-based mannose nanogels(DM NGs) was designed and choosed as an example to elucidate the mechanism of combined chemo-immunotherapy. As expected, the DM NGs exhibited prominent micellar stability, selective drug release and prolonged survival time, benefited from the enhanced tumor permeability and prolonged blood circulation. We discovered that the DOX delivered by DM NGs could induce powerful antitumor immune response facilitated by promoting ICD. Meanwhile, the released mannose from DM NGs was proved as a powerful and synergetic treatment for breast cancer in vitro and in vivo, via damaging the glucose metabolism in glycolysis and the tricarboxylic acid cycle. Overall, the regulation of tumor microenvironment with DOX-based nanogel is expected to be an effectual candidate strategy to overcome the current limitations of ICD-based immunotherapy, offering a paradigm for the exploitation of immunomodulatory nanomedicines.

关键词： Bioresponsive prodrug Nanogel Doxorubicin Mannose Immunogenic cell death Chemotherapy Immunotherapy

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YPD-30, a prodrug of YPD-29B, is an oral small-molecule inhibitor targeting PD-L1 for the treatment of human cancer

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Acta Pharmaceutica Sinica B 2022年第6期12卷 2845-2858页

作者： Fangfang Lai Ming Ji Lei Huang Yunchen Wang Nina Xue Tingting Du Kai Dong Xiaoqing Yao Jing Jin Zhiqiang Feng Xiaoguang Chen Department of Pharmacology State Key Laboratory of Bioactive Substances and Functions of Natural MedicinesInstitute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China Department of Pharmacochemistry Institute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China Tianjin Chase Sun Pharmaceutical Co. Ltd.Tianjin 300170China

PD-1 and PD-L1 antibodies have brought about extraordinary clinical benefits for cancer patients,and their indications are expanding incessantly.Currently,most PD-1/PD-L1 agents are administered intravenously,which may be uncomfortable for some cancer patients.Herein,we develop a novel oral-delivered small molecular,YPD-29B,which specifically targets human PD-L1.Our data suggested that YPD-29B could potently and selectively block the interaction between PD-L1 and PD-1,but did not inhibit any other immune checkpoints.Mechanistically,YPD-29B induced human PD-L1 dimerization and internalization,which subsequently activated T lymphocytes and therefore overcomes immunity tolerance in vitro.YDP-29B was modified as the YPD-30 prodrug to improve druggability.Using humanized mice with human PD-1 xenografts of human PD-L1 knock-in mouse MC38 cancer cells,we demonstrated that YPD-30 exhibited significant antitumor activity and was well tolerated in vivo.Taken together,our results indicate that YPD-30 serves as a promising therapeutic candidate for anti-human PD-L1 cancer immunotherapy.

关键词： PD-L1 Small molecular inhibitor prodrug Immune checkpoints Cancer immunotherapy

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Full-profile pharmacokinetics, anticancer activity and toxicity of an extended release trivalent PEGylated irinotecan prodrug

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Acta Pharmaceutica Sinica B 2023年第8期13卷 3444-3453页

作者： Shiwen Song Dong Sun Hong Wang Jinliang Wang Huijing Yan Xuan Zhao John Paul Fawcett Xin Xu Deqi Cai Jingkai Gu Research Center for Drug Metabolism School of Life SciencesJilin UniversityChangchun 130012China Center for Food and Drug Inspection of NMPA Changchun 130012China Jen Kem Technology Co. Ltd.Tianjin 300450China State Key Laboratory of Supramolecular Structure and Materials College of ChemistryJilin UniversityChangchun 130012China Beijing Institute of Drug Metabolism Beijing 102209China

Irinotecan is an anticancer topoisomerase I inhibitor that acts as a prodrug of the active metabolite,SN-38.Unfortunately,the limited utility of irinotecan is attributed to its pH-dependent stability,short half-life and dose-limiting toxicity.To address this problem,a novel trivalent PEGylated prodrug(PEG-[Irinotecan]3)has been synthesized and its full-profile pharmacokinetics,antitumor activity and toxicity compared with those of irinotecan.The results show that after intravenous administration to rats,PEG-[Irinotecan]3 undergoes stepwise loss of irinotecan to form PEG-[Irinotecan]3-x(x=1,2)and PEG-[linker]during which time the released irinotecan undergoes conversion to SN-38.As compared with conventional irinotecan,PEG-[Irinotecan]3 displays extended release of irinotecan and efficient formation of SN-38 with significantly improved AUC and half-life.In a colorectal cancer-bearing model in nude mice,the tumor concentrations of irinotecan and SN-38 produced by PEG-[Irinotecan]3 were respectively 86.2 and 2293 times higher at 48 h than produced by irinotecan.In summary,PEG-[Irinotecan]3 displays superior pharmacokinetic characteristics and antitumor activity with lower toxicity than irinotecan.This supports the view that PEG-[Irinotecan]3 is a superior anticancer drug to irinotecan and it has entered the phaseⅡtrial stage.

