Naphthalene,anthracene and pyridone endoperoxides are known to thermally release singlet oxygen.However,in the cycloreversion reaction,singlet oxygen is produced stoichiometrically;therefore,multiple singlet oxygen re...Naphthalene,anthracene and pyridone endoperoxides are known to thermally release singlet oxygen.However,in the cycloreversion reaction,singlet oxygen is produced stoichiometrically;therefore,multiple singlet oxygen releasing modules are expected to be very useful in inducing apoptosis of cancer cells.Herein,we present a potential therapeutic agent presenting three-pyridone endoperoxide modules and a mitochondria targeting group.Compared to previously reported pyridone-based monofunctional endoperoxides,the triple endoperoxide is highly effective as evidenced by assays and fluorescence microscopy.展开更多
In recent years,proteolysis-targeting chimeras(PROTACs)have gained widespread attention as an emerging therapeutic approach.PROTACs are bifunctional molecules composed of a target protein-binding ligand,an E3 ubiquiti...In recent years,proteolysis-targeting chimeras(PROTACs)have gained widespread attention as an emerging therapeutic approach.PROTACs are bifunctional molecules composed of a target protein-binding ligand,an E3 ubiquitin ligase ligand,and a linker connecting these ligands.By harnessing the cell’s intrinsic ubiquitin-proteasome system(UPS),they promote the ubiquitination of specific target proteins,leading to their degradation and therapeutic effects.PROTACs show exceptional promise in targeting conventional“undruggable”targets compared to traditional small-molecule inhibitors.This review provides an overview of PROTACs,including their molecular mechanism of action,therapeutic benefits,development history,key design aspects,current research and development challenges,and future trends in nextgeneration PROTAC technology.展开更多
Metabolic reprogramming involving branched-chain amino acids(BCAAs)—leucine,isoleucine,and valine—is increasingly recognized as pivotal in cancer progression,metastasis,and immune modulation.This review comprehensiv...Metabolic reprogramming involving branched-chain amino acids(BCAAs)—leucine,isoleucine,and valine—is increasingly recognized as pivotal in cancer progression,metastasis,and immune modulation.This review comprehensively explores how cancer cells rewire BCAA metabolism to enhance proliferation,survival,and therapy resistance.Tumors manipulate BCAA uptake and catabolism via high expression of transporters like L-type amino acid transporter 1(LAT1)and enzymes including branched chain amino acid transaminase 1(BCAT1),branched chain amino acid transaminase 2(BCAT2),branched-chain alpha-keto acid dehydrogenase(BCKDH),and branched chain alpha-keto acid dehydrogenase kinase(BCKDK).These alterations sustain energy production,biosynthesis,redox homeostasis,and oncogenic signaling(especially mammalian target of rapamycin complex 1[mTORC1]).Crucially,tumor-driven BCAA depletion also shapes an immunosuppressive microenvironment,impairing anti-tumor immunity by limiting essential nutrients for T cells and natural killer(NK)cells.Innovative therapeutic strategies targeting BCAA pathways—ranging from selective small-molecule inhibitors(e.g.,LAT1 and BCAT1/2)to dietary modulation—have shown promising preclinical and early clinical efficacy,highlighting their potential to exploit metabolic vulnerabilities in cancer cells while bolstering immune responses.By integrating multi-omics data and precision targeting approaches,this review underscores the translational significance of BCAA metabolic reprogramming,positioning it as a novel frontier in cancer treatment.展开更多
Oncology Research Editorial Office Published:19 January 2026 The published article titled“miR-202 Promotes Cell Apoptosis in Esophageal Squamous Cell Carcinoma by Targeting HSF2”has been retracted from Oncology Rese...Oncology Research Editorial Office Published:19 January 2026 The published article titled“miR-202 Promotes Cell Apoptosis in Esophageal Squamous Cell Carcinoma by Targeting HSF2”has been retracted from Oncology Research,Vol.25,No.2,2017,pp.215-223.DOI:10.3727/096504016X14732772150541 URL:https://www.techscience.com/or/v25n2/56800.展开更多
The published article titled“MicroRNA-133b Inhibits Proliferation,Cellular Migration,and Invasion via Targeting LASP1 in Hepatocarcinoma Cells”has been retracted from Oncology Research,Vol.25,No.8,2017,pp.1269–1282.
