Inflammatory bowel disease(IBD)is a chronic gastrointestinal inflammatory disease.With the emergence of biologics and other therapeutic methods,two biologics or one biologic combined with a novel small-molecule drug h...Inflammatory bowel disease(IBD)is a chronic gastrointestinal inflammatory disease.With the emergence of biologics and other therapeutic methods,two biologics or one biologic combined with a novel small-molecule drug has been proposed in recent years to treat IBD.Although treatment strategies for IBD are being optimized,their efficacy and risks still warrant further consideration.This editorial explores the current risks associated with dual-targeted treatment for IBD and the great potential that fecal microbiota transplantation(FMT)may have for use in combination therapy for IBD.We are focused on addressing refractory IBD or biologically resistant IBD based on currently available dual-targeted treatment by incorporating FMT as part of this dual-targeted treatment.In this new therapy regimen,FMT represents a promising combination therapy.展开更多
Objective: The purpose of the study was to explore the application effects of the cloud platform-based comprehensive online management for breast cancer patients using dual-targeted therapy with macromolecular monoclo...Objective: The purpose of the study was to explore the application effects of the cloud platform-based comprehensive online management for breast cancer patients using dual-targeted therapy with macromolecular monoclonal antibodies. Methods: 120 breast cancer patients treated by dual-targeted therapy with macromolecular monoclonal antibodies were managed by a cloud platform from March to November 2019. Comprehensive online management included consultation about drugs and side effects and frequently asked questions in the dual-targeted therapy with macromolecular monoclonal antibodies. Results: In the consultation about drugs and side effects, there were five patients with fever, neutrophil, cough, and fatigue;24 with diarrhea;25 with nausea;11 with oral mucosal inflammation;10 with rashes and dry skin;8 with insomnia;and 1 with palpitation. Moreover, 110 patients with anxiety about the missed or delayed treatment were properly handled. Conclusion: The comprehensive online management of dual-targeted therapy with macromolecular monoclonal antibodies based on the cloud platform is helpful to satisfy the at-home breast cancer patients’ needs, ensure the continuity of dual-targeted therapy with macromolecular monoclonal antibodies for breast cancer patients, prevent misinformation, alleviate patients’ negative psychological emotions, and reduce patients’ economic losses. The online cloud platform integrated management model is crucial for managing patients with breast cancer treated by dual-targeted therapy.展开更多
Tumor metastasis accounts for the major portion of cancer-related deaths.Magnetic resonance imaging(MRI)is a valuable imaging modality for tumor diagnosis in clinical applications,offering detailed soft tissue images ...Tumor metastasis accounts for the major portion of cancer-related deaths.Magnetic resonance imaging(MRI)is a valuable imaging modality for tumor diagnosis in clinical applications,offering detailed soft tissue images with excellent spatial resolution and good biosafety.However,the low sensitivity and the lack of specificity to disease sites limit the application of MRI contrast agents in early and precise detection of small primary and metastatic cancers.Therefore,there is an urgent need for innovative MRI contrast agents with enhanced relaxivity,target ability,and pharmacokinetics to improve imaging sensitivity and widen the detection window in the meantime.Here,we reported a dual-targeting protein MRI contrast agent(EPR-DTPA-Gd)fused by a nanobody against epidermal growth factor receptor 1(EGFR),integrinα_(v)β_(3)-binding cyclic nonapeptide,and elastin-like polypeptide.We found that this protein contrast agent exhibited high sensitivity and specificity for the tumor overexpressed EGFR and integrinα_(v)β_(3)in MRI.Furthermore,EPR-DTPA-Gd had high longitudinal relaxation rate(r_(1))(68.76 mM^(−1)s^(−1)per molecule)and an improved pharmacokinetics behavior for tumor imaging.Using T1-weighted imaging,EPR-DTPA-Gd successfully detected a series of early metastases with the smallest 0.012mm^(2)(213μm×58μm)in a liver metastasis model of human cervical carcinoma HeLa cells,which cannot be detected by the clinically approved T1-weighted contrast agent.The heightened detection sensitivity intrinsic to EPR-DTPA-Gd facilitates precise imaging of tumor lesions,supporting sophisticated image-guided interventions and early management in high-risk patient cohorts.展开更多