关键词： Irinotecan SN-38 Trivalent PEGylated irinotecan prodrug Full-profile pharmacokinetics

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Paclitaxel prodrug Nanomedicine for Potential CT-imaging Guided Breast Cancer Therapy

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Chinese Journal of Polymer Science 2023年第11期41卷 1747-1759,I0008页

作者： Jia-Wei Chen Yi Shen Qing-Song Yu Zhi-Hua Gan State Key Laboratory of Organic-Inorganic Composite Materials Beijing Laboratory of Biomedical MaterialsBeijing Advanced Innovation Center for Soft Matter Science and EngineeringCollege of Life Science and TechnologyBeijing University of Chemical TechnologyBeijing 100029China

Nanotheranostics,which combine the therapeutic and diagnostic functions in one integrated system,have received extensive attentions in cancer treatments because they enable non-invasive diagnosis,tumor-targeted drug delivery,and real-time monitoring of therapeutic response.However,due to the high systemic toxicity of commonly used chemotherapeutics,current treatment still has limitations.Herein,to simultaneously achieve safe cancer therapy and therapeutic response monitoring,an iodinated prodrug strategy was proposed.2,3,5-Triiodobenzoic acid(TIBA)was used to modify both paclitaxel(PTX)and the polymeric vehicle,so that the encapsulation efficiency of PTX could be increased and the systemic toxicity could be reduced.As-prepared prodrug nanoparticles could accumulate passively in the tumor site and promptly release loaded drugs in response to the overexpressed GSH in cancer cells,which then caused efficient cell cycle arrest and apoptosis like that of the parent PTX.With this rational design,safe and efficient antitumor therapy and real-time computer tomography(CT)imaging could be simultaneously realized,facilitating potential CT imaging-guided therapy of metastatic breast cancer.

关键词： CT imaging Paclitaxel prodrug GSH responsiveness Polymeric nanoparticles

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Vascular disrupting agent-induced amplification of tumor targeting and prodrug activation boosts anti-tumor efficacy

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Science China Chemistry 2022年第10期65卷 1994-2004页

作者： Sheng Hong Qian-Xiao Huang Ping Ji Xuan Pang Yunxia Sun Si-Xue Cheng Xian-Zheng Zhang Xuesi Chen Key Laboratory of Biomedical Polymers of Ministry of Education Department of ChemistryWuhan UniversityWuhan 430072China Key Laboratory of Polymer Ecomaterials Changchun Institute of Applied ChemistryChinese Academy of SciencesChangchun 130022China

Vadimezan,one of the typical vascular disrupting agents(VDAs) currently in clinical trials,has been extensively implemented for cancer research,whereas its clinical efficacy is adversely affected by the inevitable side effects.Inspired by Vadimezaninduced intratumoral coagulation activation and hypoxia aggravation,we report a strategy by utilizing these biological effects to achieve targeted delivery and activation of hypoxia-activated prodrug(HAP) thus to maximize the therapeutic effect of Vadimezan.By encapsulating HAP tirapazamine into poly(lactic-co-glycolic acid)(PLGA) nanocarriers along with the modification of clot-binding peptide,the obtained nanoplatform could target tumors under the coagulation activation effect of Vadimezan.Meanwhile,the aggravated hypoxia tumor microenvironment induced by Vadimezan can also boost hypoxia-activated chemotherapy.In the murine tumor model,this strategy showed 80.0% suppression of tumor growth,indicating its great potential in tumor treatment.This study offers an ingenious tactic for the combination of vascular disrupting therapy and hypoxia-activated chemotherapy,which may open up a window of the VDAs-based combination therapy.