Oncology Research Editorial Office Published:19 January 2026 The published article titled“miR-126-5p Restoration Promotes Cell Apoptosis in Cervical Cancer by Targeting Bcl2l2”has been retracted from Oncology Resear...Oncology Research Editorial Office Published:19 January 2026 The published article titled“miR-126-5p Restoration Promotes Cell Apoptosis in Cervical Cancer by Targeting Bcl2l2”has been retracted from Oncology Research,Vol.25,No.4,2017,pp.463-470.DOI:10.3727/096504016X14685034103879 URL:https://www.techscience.com/or/v25n4/56826.展开更多
Hepatic fibrosis is regulated by the synergistic actions of various cells and cytokines,with the activation and proliferation of hepatic stellate cells(HSCs) being considered the central event in this process.To achie...Hepatic fibrosis is regulated by the synergistic actions of various cells and cytokines,with the activation and proliferation of hepatic stellate cells(HSCs) being considered the central event in this process.To achieve specific targeting of activated hepatic stellate cells(a HSCs) and precise treatment of hepatic fibrosis,this study developed a dual-functional drug delivery system(SIL/c RGD-PEG-PPS PMs) with both targeting and responsive release capabilities.It aims to target the αvβ 3 receptor specifically expressed on the surface of a HSCs using the cyclic peptide c(RGDyk),and to exploit the high reactive oxygen species(ROS) level in the cellular microenvironment to achieve concentrated burst release of drugs at the pathological sites of hepatic fibrosis.Based on multiple assessments,SIL/c RGD-PEG-PPS PMs specifically enhanced the targeted delivery of silybin(SIL) to a HSCs,inhibited the proliferation and migration of a HSCs,and exhibited good biosafety.Additionally,it demonstrated excellent anti-fibrotic activity in fibrotic mice.In summary,this study shows great potential in targeted treatment of hepatic fibrosis and provides a multifunctional tool for advancing the research and therapeutic strategies of hepatic fibrosis.展开更多
Peripheral immunity forms the foundation of tumor immunity,while tumor immunity represents a more refined adaptation of peripheral immune responses.The tumor microenvironment(TME),a localized niche surrounding tumor c...Peripheral immunity forms the foundation of tumor immunity,while tumor immunity represents a more refined adaptation of peripheral immune responses.The tumor microenvironment(TME),a localized niche surrounding tumor cells,is inherently immunosuppressive(1,2).Effective tumor therapy necessitates the dismantling of this microenvironment,aiming to eradicate tumors from the host system.展开更多
Metal complexes hold significant promise in tumor diagnosis and treatment.However,their potential applications in photodynamic therapy(PDT)are hindered by issues such as poor photostability,low yield of reactive oxyge...Metal complexes hold significant promise in tumor diagnosis and treatment.However,their potential applications in photodynamic therapy(PDT)are hindered by issues such as poor photostability,low yield of reactive oxygen species(ROS),and aggregation-induced ROS quenching.To address these challenges,we present a molecular self-assembly strategy utilizing aggregation-induced emission(AIE)conjugates for metal complexes.As a proof of concept,we synthesized a mitochondrial-targeting cyclometalated Ir(Ⅲ)photosensitizer Ir-TPE.This approach significantly enhances the photodynamic effect while mitigating the dark toxicity associated with AIE groups.Ir-TPE readily self-assembles into nanoaggregates in aqueous solution,leading to a significant production of ROS upon light irradiation.Photoirradiated Ir-TPE triggers multiple modes of death by excessively accumulating ROS in the mitochondria,resulting in mitochondrial DNA damage.This damage can lead to ferroptosis and autophagy,two forms of cell death that are highly cytotoxic to cancer cells.The aggregation-enhanced photodynamic effect of Ir-TPE significantly enhances the production of ROS,leading to a more pronounced cytotoxic effect.In vitro and in vivo experiments demonstrate this aggregation-enhanced PDT approach achieves effective in situ tumor eradication.This study not only addresses the limitations of metal complexes in terms of low ROS production due to aggregation but also highlights the potential of this strategy for enhancing ROS production in PDT.展开更多
Breast cancer is a significant global concern,with limited effective treatment options.Therefore,therapies with high efficacy and low complications,unlike the existing chemotherapies,are urgently required.To address t...Breast cancer is a significant global concern,with limited effective treatment options.Therefore,therapies with high efficacy and low complications,unlike the existing chemotherapies,are urgently required.To address this issue,advances have been made in therapies targeting molecular pathways related to the murine double minute 2 protooncogene(MDM2)-tumor proteinp53(TP53)interaction.This review aims to investigate the efficacy of MDM2 inhibition in restoring TP53 activity in breast cancer cells,as evidenced by clinical studies,reviews,and trials.TP53 is a tumor suppressor and MDM2 facilitates proteasomal degradation of TP53.MDM2 and TP53 activity is tightly regulated.However,cancerous breast cells overexpress MDM2 through five hypothesized mechanisms.Consequently,TP53 levels decrease with increased tumor cell proliferation.Three strategies have been identified for controlling MDM2 upregulation in cells with wild-type or mutated TP53.MDM2 inhibitors(MDM2i)are administered in combination with existing chemotherapies to reduce their effects on healthy cells.Few clinical and preclinical studies have been conducted using MDM2i,which necessitates high-quality clinical trials to support their therapeutic potential in breast cancer therapy.展开更多
