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CCS Chemistry 2024年第3期6卷 693-708页

作者： Benkai Bao Qiong Yuan Qian Feng Ling Li Meiqi Li Yanli Tang Key Laboratory of Analytical Chemistry for Life Science of Shaanxi Province Key Laboratory of Applied Surface and Colloid ChemistryMinistry of EducationSchool of Chemistry and Chemical EngineeringShaanxi Normal UniversityXi’anShaanxi Province 710119

Regulating antioxidative stress pathways to augment oxidative stress and enhance antitumor therapy is highly desirable but very challenging.Herein,we initiated a multifunctional nanoparticle to regulate the Keap1-Nrf2 antioxidative stress pathway to promote cancer cell apoptosis.The OPFV-SnMP@GE11 nanoparticles were assembled by enzyme-activated OPFV-TLQ,tin mesoporphyrin(SnMP),and DSPEPEG-GE11.OPFV-SnMP@GE11 accumulated at tumor sites through specific targeting with GE11.OPFV-TLQ was specifically reduced to a photosensitizer OPFVNH2 by endocellular NAD(P)H:quinone oxidoreductase 1(NQO1).Under irradiation,OPFV-NH2 greatly produced reactive oxygen species(ROS)through a type I mechanism,which activated the Keap1-Nrf2 signal pathway and enhanced the transcription of NQO1,resulting in a continuous and explosive generation of ROS.Additionally,SnMP inhibited the activity of heme oxygenase-1(HO-1),further depressing antioxidative stress.This strategy provides insight into the regulation of the signal pathway to amplify oxidative stress,paving the way to studying the molecular mechanisms of cellular activities to enhance cancer therapy.

关键词： Keap1-Nrf2 pathway enzyme-activated probe reactive oxygen species oxidative stress antitumor therapy

Research Article Dynamically crosslinked nanocapsules for the efficient and serumresistant cytosolic protein delivery

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Nano Research 2024年第3期17卷 1760-1771页

作者： Qiang Yang Ningyu Liu Ziyin Zhao Xun Liu Lichen Yin Institute of Functional Nano and Soft Materials(FUNSOM) Jiangsu Key Laboratory of Carbon-Based Functional Materials and DevicesSoochow UniversitySuzhou 215123China Department of Thoracic Surgery The Second Affiliated Hospital of Soochow UniversitySuzhou 215004China

Intracellular protein delivery is critical to the development of protein-based biopharmaceuticals and therapies.However,current delivery vectors often suffer from complicated syntheses,low generality among various proteins,and insufficient serum stability.Herein,we developed an enlightened cytosolic protein delivery strategy by dynamically crosslinking epigallocatechin gallate(EGCG),low-molecular-weight polyethylenimine(PEI 1.8k),and 2-acetylphenylboric acid(2-APBA)on the protein surface,hence forming the EPP-protein nanocapsules(NCs).EGCG enhanced protein encapsulation via hydrogen bonding,and reduced the positive charge density of PEI to endow the NCs with high serum tolerance,thereby enabling effective cellular internalization in serum.The formation of reversible imine and boronate ester among 2-APBA,EGCG,and PEI 1.8k allowed acid-triggered dissociation of EPP-protein NCs in the endolysosomes,which triggered efficient intracellular release of the native proteins.Such strategy therefore showed high efficiency and universality for diversities of proteins with different molecular weights and isoelectric points,including enzyme,toxin,antibody,and CRISPR(clustered regularly interspaced short palindromic repeats)-Cas9 ribonucleoprotein(RNP),outperforming the commercial protein transduction reagent PULSin and RNP transfection reagent lipofectamine CMAX.Moreover,intravenously(i.v.)injected EPP-saporin NCs efficiently delivered saporin into 4T1 tumor cells to provoke robust antitumor effect.This simple,versatile,and robust cytosolic protein delivery system holds translational potentials for the development of protein-based therapeutics.

关键词： nanocapsules dynamic crosslinking cytosolic protein delivery serum resistance antitumor therapy genome editing

Acid-sensitive PEGylated cabazitaxel prodrugs for antitumor therapy

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Chinese Chemical Letters 2021年第5期32卷 1751-1754页

作者： Tao Liu Hui Zou Jingqing Mu Na Yu Yang Xu Guohua Liu Xingjie Liang Shutao Guo Key Laboratory of Functional Polymer Materials of Ministry of Education State Key Laboratory of Medicinal Chemical Biology and Institute of Polymer ChemistryCollege of ChemistryNankai UniversityTianjin 300071China Laboratory of Controllable Nanopharmaceuticals CAS Center for Excellence in NanoscienceCAS Key Laboratory for Biomedical Effects of Nanomaterials and NanosafetyNational Center for Nanoscience and TechnologyBeijing 100190China University of Chinese Academy of Sciences Beijing 100049China