Acute myeloid leukemia(AML)is an aggressive hematological malignancy with high mortality rates and poor prognosis,largely due to the nonspecific drug distribution and suboptimal therapeutic efficacy.To address these c...Acute myeloid leukemia(AML)is an aggressive hematological malignancy with high mortality rates and poor prognosis,largely due to the nonspecific drug distribution and suboptimal therapeutic efficacy.To address these challenges,here we proposed a CD44/Transferrin receptor dual targeted self-delivery micelle for the combination delivery of chemotherapeutic doxorubicin(DOX)and artesunate(ART),a natural product known for its ability of killing AML cells by inducing apoptosis.To improve AML targeting,the transferrin receptor targeting peptide T7 was conjugated with CD44 targeting hyaluronic acid(HA),followed by conjugation with hydrophobic ART to afford the amphiphilic polymer for DOX encapsulation(termed THAD).The resulting self-delivery micellar drug delivery system THAD significantly enhanced the cellular internalization of AML cells and facilitated in vivo tumor targeting.Compared with single drug treatment groups,the combination of ART and DOX showed a better tumor killing ability.Furthermore,THAD suppressed the tumor proliferation by 90.74%.Specifically,THAD induced significantly mitochondrial-dependent apoptosis via increasing mitochondrial membranes damage and subsequent G1 phase arrest,as evidenced by the decreased levels of pro-caspase-3 and Bcl-2,along with the increased levels of Bax and cleaved poly(ADP-ribose)polymerase(PARP).Furthermore,THAD inhibited protein kinase B(AKT)phosphorylation,leading to a decrease of c-Myc expression in response to a negative growth regulator.In the human acute myeloid leukemia cells(MOLM13)cell-bearing mouse model,THAD significantly inhibited AML cell infiltration and proliferation in both bone marrow and liver,effectively suppressing AML progression.Collectively,THAD demonstrated enhanced anti-AML effects by promoting apoptosis,offering a promising targeted self-delivery strategy for combination chemotherapy in AML treatment.展开更多
Fluorogenic probes with"off-on"fluorescence signals have emerged as powerful tools for biosensing and bioimaging of biomolecules in living systems.Conventional single-target probes,however,often suffer from ...Fluorogenic probes with"off-on"fluorescence signals have emerged as powerful tools for biosensing and bioimaging of biomolecules in living systems.Conventional single-target probes,however,often suffer from false-positive signals due to non-specific activation in non-target tissues or the diffusion of activated fluorescent products.To address these limitations,dual-targeted fluorogenic probes(DTFPs)have been developed,which simultaneously target two biomarkers to enhance detection specificity and minimize false-positive outcomes.DTFPs are designed to activate or retain fluorescence only when both biomarkers are present within a targeted region,enabling precise in vivo imaging of pathological conditions such as tumors and inflammation.This review highlights recent advances in DTFP development,focusing on their design principles,activation mechanisms,and applications in biosensing and bioimaging.We also discuss current challenges and future directions for DTFP research,aiming to inspire the design of next-generation probes with improved accuracy and specificity.By providing a comprehensive overview of DTFPs,this review seeks to advance their potential for transformative applications in biomedical imaging and diagnostics.展开更多
Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)mutations are influenced by random and uncontrollable factors,and the risk of the next widespread epidemic remains.Dual-target drugs that synergistically act ...Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)mutations are influenced by random and uncontrollable factors,and the risk of the next widespread epidemic remains.Dual-target drugs that synergistically act on two targets exhibit strong therapeutic effects and advantages against mutations.In this study,a novel computational workflow was developed to design dual-target SARS-CoV-2 candidate inhibitors with the Envelope protein and Main protease selected as the two target proteins.The drug-like molecules of our self-constructed 3D scaffold database were used as high-throughput molecular docking probes for feature extraction of two target protein pockets.A multi-layer perceptron(MLP)was employed to embed the binding affinities into a latent space as conditional vectors to control conditional distribution.Utilizing a conditional generative neural network,cG-SchNet,with 3D Euclidean group(E3)symmetries,the conditional probability distributions of molecular 3D structures were acquired and a set of novel SARS-CoV-2 dual-target candidate inhibitors were generated.The 1D probability,2D joint probability,and 2D cumulative probability distribution results indicate that the generated sets are significantly enhanced compared to the training set in the high binding affinity area.Among the 201 generated molecules,42 molecules exhibited a sum binding affinity exceeding 17.0 kcal/mol while 9 of them having a sum binding affinity exceeding 19.0 kcal/mol,demonstrating structure diversity along with strong dual-target affinities,good absorption,distribution,metabolism,excretion,and toxicity(ADMET)properties,and ease of synthesis.Dual-target drugs are rare and difficult to find,and our“high-throughput docking-multi-conditional generation”workflow offers a wide range of options for designing or optimizing potent dual-target SARS-CoV-2 inhibitors.展开更多