The potential of messenger RNA(m RNA)as a therapeutic tool for treating diseases has garnered considerable interest,especially in the wake of the successful creation of m RNA vaccines to counter corona virus disease 2...The potential of messenger RNA(m RNA)as a therapeutic tool for treating diseases has garnered considerable interest,especially in the wake of the successful creation of m RNA vaccines to counter corona virus disease 2019(COVID-19).Nucleic acid-based drug gene therapies have emerged as exceptionally promising avenues for combating disease.Furthermore,lipid nanoparticles(LNPs)are ideal carriers for nucleic acid delivery owing to their ionic nature,which enables nucleic acids to electrostatically interact with intracellular membranes,thereby promoting efficient intracellular nucleic acid release.Unfortunately,the effectiveness of LNPs in targeting organs beyond the liver is relatively poor.Thus,enhanced extrahepatic targeting is another important property that would lead to improved in vivo delivery by LNPs.This review focuses on the fundamental characteristics and functions of LNPs developed to facilitate cellular uptake and ensure effective intracellular release of m RNAs.Promising applications,possible advantages and potential challenges associated with use of LNPs in organ specific delivery and release of m RNAs are summarized.Furthermore,the need for future research to address limitations of currently developed LNPs for clinical applications of the m RNA technology is emphasized.展开更多
Recent advances in research on extracellular vesicles have significantly enhanced their potential as therapeutic agents for neurological diseases.Owing to their therapeutic properties and ability to cross the blood–b...Recent advances in research on extracellular vesicles have significantly enhanced their potential as therapeutic agents for neurological diseases.Owing to their therapeutic properties and ability to cross the blood–brain barrier,extracellular vesicles are recognized as promising drug delivery vehicles for various neurological conditions,including ischemic stroke,traumatic brain injury,neurodegenerative diseases,glioma,and psychosis.However,the clinical application of natural extracellular vesicles is hindered by their limited targeting ability and short clearance from the body.To address these limitations,multiple engineering strategies have been developed to enhance the targeting capabilities of extracellular vesicles,thereby enabling the delivery of therapeutic contents to specific tissues or cells.Therefore,this review aims to highlight the latest advancements in natural and targeting-engineered extracellular vesicles,exploring their applications in treating traumatic brain injury,ischemic stroke,Parkinson's disease,Alzheimer's disease,amyotrophic lateral sclerosis,glioma,and psychosis.Additionally,we summarized recent clinical trials involving extracellular vesicles and discussed the challenges and future prospects of using targeting-engineered extracellular vesicles for drug delivery in treating neurological diseases.This review offers new insights for developing highly targeted therapies in this field.展开更多
Nanobodies have been extensively demonstrated in biomedical imaging and therapy. However, nanobody probes often suffer from rapid renal clearance due to its small size. Herein, we reported a recombinant nanobody with ...Nanobodies have been extensively demonstrated in biomedical imaging and therapy. However, nanobody probes often suffer from rapid renal clearance due to its small size. Herein, we reported a recombinant nanobody with a 200 amino-acid polypeptide chain consisting of Pro, Ala, and Ser (PAS) at the C-terminal, which can be easily expressed in Escherichia coli with a high yield. The PASylated nanobody was functionalized with a fluorescent dye and the cell labeling properties were characterized by flow cytometry and confocal microscopy. In vivo fluorescence imaging indicated that the PASylated nanobody showed comparable blood circulation time, but ∼1.5 times higher tumor targeting ability as compared to the PEGylated nanobody of comparable molecular weight. Our findings demonstrate that nanobody PASylation is a promising approach to produce long-circulating nanobody probes for imaging and therapeutic applications.展开更多
The emerging messenger RNA(mRNA)nanomedicines have sprung up for disease treatment.Developing targeted mRNA nanomedicines has become a thrilling research hotspot in recent years,as they can be precisely delivered to s...The emerging messenger RNA(mRNA)nanomedicines have sprung up for disease treatment.Developing targeted mRNA nanomedicines has become a thrilling research hotspot in recent years,as they can be precisely delivered to specific organs or tissues to enhance efficiency and avoid side effects.Herein,we give a comprehensive review on the latest research progress of mRNA nanomedicines with targeting functions.mRNA and its carriers are first described in detail.Then,mechanisms of passive targeting,endogenous targeting,and active targeting are outlined,with a focus on various biological barriers that mRNA may encounter during in vivo delivery.Next,emphasis is placed on summarizing mRNA-based organtargeting strategies.Lastly,the advantages and challenges of mRNA nanomedicines in clinical translation are mentioned.This review is expected to inspire researchers in this field and drive further development of mRNA targeting technology.展开更多
Microneedle-mediated drug delivery systems(MDDS)have experienced robust growth in recent years,with designers leveraging their creativity to apply these systems for direct drug delivery to the skin,mucous membranes,bl...Microneedle-mediated drug delivery systems(MDDS)have experienced robust growth in recent years,with designers leveraging their creativity to apply these systems for direct drug delivery to the skin,mucous membranes,blood vessel walls and even internal organs.In order to achieve precise drug delivery,various delicately conceived drug release modes based on MDDS have been developed.Herein,to elucidate the design concepts of numerous reported MDDS,we have categorized them into two levels(Level-ⅠMDDS and Level-ⅡMDDS)depending on whether nanoscale and microscale carriers are integrated within the microneedles.In this work,the design strategies of MDDS,as well as the current status of their applications in targeted and intelligent drug delivery were reviewed,while their prospects and challenges for future industrialization and clinical applications were also discussed.展开更多
The published article titled“MicroRNA-133b Inhibits Cell Proliferation and Invasion in Osteosarcoma by Targeting Sirt1”has been retracted from Oncology Research,Vol.25,No.9,2017,pp.1421–1430.