Although the antitumor drug cabazitaxel shows great therapeutic potential,its high toxicity and poor water solubility limit its utility.However,the use of stimuli-responsive prodrugs is a promising strategy for overcoming these limitations.Herein,we report the synthesis of two highly water soluble,acidsensitive PEGylated acyclic-ketal-linked cabazitaxel prodrugs(PKCs)with improved antitumor efficacy.In an acidic tumor microenvironment,the PKCs hydrolyzed rapidly to release the native drug,whereas they were stable in the normal physiological environment.Compared with cabazitaxel injection,the PKCs had much higher maximum tolerated doses:and in an MDA-MB-231 subcutaneous xenograft nude mouse model,the PKCs showed better antitumor efficacy and safety than cabazitaxel injection.The prodrug strategy reported herein could be useful for the development of other water soluble,acidsensitive prodrugs with improved efficacy.

关键词： Prodrugs Acid-sensitive antitumor therapy Cabazitaxel PEGylation

Integrins in human hepatocellular carcinoma tumorigenesis and therapy

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Chinese Medical Journal 2023年第3期136卷 253-268页

作者： Qiong Gao Zhaolin Sun Deyu Fang College of Basic Medical Sciences Dalian Medical UniversityDalianLiaoning 116044China Department of Pathology Northwestern University Feinberg School of MedicineChicagoIL 60611USA

Integrins are a family of transmembrane receptors that connect the extracellular matrix and actin skeleton, which mediate cell adhesion, migration, signal transduction, and gene transcription. As a bi-directional signaling molecule, integrins can modulate many aspects of tumorigenesis, including tumor growth, invasion, angiogenesis, metastasis, and therapeutic resistance. Therefore, integrins have a great potential as antitumor therapeutic targets. In this review, we summarize the recent reports of integrins in human hepatocellular carcinoma (HCC), focusing on the abnormal expression, activation, and signaling of integrins in cancer cells as well as their roles in other cells in the tumor microenvironment. We also discuss the regulation and functions of integrins in hepatitis B virus-related HCC. Finally, we update the clinical and preclinical studies of integrin-related drugs in the treatment of HCC.

关键词： Integrins Hepatocellular carcinoma antitumor therapy

Super-sensitive bifunctional nanoprobe: Self-assembly of peptide-driven nanoparticles demonstrating tumor fluorescence imaging and therapy

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Acta Pharmaceutica Sinica B 2022年第3期12卷 1473-1486页

作者： Han Xiao Rui Zhang Xiaobo Fan Xinglu Jiang Mingyuan Zou Xuejiao Yan Haiping Hao Guoqiu Wu Medical School Southeast UniversityNanjing 210009China Department of Clinical Laboratory the Fifth Affiliated Hospital of Sun Yat-sen UniversityNanjing 210009China Department of Cardiology the Affiliated Changzhou No.2 People’s Hospital of Nanjing Medical UniversityNanjing 210009China State Key Laboratory of Natural Medicines Key Lab of Drug Metabolism and PharmacokineticsChina Pharmaceutical UniversityZhuhai 519000China Center of Clinical Laboratory Medicine Zhongda HospitalSoutheast UniversityNanjing 21009China Jiangsu Provincial Key Laboratory of Critical Care Medicine Southeast UniversityChangzhou 213000China

The development of nanomedicine has recently achieved several breakthroughs in the field of cancer treatment;however,biocompatibility and targeted penetration of these nanomaterials remain as limitations,which lead to serious side effects and significantly narrow the scope of their application.The self-assembly of intermediate filaments with arginine-glycine-aspartate(RGD)peptide(RGDIFP)was triggered by the hydrophobic cationic molecule 7-amino actinomycin D(7-AAD)to synthesize a bifunctional nanoparticle that could serve as a fluorescent imaging probe to visualize tumor treatment.The designed RGD-IFP peptide possessed the ability to encapsulate 7-AAD molecules through the formation of hydrogen bonds and hydrophobic interactions by a one-step method.This fluorescent nanoprobe with RGD peptide could be targeted for delivery into tumor cells and released in acidic environments such as endosomes/lysosomes,ultimately inducing cytotoxicity by arresting tumor cell cycling with inserted DNA.It is noteworthy that the RGD-IFP/7-AAD nanoprobe tail-vein injection approach demonstrated not only high tumor-targeted imaging potential,but also potent antitumor therapeutic effects in vivo.The proposed strategy may be used in peptide-driven bifunctional nanoparticles for precise imaging and cancer therapy.