Antioxidation and adjustable treatment strategies are critical for the effective treatment of Alzheimer’s disease(AD).Here,we design a dual-targeted Prussian blue nanoformulation(PTCN)that can cross the blood-brain b...Antioxidation and adjustable treatment strategies are critical for the effective treatment of Alzheimer’s disease(AD).Here,we design a dual-targeted Prussian blue nanoformulation(PTCN)that can cross the blood-brain barrier and target amyloid beta aggregates further exert antioxidant effects.An adjustable gradient dosing strategy with PTCN is used for the first time to design the preventive and therapeutic trials based on the severity of oxidative stress at different AD stages.The results show that PTCN could effectively ameliorate AD-related pathological processes,improve the cognitive decline,and rescue hippocampal atrophy of APP/PS1 mice in both preventive and therapeutic trials.Altogether,PTCN provided here is a successful combination of three traditional biomaterials with good biosafety,which has broad prospects for the early prevention,mild remission,and late treatment of AD,and is expected to be developed into personalized therapeutic drugs and healthcare products for clinical AD in the future.展开更多
Diabetes mellitus remains a major global health issue,and great attention is directed at natural therapeutics.This systematic review aimed to assess the potential of flavonoids as antidiabetic agents by investigating ...Diabetes mellitus remains a major global health issue,and great attention is directed at natural therapeutics.This systematic review aimed to assess the potential of flavonoids as antidiabetic agents by investigating their inhibitory effects onα-glucosidase andα-amylase,two key enzymes involved in starch digestion.Six scientific databases(PubMed,Virtual Health Library,EMBASE,SCOPUS,Web of Science,and WHO Global Index Medicus)were searched until August 21,2022,for in vitro studies reporting IC50 values of purified flavonoids onα-amylase andα-glucosidase,along with corresponding data for acarbose as a positive control.A total of 339 eligible articles were analyzed,resulting in the retrieval of 1643 flavonoid structures.These structures were rigorously standardized and curated,yielding 974 unique compounds,among which 177 flavonoids exhibited inhibition of bothα-glucosidase andα-amylase are presented.Quality assessment utilizing a modified CONSORT checklist and structure-activity relationship(SAR)analysis were performed,revealing crucial features for the simultaneous inhibition of flavonoids against both enzymes.Moreover,the review also addressed several limitations in the current research landscape and proposed potential solutions.The curated datasets are available online at https://github.com/MedChemUMP/FDIGA.展开更多
Objective:In B-cell acute lymphoblastic leukemia(B-ALL),current intensive chemotherapies for adult patients fail to achieve durable responses in more than 50%of cases,underscoring the urgent need for new therapeutic r...Objective:In B-cell acute lymphoblastic leukemia(B-ALL),current intensive chemotherapies for adult patients fail to achieve durable responses in more than 50%of cases,underscoring the urgent need for new therapeutic regimens for this patient population.The present study aimed to determine whether HZX-02-059,a novel dual-target inhibitor targeting both phosphatidylinositol-3-phosphate 5-kinase(PIKfyve)and tubulin,is lethal to B-ALL cells and is a potential therapeutic for B-ALL patients.Methods:Cell proliferation,vacuolization,apoptosis,cell cycle,and in-vivo tumor growth were evaluated.In addition,Genome-wide RNA-sequencing studies were conducted to elucidate the mechanisms of action underlying the anti-leukemia activity of HZX-02-059 in B-ALL.Results:HZX-02-059 was found to inhibit cell proliferation,induce vacuolization,promote apoptosis,block the cell cycle,and reduce in-vivo tumor growth.Downregulation of the p53 pathway and suppression of the phosphoinositide 3-kinase(PI3K)/AKT pathway and the downstream transcription factors c-Myc and NF-κB were responsible for these observations.Conclusion:Overall,these findings suggest that HZX-02-059 is a promising agent for the treatment of B-ALL patients resistant to conventional therapies.展开更多