Targeted covalent inhibitors,primarily targeting cysteine residues,have attracted great attention as potential drug candidates due to good potency and prolonged duration of action.However,their discovery is challengin...Targeted covalent inhibitors,primarily targeting cysteine residues,have attracted great attention as potential drug candidates due to good potency and prolonged duration of action.However,their discovery is challenging.In this research,a database-assisted liquid chromatography-tandem mass spectrometry(LC-MS/MS)strategy was developed to quickly discover potential cysteine-targeting compounds.First,compounds with potential reactive groups were selected and incubated with N-acetyl-cysteine in microsomes.And the precursor ions of possible cysteine-adducts were predicted based on covalent binding mechanisms to establish in-house database.Second,substrate-independent product ions produced from N-acetyl-cysteine moiety were selected.Third,multiple reaction monitoring scan was conducted to achieve sensitive screening for cysteine-targeting compounds.This strategy showed broad applicability,and covalent compounds with diverse structures were screened out,offering structural resources for covalent inhibitors development.Moreover,the screened compounds,norketamine and hydroxynorketamine,could modify synaptic transmission-related proteins in vivo,indicating their potential as covalent inhibitors.This experimental-based screening strategy provides a quick and reliable guidance for the design and discovery of covalent inhibitors.展开更多
Using the back skin of the mice as the test object,UPLC was used to determine the retention rate of Glabridin(GLA)in the skin and subcutaneous fat pf mice with different dosage forms and different administration times...Using the back skin of the mice as the test object,UPLC was used to determine the retention rate of Glabridin(GLA)in the skin and subcutaneous fat pf mice with different dosage forms and different administration times,and to investigate the transdermal absorption effect of liquid crystal cream.The experimental results showed that the 0.5,1,2,4,6 and 8h skin retention rates of GLA in the liquid crystal cream group were 1.67,0.79,1.73,1.47,1.17 and 1.15 times higher than those of the ordinary cream group under the same dosage of administration,respectively.The 0.5,1,2,4,6 and 8 h fat retention rates of GLA in the normal cream group were 0.86,1.87,1.37,1.20,1.35 and 1.19 times higher than those in the liquid crystal group,respectively.Liquid crystal cream can significantly improve the skin retention of GLA,with certain slow and controlled release,and possesses certain skin targeting properties.展开更多
Nanomedicine holds considerable promise for advancing cancer therapy,however,effective delivery of drugs to solid tumors remains a challenge due to rapid systemic clearance and inefficient cellular uptake.Herein,we ha...Nanomedicine holds considerable promise for advancing cancer therapy,however,effective delivery of drugs to solid tumors remains a challenge due to rapid systemic clearance and inefficient cellular uptake.Herein,we have developed a novel charge-reversible nanogel to deliver paclitaxel(PTX)dimers(DPP)with enhanced stability and targeting precision.The nanogels exhibit a dynamic charge-reversal mechanism responsive to the acidic tumor microenvironment(TME),optimizing the cellular uptake of prodrugs.In the high glutathione(GSH)conditions within cancer cells,the disulfide bonds in the DPP are cleaved,resulting in the intracellular release of active PTX and reduced drug toxicity to normal cells.In vivo pharmacokinetic studies revealed an extended plasma elimination half-life for the charge-reversible nanocarriers,and antitumor efficacy studies demonstrated superior tumor suppression with minimal systemic toxicity.This research underscores the potential of integrating charge-reversal and responsive release mechanisms into one nanocarrier system,balancing the long circulation and high tumor cell internalization capacity of the nanocarrier,and providing a promising strategy for targeted delivery of nanomedicine.展开更多
Osteopontin(OPN),a key extracellular matrix protein,promotes gastrointestinal tumor progression by activating the phosphatidylinositol 3-kinase(PI3K)/protein kinase B(AKT)pathway.OPN enhances tumor proliferation and s...Osteopontin(OPN),a key extracellular matrix protein,promotes gastrointestinal tumor progression by activating the phosphatidylinositol 3-kinase(PI3K)/protein kinase B(AKT)pathway.OPN enhances tumor proliferation and survival through mechanistic target of rapamycin and B-cell lymphoma 2 upregulation(e.g.,via denticleless E3 ubiquitin protein ligase homolog in hepatocellular carcinoma)and drives metastasis via PI3K/AKT-mediated epithelial-mesenchymal transition and androgen receptor(AR)activation(e.g.,via the OPN-RAN-AR axis in pancreatic cancer).Additionally,OPN induces chemoresistance by activating anti-apoptotic proteins(e.g.,XIAP via CXCR3/PI3K/AKT in colorectal cancer)and remodels the tumor microenvironment through VEGF-dependent angiogenesis and cluster of differentiation 44-PI3K/AKT-mediated immune evasion.Its interaction with TLR4,WNT,and other pathways amplifies oncogenic effects.Therapies targeting the OPN-PI3K/AKT axis(e.g.,PI3K inhibitors like LY294002)or combination treatments(e.g.,with EGFR-TKIs)show promise for reversing drug resistance.Future research should focus on OPN isoform specificity,clinical translation,and interactions with autophagy and long non-coding RNAs to refine precision therapies.This review summarizes recent advances in understanding the molecular mechanisms,therapeutic targets,and clinical challenges of the OPN-PI3K/AKT axis in gastrointestinal tumors,providing a foundation for overcoming resistance and developing precision therapies.展开更多
基金supported by the National Natural Science Foundation of China(22007008,22178048).