关键词： tumor therapy prodrug vascular disrupting agent tirapazamine hypoxia

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A prodrug nanoplatform via esterification of STING agonist and IDO inhibitor for synergistic cancer immunotherapy

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Nano Research 2022年第10期15卷 9215-9222页

作者： Madiha Zahra Syeda Tu Hong Min Zhang Yanfei Han Xiaoling Zhu Songmin Ying Longguang Tang International Institutes of Medicine the Fourth Affiliated Hospital of Zhejiang University School of MedicineYiwu 322000China Department of Pharmacology and Department of Respiratory and Critical Care Medicine of the Second Affiliated Hospital Zhejiang University School of MedicineKey Laboratory of Respiratory Disease of Zhejiang ProvinceHangzhou 310009China

Cancer immunotherapy has made significant progress in the last few decades,revolutionizing oncology.However,low patient response rates and potential immune-related adverse events continue to be major clinical challenges.Cancer nanomedicine,by virtue of its regulated delivery and modular flexibility,has shown the potential to strengthen antitumor immune responses and sensitize tumors to immunotherapy.In this study,we developed tumor microenvironment(TME)responsive nanomedicine to achieve specific and localized amplification of the immune response in tumor tissue in a safe and effective manner,while simultaneously reducing immune-related side effects.We synthesized the TME responsive prodrug by coupling MSA-2,a stimulator of interferon genes(STING)agonist,and NLG-919,an indoleamine 2,3 dioxygenase(IDO)inhibitor.The prodrug was assembled into nanoparticles to enhance the solubility and bioavailability.By synthesizing a TME responsive prodrug,we aim to explore the therapeutic efficacy of combined regimen(STING agonist and IDO inhibitor)for cancer,and reduce the unwanted side effects of STING agonism on normal tissues.Free prodrug and nanoparticles were characterized by mass spectrometry,dynamic light scattering(DLS),and transmission electron microscopy(TEM).Following that,we investigated the tumor accumulation,anti-tumor activity,and toxicity in vitro and in vivo.prodrug nanoparticles demonstrated the ability to inhibit the tumor growth and activate antitumor immune response by modulating immune cells populations in tumor microenvironment.The TME responsive nanomedicine provided an effective tool for precise targeting,promoting antitumor immunity,and efficient tumor growth inhibition with safety.Outcomes of this study may have implications for future clinical trials.

关键词： prodrug esterase-responsive immunotherapy stimulator of interferon genes(STING) indoleamine 2 3 dioxygenase(IDO)

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Impact of the amount of PEG on prodrug nanoassemblies for efficient cancer therapy

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Asian Journal of Pharmaceutical Sciences 2022年第2期17卷 241-252页

作者： Yaqiao Li Lingxiao Li Qianhui Jin Tian Liu Jin Sun Yongjun Wang Zhijun Yang Zhonggui He Bingjun Sun Wuya College of Innovation Shenyang Pharmaceutical UniversityShenyang 110016China School of Chinese Medicine Hong Kong Baptist UniversityHong Kong 999077China

PEGylation has been widely used to improve the pharmacokinetic properties of prodrug self-assembled nanoparticles(prodrug-SANPs).However,the impacts of the amount of PEG on the self-assemble stability,cellular uptake,pharmacokinetics,and antitumor efficacy of prodrug-SANPs are still unknown.Herein,selenoether bond bridged docetaxel dimeric prodrug was synthesized as the model prodrug.Five prodrug-SANPs were designed by using different mass ratios of prodrugs to PEG(W_(prodrug)/W_(DSPE-mPEG2000)=10:0,9:1,8:2,7:3 and 6:4),and defined as Pure drug NPs,9:1NPs,8:2NPs,7:3 NPs and 6:4 NPs,respectively.Interestingly,8:2 NPs formed the most compact nanostructure,thus improving the self-assemble stability and pharmacokinetics behavior.In addition,the difference of these prodrug-SANPs in cellular uptake was investigated,and the influence of PEG on cytotoxicity and antitumor efficacy was also clarified in details.The 8:2 NPs exhibited much better antitumor efficacy than other prodrug-SANPs and even commercial product.Our findings demonstrated the pivotal role of the amount of PEG on prodrug-SANPs.

关键词： PEGylation prodrug Self-assembly nanoparticles Docetaxel Oxidation responsive

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