Micro RNA-133a(mi RNA-133a) and cardiac troponin I(c Tn I) are different-type crucial biomarkers of acute myocardial infarction(AMI), whose levels are great significance for AMI diagnosis and treatment. Herein,a novel...Micro RNA-133a(mi RNA-133a) and cardiac troponin I(c Tn I) are different-type crucial biomarkers of acute myocardial infarction(AMI), whose levels are great significance for AMI diagnosis and treatment. Herein,a novel photoelectrochemical-electrochemical(PEC-EC) dual-mode biosensing platform for dual-target assays of mi RNA-133a and c Tn I was developed. In which, a PEC-EC dual-mode sensing platform for mi RNA-133a was constructed based on the changes of the photocurrent inhibition effect and the electrochemical signal of Fc on the Fc-hairpin DNA probe(Fc-HP)/Zn Cd S-quantum dots(QDs)/ITO electrode. Furthermore, under magnetic separation and the specific interaction between c Tn I and its aptamer, the N-doped porous carbon-Zn O polyhedra(NPC-Zn O)-hemin-capture DNA probe hybrid(NH-CP) was obtained and introduced to the Fc-HP/Zn Cd S-QDs/ITO electrode via hybridization between NH-CP and Fc-HP. The hemin molecules encapsulated in NH-CP could effectively induce the photocurrent-polarity-switching of the FcHP/Zn Cd S-QDs/ITO electrode and generate a new electrochemical signal originating from hemin. Thus,c Tn I was assayed sensitively and selectively by the PEC-EC dual-mode biosensing platform. Here, Fc and hemin not only serve as the electrochemical indicators, but also respectively inhibit the photocurrent and switch the photocurrent polarity of Zn Cd S-QDs. Furthermore, the proposed biosensing platform could be easily expanded to the detection of other multiplex-type biomarkers via the change of the sequences of the related DNA probes, implying its significant potential in clinical diagnosis and biological analysis.展开更多
The treatment of patients with inflammatory bowel disease(IBD),especially those with severe or refractory disease,represents an important challenge for the clinical gastroenterologist.It seems to be no exaggeration to...The treatment of patients with inflammatory bowel disease(IBD),especially those with severe or refractory disease,represents an important challenge for the clinical gastroenterologist.It seems to be no exaggeration to say that in these patients,not only the scientific background of the gastroenterologist is tested,but also the abundance of“gifts”that he should possess(insight,intuition,determ-ination,ability to take initiative,etc.)for the successful outcome of the treatment.In daily clinical practice,depending on the severity of the attack,IBD is treated with one or a combination of two or more pharmaceutical agents.These combin-ations include not only the first-line drugs(e.g.,mesalazine,corticosteroids,antibiotics,etc)but also second-and third-line drugs(immunosuppressants and biologic agents).It is a fact that despite the significant therapeutic advances there is still a significant percentage of patients who do not satisfactorily respond to the treatment applied.Therefore,a part of these patients are going to surgery.In recent years,several small-size clinical studies,reviews,and case reports have been published combining not only biological agents with other drugs(e.g.,immunosuppressants or corticosteroids)but also the combination of two biologi-cal agents simultaneously,especially in severe cases.In our opinion,it is at least a strange(and largely unexplained)fact that we often use combinations of drugs in a given patient although studies comparing the simultaneous administration of two or more drugs with monotherapy are very few.As mentioned above,there is a timid tendency in the literature to combine two biological agents in severe cases unresponsive to the applied treatment or patients with severe extraintestinal manifestations.The appropriate dosage,the duration of the administration,the suitable timing for checking the clinical and laboratory outcome,as well as the treatment side-effects,should be the subject of intense clinical research shortly.In this editorial,we attempt to summarize the existing data regarding the already applied combination therapies and to humbly formulate thoughts and suggestions for the future application of the combination treatment of biological agents in a well-defined category of patients.We suggest that the application of biomarkers and artificial intelligence could help in establishing new forms of treatment using the available modern drugs in patients with IBD resistant to treatment.展开更多