文摘Naphthalene,anthracene and pyridone endoperoxides are known to thermally release singlet oxygen.However,in the cycloreversion reaction,singlet oxygen is produced stoichiometrically;therefore,multiple singlet oxygen releasing modules are expected to be very useful in inducing apoptosis of cancer cells.Herein,we present a potential therapeutic agent presenting three-pyridone endoperoxide modules and a mitochondria targeting group.Compared to previously reported pyridone-based monofunctional endoperoxides,the triple endoperoxide is highly effective as evidenced by assays and fluorescence microscopy.
文摘In recent years,proteolysis-targeting chimeras(PROTACs)have gained widespread attention as an emerging therapeutic approach.PROTACs are bifunctional molecules composed of a target protein-binding ligand,an E3 ubiquitin ligase ligand,and a linker connecting these ligands.By harnessing the cell’s intrinsic ubiquitin-proteasome system(UPS),they promote the ubiquitination of specific target proteins,leading to their degradation and therapeutic effects.PROTACs show exceptional promise in targeting conventional“undruggable”targets compared to traditional small-molecule inhibitors.This review provides an overview of PROTACs,including their molecular mechanism of action,therapeutic benefits,development history,key design aspects,current research and development challenges,and future trends in nextgeneration PROTAC technology.
基金supported by a grant from the Dalian Science and Technology Innovation Fund Program(No.2024JJ13PT070)United Foundation for Dalian Institute of Chemical Physics,Chinese Academy of Sciences and the Second Hospital of Dalian Medical University(No.DMU-2&DICP UN202410)Dalian Life and Health Field Guidance Program Project(No.2024ZDJH01PT084).
文摘Metabolic reprogramming involving branched-chain amino acids(BCAAs)—leucine,isoleucine,and valine—is increasingly recognized as pivotal in cancer progression,metastasis,and immune modulation.This review comprehensively explores how cancer cells rewire BCAA metabolism to enhance proliferation,survival,and therapy resistance.Tumors manipulate BCAA uptake and catabolism via high expression of transporters like L-type amino acid transporter 1(LAT1)and enzymes including branched chain amino acid transaminase 1(BCAT1),branched chain amino acid transaminase 2(BCAT2),branched-chain alpha-keto acid dehydrogenase(BCKDH),and branched chain alpha-keto acid dehydrogenase kinase(BCKDK).These alterations sustain energy production,biosynthesis,redox homeostasis,and oncogenic signaling(especially mammalian target of rapamycin complex 1[mTORC1]).Crucially,tumor-driven BCAA depletion also shapes an immunosuppressive microenvironment,impairing anti-tumor immunity by limiting essential nutrients for T cells and natural killer(NK)cells.Innovative therapeutic strategies targeting BCAA pathways—ranging from selective small-molecule inhibitors(e.g.,LAT1 and BCAT1/2)to dietary modulation—have shown promising preclinical and early clinical efficacy,highlighting their potential to exploit metabolic vulnerabilities in cancer cells while bolstering immune responses.By integrating multi-omics data and precision targeting approaches,this review underscores the translational significance of BCAA metabolic reprogramming,positioning it as a novel frontier in cancer treatment.
文摘Oncology Research Editorial Office Published:19 January 2026 The published article titled“miR-202 Promotes Cell Apoptosis in Esophageal Squamous Cell Carcinoma by Targeting HSF2”has been retracted from Oncology Research,Vol.25,No.2,2017,pp.215-223.DOI:10.3727/096504016X14732772150541 URL:https://www.techscience.com/or/v25n2/56800.
文摘The published article titled“MicroRNA-133b Inhibits Proliferation,Cellular Migration,and Invasion via Targeting LASP1 in Hepatocarcinoma Cells”has been retracted from Oncology Research,Vol.25,No.8,2017,pp.1269–1282.
文摘Oncology Research Editorial Office Published:19 January 2026 The published article titled“miR-126-5p Restoration Promotes Cell Apoptosis in Cervical Cancer by Targeting Bcl2l2”has been retracted from Oncology Research,Vol.25,No.4,2017,pp.463-470.DOI:10.3727/096504016X14685034103879 URL:https://www.techscience.com/or/v25n4/56826.
基金supported by the financial assistance from Natural Science Fund Project of Science and Technology Department of Jilin Province (Nos.YDZJ202301ZYTS141,YDZJ202501ZYTS793)。
文摘Hepatic fibrosis is regulated by the synergistic actions of various cells and cytokines,with the activation and proliferation of hepatic stellate cells(HSCs) being considered the central event in this process.To achieve specific targeting of activated hepatic stellate cells(a HSCs) and precise treatment of hepatic fibrosis,this study developed a dual-functional drug delivery system(SIL/c RGD-PEG-PPS PMs) with both targeting and responsive release capabilities.It aims to target the αvβ 3 receptor specifically expressed on the surface of a HSCs using the cyclic peptide c(RGDyk),and to exploit the high reactive oxygen species(ROS) level in the cellular microenvironment to achieve concentrated burst release of drugs at the pathological sites of hepatic fibrosis.Based on multiple assessments,SIL/c RGD-PEG-PPS PMs specifically enhanced the targeted delivery of silybin(SIL) to a HSCs,inhibited the proliferation and migration of a HSCs,and exhibited good biosafety.Additionally,it demonstrated excellent anti-fibrotic activity in fibrotic mice.In summary,this study shows great potential in targeted treatment of hepatic fibrosis and provides a multifunctional tool for advancing the research and therapeutic strategies of hepatic fibrosis.