关键词： Nanoprobe 7-Amino actinomycin D Intermediate filament protein Tumor image antitumor therapy Integrin avβ3

Recent advances for liquid metals:Synthesis,modification and bio-applications

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Journal of Materials Science & Technology 2023年第12期143卷 153-168页

作者： Zhenhu Guo Xiaohan Gao Jingsong Lu Wanling Xu Jielin Ye Ying Li Wensheng Xie Lingyun Zhao Key Laboratory of Advanced Materials Ministry of Education of ChinaSchool of Materials Science and EngineeringTsinghua UniversityBeijing 100084China State Key Laboratory of New Ceramics and Fine Processing School of Materials Science and EngineeringTsinghua UniversityBeijing 100084China School of Medicine Tsinghua UniversityBeijing 100084China Department of Neurosurgery Yuquan HospitalSchool of Clinical MedicineTsinghua UniversityBeijing 100084China The Key Laboratory of Bioorganic Phosphorus Chemistry&Chemical Biology(Ministry of Education) Department of ChemistryTsinghua UniversityBeijing 100084China

Considering the application requirements for modern biomedicine,research into novel biomaterials with unusual functions is highly desired.As an alternative,liquid metals(LMs),a nontraditional family of metal materials,have piqued the interest of biomedical researchers and made significant advances in biomed-ical areas,owing to their shape transformability,self-healing capability,excellent electrical,and thermal conductivities.In particular,many functionalized strategies for the preparation and modification of LMs or LMs-based composites to achieve extended biomedical applications have been investigated in recent years.These findings provided inspiring while constructive reference for the fabrication and engineering of novel LMs-based composites.Herein,in this topic review,we elaborate on the recent advances of LMs-based functional materials,with particular focuses on the synthesis,modification,and bio-applications,especially in antitumor therapy,antibacterial,contrast agent for imaging,bone repair,electronic skin sen-sor,and nerve connection agent.Further on,the current challenges and future prospects of LMs-based composites are carefully discussed.

关键词： Liquid metals Synthesis Composites antitumor therapy Bio-application

In situ triggering antitumor efficacy of alcoholabuse drug disulfiram through Cu-based metalorganic framework nanoparticles

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Acta Pharmaceutica Sinica B 2021年第7期11卷 2016-2030页

作者： Lin Hou Yanlong Liu Wei Liu Mervat Balash Hongling Zhang Yi Zhang Huijuan Zhang Zhenzhong Zhang Biotherapy Center the First Affiliated Hospital of Zhengzhou UniversityZhengzhou UniversityZhengzhou 450052China School of Pharmacy School of Pharmaceutical SciencesZhengzhou UniversityKey Laboratory of Targeting Therapy and Diagnosis for Critical DiseasesZhengzhou 450001China

Although approved as an alcohol-abuse drug,disulfiram(DSF)exhibited potential anticancer activity when chelated with copper(Cu).However,the low level of intrinsic Cu,toxicity originated from exogenous Cu supplementation,and poor stability of DSF in vivo severely limited its application in cancer treatment.Herein,we proposed an in situ DSF antitumor efficacy triggered system,taking advantages of Cu-based metal-organic framework(MOF).In detail,DSF was encapsulated into Cu-MOF nanoparticles(NPs)during its formation,and the obtained NPs were coated with hyaluronic acid to enhance the tumor targetability and biocompatibility.Notably,DSF loaded Cu-MOF NPs maintained stability and integrity without Cu;leakage in blood circulation,thus showing excellent biosafety.Once accumulating at tumor site,NPs were internalized into tumor cells via receptor-mediated endocytosis and released DSF and Cu;simultaneously in the hyaluronidase-enriched and acidic intracellular tumor microenvironment.This profile lead to in situ chelation reaction between DSF and Cu;,generating toxic DSF/Cu complex against tumor cells.Both in vitro and in vivo results demonstrated the programmed degradation and recombination property of Cu-based MOF NPs,which facilitated the tumor-specific chemotherapeutic effects of DSF.This system provided a promising strategy for the application of DSF in tumor therapy.

关键词： Disulfiram Copper Metal-organic framework Hyaluronic acid Lysosomal escape DSF/Cu complex In situ antitumor therapy

Construction of curcumin-loaded micelles and evaluation of the anti-tumor effect based on angiogenesis

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Acupuncture and Herbal Medicine 2023年第4期3卷 343-356页

作者： Rui Liu Zhongyan Liu Xueli Guo Dereje Kebebe Jiaxin Pi Pan Guo State Key Laboratory of Component-Based Chinese Medicine Tianjin University of Traditional Chinese MedicineTianjinChina Engineering Research Center of Modern Chinese Medicine Discovery and Preparation Technique Ministry of EducationTianjinChina Haihe Laboratory of Modern Chinese Medicine TianjinChina School of Pharmacy Institute of HealthJimma UniversityJimmaEthiopia