Organelles are specialized areas where cells perform specific processes necessary for life and actively communicate with each other to keep the whole cell func-tioning.Disorders of the organelle networks are associate...Organelles are specialized areas where cells perform specific processes necessary for life and actively communicate with each other to keep the whole cell func-tioning.Disorders of the organelle networks are associated with multiple patho-logical processes.However,clearly and intuitively visualizing the highly dynamic interactions between ultrafine organelles is challenging.Fluorescence imaging technology provides opportunities due to the distinct advantages of facile,non-invasiveness and dynamic detection,making it particularly well-suited for appli-cations in uncovering the mysterious veil of organelle interactions.Regrettably,the lack of ideal fluorescence agents has always been an obstacle in imaging the intricate behaviors of organelles.In this review,we provide a systematic discussion on the existing dual-color and dual-targetable molecular sensors used in moni-toring organelle interactions,with a specific focus on their targeting strategies,imaging mechanisms and biological applications.Additionally,the current limi-tations and future development directions of dual-targetable probes and dual-emissives are briefly discussed.This review aims to provide guidance for re-searchers to develop more improved probes for studying organelle interactions in the biomedical field.展开更多
Optogenetic techniques provide precise control over the activity of specific neurons within the nucleus,offering more accurate regulatory effects compared to deep brain stimulation.The heterogeneity of the globus pall...Optogenetic techniques provide precise control over the activity of specific neurons within the nucleus,offering more accurate regulatory effects compared to deep brain stimulation.The heterogeneity of the globus pallidus externa(GPe)has garnered wide attention,wherein significant differences in pathological changes emphasize its potential as a stimulation target with distinct mechanisms.A basal ganglia-thalamus(BG-Th)network model incorporating heterogeneous GPe is developed to explore potential optogenetic stimulation targets for treating Parkinson's disease(PD).Initially,the modulation mechanisms of single-target optogenetic stimulation on the abnormal rhythmic oscillations of BG nuclei are examined.Excitation of D1 medium spine neuron(MSN),calcium-binding protein parvalbumin(PV)GPe,and inhibition of globus pallidus interna(GPi)can effectively suppress synchronous bursting activity in GPi,while excitation of GPi promotes high-frequency discharge to disrupt beta oscillations.Furthermore,dual-target optogenetic stimulation strategies are devised to reduce energy consumption.Results show that targets with similar mechanisms exhibit additive effects,whereas targets with opposing mechanisms lead to cancellation.The underlying effective mechanisms of dual-target strategies are:enhancing the inhibitory input to GPi thus inhibiting the activity of GPi,or disrupting beta oscillations by restoring high-frequency discharges in GPi.The strategy composed of exciting D1 MSN and inhibiting GPi requires the minimum total light intensity among single-target and dual-target strategies in our simulation.Furthermore,simultaneously enhancing PV GPe and inhibiting D2 MSN achieves the greatest reduction in total energy consumption(40.8%reduction),compared to only enhancing PV GPe.The findings unveil effective circuit mechanisms of optogenetic stimulation and provide novel insights for designing precise regulatory strategies for PD.展开更多
Glioma represents the most prevalent malignant tumor of the central nervous system,with chemotherapy serving as an essential adjunctive treatment.However,most chemotherapeutic agents exhibit limited ability to penetra...Glioma represents the most prevalent malignant tumor of the central nervous system,with chemotherapy serving as an essential adjunctive treatment.However,most chemotherapeutic agents exhibit limited ability to penetrate the blood-brain barrier(BBB).This study introduced a novel dualtargeting strategy for glioma therapy by modulating the formation of nanobody-driven protein coronas to enhance the brain and tumor-targeting efficiency of hydrophobic cisplatin prodrug-loaded lipid nanoparticles(C8Pt-Ls).Specifically,nanobodies(Nbs)with fibrinogen-binding capabilities were conjugated to the surface of C8Pt-Ls,resulting in the generation of Nb-C8Pt-Ls.Within the bloodstream,Nb-C8Pt-Ls could bound more fibrinogen,forming the protein corona that specifically interacted with LRP-1,a receptor highly expressed on the BBB.This interaction enabled a“Hitchhiking Effect”mechanism,facilitating efficient trans-BBB transport and promoting effective brain targeting.Additionally,the protein corona interacted with LRP-1,which is also overexpressed in glioma cells,achieving precise tumor targeting.Computational simulations and SPR detection clarified the molecular interaction mechanism of the Nb-fibrinogen-(LRP-1)complex,confirming its binding specificity and stability.Our results demonstrated that this strategy significantly enhanced C8Pt accumulation in brain tissues and tumors,induced apoptosis in glioma cells,and improved therapeutic efficacy.This study provides a novel framework for glioma therapy and underscores the potential of protein corona modulation-based dual-targeting strategies in advancing treatments for brain tumors.展开更多