文摘Peripheral immunity forms the foundation of tumor immunity,while tumor immunity represents a more refined adaptation of peripheral immune responses.The tumor microenvironment(TME),a localized niche surrounding tumor cells,is inherently immunosuppressive(1,2).Effective tumor therapy necessitates the dismantling of this microenvironment,aiming to eradicate tumors from the host system.
基金support from the National Natural Science Foundation of China(Nos.22277056,21977052)the Distinguished Young Scholars of Jiangsu Province(No.BK20230006)+2 种基金the Natural Science Foundation of Jiangsu Province(Nos.BK20230977,BK20231090)the Natural Science Foundation of the Higher Education Institutions of Jiangsu Province(No.23KJB150020)the Jiangsu Excellent Postdoctoral Program(No.2022ZB758)。
文摘Metal complexes hold significant promise in tumor diagnosis and treatment.However,their potential applications in photodynamic therapy(PDT)are hindered by issues such as poor photostability,low yield of reactive oxygen species(ROS),and aggregation-induced ROS quenching.To address these challenges,we present a molecular self-assembly strategy utilizing aggregation-induced emission(AIE)conjugates for metal complexes.As a proof of concept,we synthesized a mitochondrial-targeting cyclometalated Ir(Ⅲ)photosensitizer Ir-TPE.This approach significantly enhances the photodynamic effect while mitigating the dark toxicity associated with AIE groups.Ir-TPE readily self-assembles into nanoaggregates in aqueous solution,leading to a significant production of ROS upon light irradiation.Photoirradiated Ir-TPE triggers multiple modes of death by excessively accumulating ROS in the mitochondria,resulting in mitochondrial DNA damage.This damage can lead to ferroptosis and autophagy,two forms of cell death that are highly cytotoxic to cancer cells.The aggregation-enhanced photodynamic effect of Ir-TPE significantly enhances the production of ROS,leading to a more pronounced cytotoxic effect.In vitro and in vivo experiments demonstrate this aggregation-enhanced PDT approach achieves effective in situ tumor eradication.This study not only addresses the limitations of metal complexes in terms of low ROS production due to aggregation but also highlights the potential of this strategy for enhancing ROS production in PDT.
文摘Breast cancer is a significant global concern,with limited effective treatment options.Therefore,therapies with high efficacy and low complications,unlike the existing chemotherapies,are urgently required.To address this issue,advances have been made in therapies targeting molecular pathways related to the murine double minute 2 protooncogene(MDM2)-tumor proteinp53(TP53)interaction.This review aims to investigate the efficacy of MDM2 inhibition in restoring TP53 activity in breast cancer cells,as evidenced by clinical studies,reviews,and trials.TP53 is a tumor suppressor and MDM2 facilitates proteasomal degradation of TP53.MDM2 and TP53 activity is tightly regulated.However,cancerous breast cells overexpress MDM2 through five hypothesized mechanisms.Consequently,TP53 levels decrease with increased tumor cell proliferation.Three strategies have been identified for controlling MDM2 upregulation in cells with wild-type or mutated TP53.MDM2 inhibitors(MDM2i)are administered in combination with existing chemotherapies to reduce their effects on healthy cells.Few clinical and preclinical studies have been conducted using MDM2i,which necessitates high-quality clinical trials to support their therapeutic potential in breast cancer therapy.
基金supported by Guang Dong Basic and Applied Basic Research Foundation(No.2023B1515120001)Shenzhen University 2035 Program for Excellent Research(Nos.00000208 and 00000225)。
文摘The potential of messenger RNA(m RNA)as a therapeutic tool for treating diseases has garnered considerable interest,especially in the wake of the successful creation of m RNA vaccines to counter corona virus disease 2019(COVID-19).Nucleic acid-based drug gene therapies have emerged as exceptionally promising avenues for combating disease.Furthermore,lipid nanoparticles(LNPs)are ideal carriers for nucleic acid delivery owing to their ionic nature,which enables nucleic acids to electrostatically interact with intracellular membranes,thereby promoting efficient intracellular nucleic acid release.Unfortunately,the effectiveness of LNPs in targeting organs beyond the liver is relatively poor.Thus,enhanced extrahepatic targeting is another important property that would lead to improved in vivo delivery by LNPs.This review focuses on the fundamental characteristics and functions of LNPs developed to facilitate cellular uptake and ensure effective intracellular release of m RNAs.Promising applications,possible advantages and potential challenges associated with use of LNPs in organ specific delivery and release of m RNAs are summarized.Furthermore,the need for future research to address limitations of currently developed LNPs for clinical applications of the m RNA technology is emphasized.
