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Fine-tuning the activation behaviors of ternary modular cabazitaxel prodrugs for efficient and on-target oral anti-cancer therapy

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Asian Journal of Pharmaceutical Sciences 2024年第2期19卷 188-203页

作者： Mingyang Zhang Yifan Miao Can Zhao Tong Liu Xiyan Wang Zixuan Wang Wenxin Zhong Zhonggui He Chutong Tian Jin Sun Department of Pharmaceutics Wuya College of InnovationShenyang Pharmaceutical UniversityShenyang 110016China Key Laboratory of Advanced drug Delivery Systems of Zhejiang Province Hangzhou 310058China Joint International research Laboratory of Intelligent drug Delivery Systems Ministry of EducationShenyang 110016China Liaoning Provincial institute of drug Inspection and Testing Shenyang 110036China

The disulfide bond plays a crucial role in the design of anti-tumor prodrugs due to its exceptional tumor-specific redox responsiveness. However, premature breaking of disulfide bonds is triggered by small amounts of reducing substances (e.g., ascorbic acid, glutathione, uric acid and tea polyphenols) in the systemic circulation. This may lead to toxicity, particularly in oral prodrugs that require more frequent and high-dose treatments. Fine-tuning the activation kinetics of these prodrugs is a promising prospect for more efficient on-target cancer therapies. In this study, disulfide, steric disulfide, and ester bonds were used to bridge cabazitaxel (CTX) to an intestinal lymph vessel-directed triglyceride (TG) module. Then, synthetic prodrugs were efficiently incorporated into self-nanoemulsifying drug delivery system (corn oil and Maisine CC were used as the oil phase and Cremophor EL as the surfactant). All three prodrugs had excellent gastric stability and intestinal permeability. The oral bioavailability of the disulfide bond-based prodrugs (CTX-(C)S-(C)S-TG and CTX-S-S-TG) was 11.5- and 19.1-fold higher than that of the CTX solution, respectively, demonstrating good oral delivery efficiency. However, the excessive reduction sensitivity of the disulfide bond resulted in lower plasma stability and safety of CTX-S-S-TG than that of CTX-(C)S-(C)S-TG. Moreover, introducing steric hindrance into disulfide bonds could also modulate drug release and cytotoxicity, significantly improving the anti-tumor activity even compared to that of intravenous CTX solution at half dosage while minimizing off-target adverse effects. Our findings provide insights into the design and fine-tuning of different disulfide bond-based linkers, which may help identify oral prodrugs with more potent therapeutic efficacy and safety for cancer therapy.

关键词： Steric disulfide bond Triglyceride-like pr odrugs Cabazitaxel Lymphatic transport Oral chemotherapy

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Overexpression of wild-type HRAS drives non-alcoholic steatohepatitis to hepatocellular carcinoma in mice

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Zoological research 2024年第3期45卷 551-566页

作者： Chen Ling Su-Su Liu Yu-Ya Wang Gui-Tao Huo Yan-Wei Yang Nan Xu Hong Wang Yong Wu Yu-Fa Miao Rui Fu Yu-Wei Zhao Chang-Fa Fan College of Life Sciences Northwest UniversityProvincial Key Laboratory of Biotechnology of Shaanxi ProvinceXi’anShaanxi 710069China Division of Animal Model research Institute for Laboratory Animal ResourcesNational Institutes for Food and Drug Control(NIFDC)Beijing 102629China National Center for Safety Evaluation of drugs National Institutes for Food and Drug Control(NIFDC)Beijing 100176China Division of HIV/AIDS and Sexually Transmitted Virus Vaccines Institute for Biological Products ControlNational Institutes for Food and Drug Control(NIFDC)Beijing 102629China Division of Laboratory Animal Monitoring Institute for Laboratory Animal ResourcesNational Institutes for Food and Drug Control(NIFDC)Beijing 102629China

Hepatocellular carcinoma(HCC),a prevalent solid carcinoma of significant concern,is an aggressive and often fatal disease with increasing global incidence rates and poor therapeutic *** etiology and pathological progression of non-alcoholic steatohepatitis(NASH)-related HCC is multifactorial and ***,no single animal model can accurately mimic the full NASH-related HCC pathological progression,posing considerable challenges to transition and mechanistic ***,a novel conditional inducible wild-type human HRAS overexpressed mouse model(HRAS-HCC)was established,demonstrating 100%morbidity and mortality within approximately one month under normal dietary and lifestyle *** symptoms of HCC such as ascites,thrombus,internal hemorrhage,jaundice,and lung metastasis were successfully replicated in ***-depth pathological features of NASH-related HCC were demonstrated by pathological staining,biochemical analyses,and typical marker gene *** murine anti-PD-1 and sorafenib treatment effectively prolonged mouse survival,further confirming the accuracy and reliability of the *** on protein-protein interaction(PPI)network and RNA sequencing analyses,we speculated that overexpression of HRAS may initiate the THBS1-COL4A3 axis to induce NASH with severe fibrosis,with subsequent progression to ***,our study successfully duplicated natural sequential progression in a single murine model over a very short period,providing an accurate and reliable preclinical tool for therapeutic evaluations targeting the NASH to HCC continuum.