Developing selectively targeted photothermal agents to reduce side effects in photothermal therapy remains a great challenge. Inspired by the key role of endoplasmic reticulum in the protein synthesis and intracellula...Developing selectively targeted photothermal agents to reduce side effects in photothermal therapy remains a great challenge. Inspired by the key role of endoplasmic reticulum in the protein synthesis and intracellular signal transduction, particularly for the immunogenic cell death induced by endoplasmic reticulum stress, we developed an endoplasmic reticulum-targeted organic photothermal agent(Ts-PTRGD) for enhancing photothermal therapy of tumor. The photothermal agent was covalently attached with 4-methylbenzenesulfonamide and cyclic Arg-Gly-Asp(c RGD) peptide for realizing the targeting of endoplasmic reticulum and tumor cell. Owing to its amphiphilic properties, it readily self-assembles in water to form nanoparticles. The photothermal agent possesses excellent photophysical properties and biological compatibility. In vitro and in vivo experiments demonstrate that it can actively target endoplasmic reticulum and effectively ablate tumor with near-infrared laser.展开更多
KRAS-TP53 co-mutation is strongly associated with poor prognosis and high malignancy in gastrointestinal cancers.Therefore,a novel approach to oncotherapy may lie in combination therapy targeting both KRAS and TP53.He...KRAS-TP53 co-mutation is strongly associated with poor prognosis and high malignancy in gastrointestinal cancers.Therefore,a novel approach to oncotherapy may lie in combination therapy targeting both KRAS and TP53.Herein,we present a novel self-assembled nanoparticle(HA-TPP/A)that are functionalized nano-carrier hyaluronic acid(HA)-TPP conjugate(HA-TPP)to degrade mutant p53 proteins(mutp53)and co-deliver AMG510 for treating KRAS-TP53 co-alteration of gastrointestinal cancers by inhibiting the mutant KRAS and mutp53 signaling pathways.The HA-TPP/A nanoparticles led to ubiquitination-dependent proteasomal degradation of mutp53 by targeting damage to mitochondria.Furthermore,these nanoparticles abrogated the gain-of-function(GOF)phenotypes of mutp53 and increased sensitivity to AMG510-induced cell killing,thereby reducing cell proliferation and migration in gastrointestinal cancer with KRAS-TP53 co-mutation.The co-loaded HA-TPP/A nanoparticles demonstrated remarkable therapeutic efficacy in a tumor-bearing mouse model,particularly in KRAS-TP53 double mutant expressing cancer cells,compared with single drug and combined free drug groups.Notably,HA-TPP/A is the first reported nanoparticle with an ability to co-target KRAS-TP53,providing a promising approach for therapy in highly malignant gastrointestinal tumors and potentially expanding clinical indications for AMG510 targeted therapies in gastrointestinal tumors.展开更多
The dynamic or flowing tumor cells just as leukemia cells and circulating tumor cells face a microenvironment difference from the solid tumors,and the related targeting nanomedicines are rarely reported.The existence ...The dynamic or flowing tumor cells just as leukemia cells and circulating tumor cells face a microenvironment difference from the solid tumors,and the related targeting nanomedicines are rarely reported.The existence of fluidic shear stress in blood circulation seems not favorable for the binding of ligand modified nanodrugs with their target receptor.Namely,the binding feature is very essential in this case.Herein,we utilized HSPC,PEG-DSPE,cholesterol and two avb3 ligands(RGDm7 and DT4)with different binding rates to build dual-targeting nanovesicles,in an effort to achieve a"fast-binding/slow-unbinding"function.It was demonstrated that the dual-targeting nanovesicles actualized effi-cient cellular uptake and antitumor effect in vitro both for static and dynamic tumor cells.Besides,the potency of the dual-targeting vesicles for flowing tumor cells was better than that for static tumor cells.Then,a tumor metastasis mice model and a leukemia mice model were established to detect the killing ability of the drug-loaded dual-targeting vesicles to dynamic tumor cells in vivo.The therapy efficacy of the dual-targeting system was higher than other controls including single-targeting ones.Generally,it seems possible to strengthen drug-targeting to dynamic tumor cells via the control of ligandereceptor interaction.展开更多