基金supported by the National Natural Science Foundation of China,Nos.82171363,82371381(to PL),82171458(to XJ)Key Research and Development Project of Shaa nxi Province,Nos.2024SF-YBXM-404(to KY)。
文摘Recent advances in research on extracellular vesicles have significantly enhanced their potential as therapeutic agents for neurological diseases.Owing to their therapeutic properties and ability to cross the blood–brain barrier,extracellular vesicles are recognized as promising drug delivery vehicles for various neurological conditions,including ischemic stroke,traumatic brain injury,neurodegenerative diseases,glioma,and psychosis.However,the clinical application of natural extracellular vesicles is hindered by their limited targeting ability and short clearance from the body.To address these limitations,multiple engineering strategies have been developed to enhance the targeting capabilities of extracellular vesicles,thereby enabling the delivery of therapeutic contents to specific tissues or cells.Therefore,this review aims to highlight the latest advancements in natural and targeting-engineered extracellular vesicles,exploring their applications in treating traumatic brain injury,ischemic stroke,Parkinson's disease,Alzheimer's disease,amyotrophic lateral sclerosis,glioma,and psychosis.Additionally,we summarized recent clinical trials involving extracellular vesicles and discussed the challenges and future prospects of using targeting-engineered extracellular vesicles for drug delivery in treating neurological diseases.This review offers new insights for developing highly targeted therapies in this field.
基金support by the National Key R&D Program of China(Grant No.2020YFA0909000)National Natural Science Foundation of China(Grant Nos.62235007 and 22204070)+2 种基金Shenzhen Science and Technology Program(Grant Nos.KQTD20170810111314625,JCYJ20210324115807021,and SGDX20211123114002003)Shenzhen Bay Laboratory(SZBL 2021080601002)Guangdong Provincial Key Laboratory of Advanced Biomaterials(2022 B1212010003).
文摘Nanobodies have been extensively demonstrated in biomedical imaging and therapy. However, nanobody probes often suffer from rapid renal clearance due to its small size. Herein, we reported a recombinant nanobody with a 200 amino-acid polypeptide chain consisting of Pro, Ala, and Ser (PAS) at the C-terminal, which can be easily expressed in Escherichia coli with a high yield. The PASylated nanobody was functionalized with a fluorescent dye and the cell labeling properties were characterized by flow cytometry and confocal microscopy. In vivo fluorescence imaging indicated that the PASylated nanobody showed comparable blood circulation time, but ∼1.5 times higher tumor targeting ability as compared to the PEGylated nanobody of comparable molecular weight. Our findings demonstrate that nanobody PASylation is a promising approach to produce long-circulating nanobody probes for imaging and therapeutic applications.
基金supported by the National Key Research and Development Program of China(2022YFA1105304)the National Natural Science Foundation of China(T2225003 and 61927805)+5 种基金the Nanjing Medical Science and Technique Development Foundation(ZKX21019)the Clinical Trials from Nanjing Drum Tower Hospital(2022-LCYJ-ZD-01)the Jiangsu Funding Program for Excellent Postdoctoral Talent(2023ZB032)the Natural Science Foundation of Jiangsu Province(BK20240223)the Project of Institute of Chinese Medicine of Nanjing University(ICM2024011)the Aid Project of Nanjing Drum Tower Hospital Health,Education&Research Foundation.
文摘The emerging messenger RNA(mRNA)nanomedicines have sprung up for disease treatment.Developing targeted mRNA nanomedicines has become a thrilling research hotspot in recent years,as they can be precisely delivered to specific organs or tissues to enhance efficiency and avoid side effects.Herein,we give a comprehensive review on the latest research progress of mRNA nanomedicines with targeting functions.mRNA and its carriers are first described in detail.Then,mechanisms of passive targeting,endogenous targeting,and active targeting are outlined,with a focus on various biological barriers that mRNA may encounter during in vivo delivery.Next,emphasis is placed on summarizing mRNA-based organtargeting strategies.Lastly,the advantages and challenges of mRNA nanomedicines in clinical translation are mentioned.This review is expected to inspire researchers in this field and drive further development of mRNA targeting technology.
基金supported by the National Natural Science Foundation of China(Grant number 82074031)the Program for Professor of Special Appointment(Eastern Scholar)at Shanghai Institutions of Higher Learning(Grant number TP2020054)+1 种基金Shanghai Sailing Program(21YF1447400)the Program for Shanghai High-Level Local University Innovation Team(SZY20220315).
文摘Microneedle-mediated drug delivery systems(MDDS)have experienced robust growth in recent years,with designers leveraging their creativity to apply these systems for direct drug delivery to the skin,mucous membranes,blood vessel walls and even internal organs.In order to achieve precise drug delivery,various delicately conceived drug release modes based on MDDS have been developed.Herein,to elucidate the design concepts of numerous reported MDDS,we have categorized them into two levels(Level-ⅠMDDS and Level-ⅡMDDS)depending on whether nanoscale and microscale carriers are integrated within the microneedles.In this work,the design strategies of MDDS,as well as the current status of their applications in targeted and intelligent drug delivery were reviewed,while their prospects and challenges for future industrialization and clinical applications were also discussed.
文摘The published article titled“MicroRNA-133b Inhibits Cell Proliferation and Invasion in Osteosarcoma by Targeting Sirt1”has been retracted from Oncology Research,Vol.25,No.9,2017,pp.1421–1430.