关键词： HRAS THBS1 HCC driver factor NASH Fibrosis Cirrhosis HCC Treatment evaluation

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A novel strategy for treating oncogene-mutated tumors by targeting tumor microenvironment and synergistically enhancing anti-PD-1 immunotherapy

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Cancer Communications 2024年第3期44卷 438-442页

作者： Yingqiang Liu Linjiang Tong Mengge Zhang Qi Zhang Qiupei Liu Fang Feng Yan Li Mengzhen Lai Haotian Tang Yi Chen Meiyu Geng Wenhu Duan Jian Ding Hua Xie Division of Antitumor Pharmacology&State Key Laboratory of drug research Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghaiP.R.China University of Chinese Academy of Sciences BeijingP.R.China Department of Chemical and Environmental Engineering University of Nottingham Ningbo ChinaNingboZhejiangP.R.China Zhongshan institute for drug Discovery Shanghai Institute of Materia MedicaChinese Academy of SciencesZhongshanGuangdongP.R.China Shandong Laboratory of Yantai drug Discovery Bohai Rim Advanced Research Institute for Drug DiscoveryYantaiShandongP.R.China Small-Molecule drug research Center Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghaiP.R.China

Oncogenes are critical factors in tumorigenesis of diverse cancer types and play essential roles in tumor immune *** in Kirsten rat sarcoma viral oncogene homolog(KRAS)and epidermal growth factor receptor(EGFR)are among the most frequent gain-of-function alterations[1].After many years of in-depth research,inhibitors targeting EGFR or KRAS mutations have been successfully developed,however,their clinical benefit is relatively limited,and they will inevitably encounter the challenge of drug *** emergence of resistance is attributed to secondary mutations in driver genes and other complicated factors.

关键词： alterations KRAS sarcoma

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The inhibitory effect of adenosine on tumor adaptive immunity and intervention strategies

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Acta Pharmaceutica Sinica B 2024年第5期14卷 1951-1964页

作者： Longsheng Wang Jie Zhang Wenxin Zhang Mingming Zheng Hongjie Guo Xiaohui Pan Wen Li Bo Yang Ling Ding Zhejiang Province Key Laboratory of Anti-Cancer drug research Institute of Pharmacology and ToxicologyCollege of Pharmaceutical SciencesZhejiang UniversityHangzhou 310058China The Innovation institute for Artificial Intelligence in Medicine Zhejiang UniversityHangzhou 310018China Nanhu Brain-Computer Interface institute Hangzhou 311100China

Adenosine(Ado)is significantly elevated in the tumor microenvironment(TME)compared to normal *** binds to adenosine receptors(AdoRs),suppressing tumor antigen presentation and immune cell activation,thereby inhibiting tumor adaptive *** downregulates major histocompatibility complex II(MHC II)and co-stimulatory factors on dendritic cells(DCs)and macrophages,inhibiting antigen *** suppresses anti-tumor cytokine secretion and T cell activation by disrupting T cell receptor(TCR)binding and signal *** also inhibits chemokine secretion and KCa3.1 channel activity,impeding effector T cell trafficking and infiltration into the tumor ***,Ado diminishes T cell cytotoxicity against tumor cells by promoting immune-suppressive cytokine secretion,upregulating immune checkpoint proteins,and enhancing immune-suppressive cell *** Ado production in the TME can significantly enhance anti-tumor immune responses and improve the efficacy of other *** and clinical development of inhibitors targeting Ado generation or AdoRs is ***,this article will summarize and analyze the inhibitory effects and molecular mechanisms of Ado on tumor adaptive immunity,as well as provide an overview of the latest advancements in targeting Ado pathways in anti-tumor immune responses.