Fluorescence-guided surgery(FGS)with tumor-targeted imaging agents,particularly those using the near-infrared wavelength,has emerged as a real-time technique to highlight the tumor location and margins during a surgic...Fluorescence-guided surgery(FGS)with tumor-targeted imaging agents,particularly those using the near-infrared wavelength,has emerged as a real-time technique to highlight the tumor location and margins during a surgical procedure.For accurate visualization of prostate cancer(PCa)boundary and lymphatic metastasis,we developed a new approach involving an efficient self-quenched near-infrared fluorescence probe,Cy-KUE-OA,with dual PCa-membrane affinity.Cy-KUE-OA specifically targeted the prostate-specific membrane antigen(PSMA),anchored into the phospholipids of the cell membrane of PCa cells and consequently showed a strong Cy7-de-quenching effect.This dual–membrane-targeting probe allowed us to detect PSMA-expressing PCa cells both in vitro and in vivo and enabled clear visualization of the tumor boundary during fluorescence-guided laparoscopic surgery in PCa mouse models.Furthermore,the high PCa preference of Cy-KUE-OA was confirmed on surgically resected patient specimens of healthy tissues,PCa,and lymph node metastases.Taken together,our results serve as a bridge between preclinical and clinical research in FGS of PCa and lay a solid foundation for further clinical research.展开更多
Researches on indoleamine-2,3-dioxygenase-1(IDO1),a neoplastic pathogenesis-related protein,have provided a new angle of view to regulate malignancy-related immunosuppression.However,the therapeutic efficacy of IDO1 i...Researches on indoleamine-2,3-dioxygenase-1(IDO1),a neoplastic pathogenesis-related protein,have provided a new angle of view to regulate malignancy-related immunosuppression.However,the therapeutic efficacy of IDO1 inhibitors is subject to key limitations as both cancer and dendritic cells tend to be trapped in the IDO1-mediated immune dysfunction,which poses challenges to the inhibitory potency of drug regimens in multiple targets.Here,we report on the fabrication technique of a biomimetic nanocarrier that is endowed with the whole array of cancer cell membrane proteins for encapsulating the most used IDO1 probe indoximod(IND).By fully utilizing the homologous adhesion proteins and antigenic motifs on cytomembrane,these nanoparticulate particles are capable of infiltrating tumors and actively accumulating in cancer and dendritic cells,as well as hitching a ride on dendritic cells to tumor-draining lymph nodes.Ultimately,by increasing the distribution of drugs in both tumor cells and dendritic cells in tumor-draining lymph nodes,these formulations greatly enhance the efficacy of IND without the aid of chemotherapeutic drugs,achieving substantial control of tumor growth.Overall,this leverage of bionanotechnology maximizes the therapeutic potential of IND and can provide a theoretical reference for the clinical application of IDO1 inhibitors.展开更多
Intraneuronal dysproteostasis and extraneuronal microenvironmental abnormalities in Alzheimer’s disease(AD)collectively culminate in neuronal deterioration.In the context of AD,autophagy dysfunction,a multi-link obst...Intraneuronal dysproteostasis and extraneuronal microenvironmental abnormalities in Alzheimer’s disease(AD)collectively culminate in neuronal deterioration.In the context of AD,autophagy dysfunction,a multi-link obstacle involving autophagy downregulation and lysosome defects in neurons/microglia is highly implicated in intra/extraneuronal pathological processes.Therefore,multidimensional autophagy regulation strategies co-manipulating“autophagy induction”and“lysosome degradation”in dual targets(neuron and microglia)are more reliable for AD treatment.Accordingly,we designed an RP-1 peptide-modified reactive oxygen species(ROS)-responsive micelles(RT-NM)loading rapamycin or gypenoside XVII.Guided by RP-1 peptide,the ligand of receptor for advanced glycation end products(RAGE),RT-NM efficiently targeted neurons and microglia in AD-affected region.This nanocombination therapy activated the whole autophagy-lysosome pathway by autophagy induction(rapamycin)and lysosome improvement(gypenoside XVII),thus enhancing autophagic degradation of neurotoxic aggregates and inflammasomes,and promoting Aβ phagocytosis.Resultantly,it decreased aberrant protein burden,alleviated neuroinflammation,and eventually ameliorated memory defects in 3×Tg-AD transgenic mice.Our research developed a multidimensional autophagy nano-regulator to boost the efficacy of autophagy-centered AD therapy.展开更多
基金Supported by The Science and Technology Plan of Liaoning Province,China,No.2022JH2/101500063.
文摘Inflammatory bowel disease(IBD)is a chronic gastrointestinal inflammatory disease.With the emergence of biologics and other therapeutic methods,two biologics or one biologic combined with a novel small-molecule drug has been proposed in recent years to treat IBD.Although treatment strategies for IBD are being optimized,their efficacy and risks still warrant further consideration.This editorial explores the current risks associated with dual-targeted treatment for IBD and the great potential that fecal microbiota transplantation(FMT)may have for use in combination therapy for IBD.We are focused on addressing refractory IBD or biologically resistant IBD based on currently available dual-targeted treatment by incorporating FMT as part of this dual-targeted treatment.In this new therapy regimen,FMT represents a promising combination therapy.