基金supported by the Science and Technology Development Fund,Macao SAR,China(Grant Nos.:FDCT 0001/2020/AKP and 006/2023/SKL)Guangxi Science and Technology Major Program,China(Program No.:Guike AA22096022).
文摘Targeted covalent inhibitors,primarily targeting cysteine residues,have attracted great attention as potential drug candidates due to good potency and prolonged duration of action.However,their discovery is challenging.In this research,a database-assisted liquid chromatography-tandem mass spectrometry(LC-MS/MS)strategy was developed to quickly discover potential cysteine-targeting compounds.First,compounds with potential reactive groups were selected and incubated with N-acetyl-cysteine in microsomes.And the precursor ions of possible cysteine-adducts were predicted based on covalent binding mechanisms to establish in-house database.Second,substrate-independent product ions produced from N-acetyl-cysteine moiety were selected.Third,multiple reaction monitoring scan was conducted to achieve sensitive screening for cysteine-targeting compounds.This strategy showed broad applicability,and covalent compounds with diverse structures were screened out,offering structural resources for covalent inhibitors development.Moreover,the screened compounds,norketamine and hydroxynorketamine,could modify synaptic transmission-related proteins in vivo,indicating their potential as covalent inhibitors.This experimental-based screening strategy provides a quick and reliable guidance for the design and discovery of covalent inhibitors.
文摘Using the back skin of the mice as the test object,UPLC was used to determine the retention rate of Glabridin(GLA)in the skin and subcutaneous fat pf mice with different dosage forms and different administration times,and to investigate the transdermal absorption effect of liquid crystal cream.The experimental results showed that the 0.5,1,2,4,6 and 8h skin retention rates of GLA in the liquid crystal cream group were 1.67,0.79,1.73,1.47,1.17 and 1.15 times higher than those of the ordinary cream group under the same dosage of administration,respectively.The 0.5,1,2,4,6 and 8 h fat retention rates of GLA in the normal cream group were 0.86,1.87,1.37,1.20,1.35 and 1.19 times higher than those in the liquid crystal group,respectively.Liquid crystal cream can significantly improve the skin retention of GLA,with certain slow and controlled release,and possesses certain skin targeting properties.
基金supported by the Natural Science Foundation of Jilin Province(No.20240101003JJ)the National Natural Science Foundation of China(Nos.22275065,52073116)。
文摘Nanomedicine holds considerable promise for advancing cancer therapy,however,effective delivery of drugs to solid tumors remains a challenge due to rapid systemic clearance and inefficient cellular uptake.Herein,we have developed a novel charge-reversible nanogel to deliver paclitaxel(PTX)dimers(DPP)with enhanced stability and targeting precision.The nanogels exhibit a dynamic charge-reversal mechanism responsive to the acidic tumor microenvironment(TME),optimizing the cellular uptake of prodrugs.In the high glutathione(GSH)conditions within cancer cells,the disulfide bonds in the DPP are cleaved,resulting in the intracellular release of active PTX and reduced drug toxicity to normal cells.In vivo pharmacokinetic studies revealed an extended plasma elimination half-life for the charge-reversible nanocarriers,and antitumor efficacy studies demonstrated superior tumor suppression with minimal systemic toxicity.This research underscores the potential of integrating charge-reversal and responsive release mechanisms into one nanocarrier system,balancing the long circulation and high tumor cell internalization capacity of the nanocarrier,and providing a promising strategy for targeted delivery of nanomedicine.
基金Supported by Hongkou District Health Commission of Shanghai Municipality,No.“Hongwei”2303-10.
文摘Osteopontin(OPN),a key extracellular matrix protein,promotes gastrointestinal tumor progression by activating the phosphatidylinositol 3-kinase(PI3K)/protein kinase B(AKT)pathway.OPN enhances tumor proliferation and survival through mechanistic target of rapamycin and B-cell lymphoma 2 upregulation(e.g.,via denticleless E3 ubiquitin protein ligase homolog in hepatocellular carcinoma)and drives metastasis via PI3K/AKT-mediated epithelial-mesenchymal transition and androgen receptor(AR)activation(e.g.,via the OPN-RAN-AR axis in pancreatic cancer).Additionally,OPN induces chemoresistance by activating anti-apoptotic proteins(e.g.,XIAP via CXCR3/PI3K/AKT in colorectal cancer)and remodels the tumor microenvironment through VEGF-dependent angiogenesis and cluster of differentiation 44-PI3K/AKT-mediated immune evasion.Its interaction with TLR4,WNT,and other pathways amplifies oncogenic effects.Therapies targeting the OPN-PI3K/AKT axis(e.g.,PI3K inhibitors like LY294002)or combination treatments(e.g.,with EGFR-TKIs)show promise for reversing drug resistance.Future research should focus on OPN isoform specificity,clinical translation,and interactions with autophagy and long non-coding RNAs to refine precision therapies.This review summarizes recent advances in understanding the molecular mechanisms,therapeutic targets,and clinical challenges of the OPN-PI3K/AKT axis in gastrointestinal tumors,providing a foundation for overcoming resistance and developing precision therapies.