关键词： Adenosine Adenosine receptors Adenosine-generating enzymes Tumor microenvironment Immune suppression Immune escape Clinical treatment Targeting drugs

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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

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On the Innovation,Design,Construction,and Experiments of OMEGA-Based SSPS Prototype:The Sun-Chasing Project

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Engineering 2024年第5期36卷 90-101页

作者： Baoyan Duan Yiqun Zhang Guangda Chen Ze Zhao Jianwei Mi Xun Li Lin Yang Xi Li research institute on Mechatronics Xidian UniversityXi’an 710071China research institute of Antenna Xidian UniversityXi’an 710071China

This study systematically introduces the development of the world’s first full-link and full-system ground demonstration and verification system for the OMEGA space solar power satellite(SSPS).First,the OMEGA 2.0 innovation design was ***,field-coupling theoretical models of sunlight concentration,photoelectric conversion,and transmitting antennas were established,and a systematic optimization design method was ***,a beam waveform optimization methodology considering both a high beam collection efficiency and a circular stepped beam shape was ***,a control strategy was developed to control the condenser pointing toward the sun while maintaining the transmitting antenna toward the ***,a high-efficiency heat radiator design method based on bionics and topology optimization was ***,a method for improving the rectenna array’s reception,rectification,and direct current(DC)power synthesis efficiencies is ***,high-precision measurement technology for high-accuracy beam-pointing control was ***,a smart mechanical structure was designed and ***,the developed SSPS ground demonstration and verification system has the capacity for sun tracking,a high concentration ratio,photoelectric conversion,microwave conversion and emission,microwave reception,and rectification,and thus satisfactory results were obtained.

关键词： OMEGA-SSPS Full-link and full-system Beam collection efficiency Circular stepped beam shape Smart structure Field coupling theoretical model `Beam pointing control

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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 ***,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

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Investigating epithelial-neuronal signaling contribution in visceral pain through colon organoid-dorsal root ganglion neuron co-cultures

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Neural Regeneration research 2024年第6期19卷 1199-1200页

作者： Francesco Margiotta Lorenzo Di Cesare Mannelli Antonino Morabito Carla Ghelardini Elena Lucarini Department of Neuroscience PsychologyDrug Research and Child Health-NEUROFARBA-Pharmacology and Toxicology SectionUniversity of FlorenceFlorenceItaly Department of Neuroscience PsychologyDrug Research and Child Health-NEUROFARBAUniversity of FlorenceFlorenceItaly Meyer Children’s Hospital IRCCS FlorenceItaly

Abdominal pain is a common symptom associated with irritable bowel syndrome and inflammatory bowel diseases(IBDs),affecting about 20%of the global population(Grundy et al.,2019).Current pain therapies are poorly effective on visceral pain of intestinal origin and present several side effects,hence the need to identify novel molecular and cellular targets for drug development.

关键词： pain visceral colon

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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

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SRY-Box transcription factor 9 triggers YAP nuclear entry via direct interaction in tumors

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Signal Transduction and Targeted Therapy 2024年第5期9卷 2285-2297页

作者： Hui Qian Chen-Hong Ding Fang Liu Shi-Jie Chen Chen-Kai Huang Meng-Chao Xiao Xia-Lu Hong Ming-Chen Wang Fang-Zhi Yan Kai Ding Ya-Lu Cui Bai-Nan Zheng Jin Ding Cheng Luo Xin Zhang Wei-Fen Xie Department of Gastroenterology Changzheng HospitalNaval Medical UniversityShanghaiChina Department of Gastroenterology Shanghai East HospitalSchool of MedicineTongji UniversityShanghaiChina drug Discovery and Design Center CAS Key Laboratory of Receptor ResearchState Key Laboratory of Drug ResearchShanghai Institute of Materia MedicaChinese Academy of SciencesShanghaiChina Department of Gastroenterology First Affiliated Hospital of Nanchang UniversityNanchangChina Clinical Cancer institute Center for Translational MedicineNaval Medical UniversityShanghaiChina

The translocation of YAP from the cytoplasm to the nucleus is critical for its activation and plays a key role in tumor ***,the precise molecular mechanisms governing the nuclear import of YAP are not fully *** this study,we have uncovered a crucial role of SOX9 in the activation of ***9 promotes the nuclear translocation of YAP by direct ***,we have identified that the binding between Asp-125 of SOX9 and Arg-124 of YAP is essential for SOX9-YAP interaction and subsequent nuclear entry of ***,we have discovered a novel asymmetrical dimethylation of YAP at Arg-124(YAP-R124me2a)catalyzed by ***-R124me2a enhances the interaction between YAP and SOX9 and is associated with poor prognosis in multiple ***,we disrupted the interaction between SOX9 and YAP using a competitive peptide,S-A1,which mimics anα-helix of SOX9 containing Asp-125.S-A1 significantly inhibits YAP nuclear translocation and effectively suppresses tumor *** study provides the first evidence of SOX9 as a pivotal regulator driving YAP nuclear translocation and presents a potential therapeutic strategy for YAP-driven human cancers by targeting SOX9-YAP interaction.

关键词： interaction interaction precise

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