Objective:Inhibition of tumor angiogenesis has become a new targeted tumor therapy.In this study,we established a micellar carrier with a tumor neovascularization-targeting effect modified by the neovascularization-targeting peptide NGR.Methods:The targeted polymer poly(ethylene glycol)-b-poly(lactide-co-glycolide)(PEG-PLGA)modified with Asn–Gly–Arg(NGR)peptide was prepared and characterized by 1H nuclear magnetic resonance and Fourier-transform infrared spectrometry.NGR-PEG-PLGA was used to construct curcumin(Cur)-loaded micelles by the solvent evaporation method.The physicochemical properties of the micelles were also investigated.Additionally,we evaluated the antitumor efficacy of the polymer micelles(PM)using in vitro cytology experiments and in vivo animal studies.Results:The particle size of Cur-NGR-PM was 139.70±2.51 nm,and the drug-loading capacity was 14.37±0.06%.In vitro cytological evaluation showed that NGR-modified micelles showed higher cellular uptake through receptor-mediated endocytosis pathways than did unmodified micelles,leading to the apoptosis of tumor cells.Then,in vivo antitumor experiments showed that the modified micelles significantly inhibited tumor growth and were safe.Conclusions:NGR-modified micelles significantly optimized the therapeutic efficacy of Cur.This strategy offers a viable avenue for cancer treatment.

关键词： antitumor therapy Curcumin(Cur) Micelles NGR Tumor angiogenesis

Cyclin-dependent kinases-based synthetic lethality: Evidence, concept, and strategy

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Acta Pharmaceutica Sinica B 2021年第9期11卷 2738-2748页

作者： Kailin Li Jieqiong You Qian Wu Wen Meng Qiaojun He Bo Yang Chengliang Zhu Ji Cao College of Pharmaceutical Sciences Zhejiang UniversityHangzhou 310058China Innovation Institute for Artificial Intelligence in Medicine Zhejiang UniversityHangzhou 310058China Affiliated Hangzhou First People’s Hospital Zhejiang University School of MedicineHangzhou 310058China Cancer Center of Zhejiang University Hangzhou 310058China

Synthetic lethality is a proven effective antitumor strategy that has attracted great attention.Large-scale screening has revealed many synthetic lethal genetic phenotypes,and relevant smallmolecule drugs have also been implemented in clinical practice.Increasing evidence suggests that CDKs,constituting a kinase family predominantly involved in cell cycle control,are synthetic lethal factors when combined with certain oncogenes,such as MFC,TP53,and RAS,which facilitate numerous antitumor treatment options based on CDK-related synthetic lethality.In this review,we focus on the synthetic lethal phenotype and mechanism related to CDKs and summarize the preclinical and clinical discoveries of CDK inhibitors to explore the prospect of CDK inhibitors as antitumor compounds for strategic synthesis lethality in the future.

关键词： Synthetic lethality Cyclin-dependent kinase antitumor therapy Oncogenes MYC P53 RAS PARP

The TLR7 agonists imiquimod and gardiquimod improve DC-based immunotherapy for melanoma in mice

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Cellular & Molecular Immunology 2010年第5期7卷 381-388页

作者： Fang Ma Jianhua Zhang Jian Zhang Cai Zhang Institute of Immunopharmacology and Immunotherapy School of Pharmaceutical SciencesShandong UniversityJinanChina

Toll-like receptors(TLRs)are a family of highly conserved germline-encoded pattern-recognition receptors that are essential for host immune responses.TLR ligands represent a promising class of immunotherapeutics or vaccine adjuvants with the potential to generate an effective antitumor immune response.The TLR7/8 agonists have aroused interest because they not only activate antigen-presenting cells but also promote activation of T and natural killer(NK)cells.However,the exact mechanism by which stimulation of these TLRs promotes immune responses remains unclear,and different TLR7/8 agonists have been found to induce different responses.In this study,we demonstrate that both gardiquimod and imiquimod promote the proliferation of murine splenocytes,stimulate the activation of splenic T,NK and natural killer T(NKT)cells,increase the cytolytic activity of splenocytes against B16 and MCA-38 tumor cell lines,and enhance the expression of costimulatory molecules and IL-12 by macrophages and bone marrow-derived dendritic cells(DCs).In a murine model,both agonists improved the antitumor effects of tumor lysate-loaded DCs,resulting in delayed growth of subcutaneous B16 melanoma tumors and suppression of pulmonary metastasis.Further,we found that gardiquimod demonstrated more potent antitumor activity than imiquimod.These results suggest that TLR7/8 agonists may serve as potent innate and adaptive immune response modifiers in tumor therapy.More importantly,they can be used as vaccine adjuvants to potentiate the efficiency of DC-based tumor immunotherapy.

关键词： antitumor therapy DC vaccine melanoma TLR TLR7/8 agonist