文摘Objective: The purpose of the study was to explore the application effects of the cloud platform-based comprehensive online management for breast cancer patients using dual-targeted therapy with macromolecular monoclonal antibodies. Methods: 120 breast cancer patients treated by dual-targeted therapy with macromolecular monoclonal antibodies were managed by a cloud platform from March to November 2019. Comprehensive online management included consultation about drugs and side effects and frequently asked questions in the dual-targeted therapy with macromolecular monoclonal antibodies. Results: In the consultation about drugs and side effects, there were five patients with fever, neutrophil, cough, and fatigue;24 with diarrhea;25 with nausea;11 with oral mucosal inflammation;10 with rashes and dry skin;8 with insomnia;and 1 with palpitation. Moreover, 110 patients with anxiety about the missed or delayed treatment were properly handled. Conclusion: The comprehensive online management of dual-targeted therapy with macromolecular monoclonal antibodies based on the cloud platform is helpful to satisfy the at-home breast cancer patients’ needs, ensure the continuity of dual-targeted therapy with macromolecular monoclonal antibodies for breast cancer patients, prevent misinformation, alleviate patients’ negative psychological emotions, and reduce patients’ economic losses. The online cloud platform integrated management model is crucial for managing patients with breast cancer treated by dual-targeted therapy.
基金supported by the National Key R&D Program of China(No.2023YFF071)the National Natural Science Foundation of China(Nos.92163214,52333003,and 52373288)+2 种基金the Basic Research Program of Jiangsu(No.BK20244003)the Natural Science Foundation of Jiangsu Province(No.BK20202002)Fundamental Research Funds for the Central University(No.020514380274).
文摘Tumor metastasis accounts for the major portion of cancer-related deaths.Magnetic resonance imaging(MRI)is a valuable imaging modality for tumor diagnosis in clinical applications,offering detailed soft tissue images with excellent spatial resolution and good biosafety.However,the low sensitivity and the lack of specificity to disease sites limit the application of MRI contrast agents in early and precise detection of small primary and metastatic cancers.Therefore,there is an urgent need for innovative MRI contrast agents with enhanced relaxivity,target ability,and pharmacokinetics to improve imaging sensitivity and widen the detection window in the meantime.Here,we reported a dual-targeting protein MRI contrast agent(EPR-DTPA-Gd)fused by a nanobody against epidermal growth factor receptor 1(EGFR),integrinα_(v)β_(3)-binding cyclic nonapeptide,and elastin-like polypeptide.We found that this protein contrast agent exhibited high sensitivity and specificity for the tumor overexpressed EGFR and integrinα_(v)β_(3)in MRI.Furthermore,EPR-DTPA-Gd had high longitudinal relaxation rate(r_(1))(68.76 mM^(−1)s^(−1)per molecule)and an improved pharmacokinetics behavior for tumor imaging.Using T1-weighted imaging,EPR-DTPA-Gd successfully detected a series of early metastases with the smallest 0.012mm^(2)(213μm×58μm)in a liver metastasis model of human cervical carcinoma HeLa cells,which cannot be detected by the clinically approved T1-weighted contrast agent.The heightened detection sensitivity intrinsic to EPR-DTPA-Gd facilitates precise imaging of tumor lesions,supporting sophisticated image-guided interventions and early management in high-risk patient cohorts.
基金supported by the Sichuan Science and Technology program(No.2025ZNSFSC0682)the Fundamental Research Funds for the Central Universities,the Program Sichuan Veterinary Medicine and Drug Innovation Group of China Agricultural Research System(No.SCCXTD-2025-18)the National Postdoctoral Program(No.GZC20231780).
文摘Acute myeloid leukemia(AML)is an aggressive hematological malignancy with high mortality rates and poor prognosis,largely due to the nonspecific drug distribution and suboptimal therapeutic efficacy.To address these challenges,here we proposed a CD44/Transferrin receptor dual targeted self-delivery micelle for the combination delivery of chemotherapeutic doxorubicin(DOX)and artesunate(ART),a natural product known for its ability of killing AML cells by inducing apoptosis.To improve AML targeting,the transferrin receptor targeting peptide T7 was conjugated with CD44 targeting hyaluronic acid(HA),followed by conjugation with hydrophobic ART to afford the amphiphilic polymer for DOX encapsulation(termed THAD).The resulting self-delivery micellar drug delivery system THAD significantly enhanced the cellular internalization of AML cells and facilitated in vivo tumor targeting.Compared with single drug treatment groups,the combination of ART and DOX showed a better tumor killing ability.Furthermore,THAD suppressed the tumor proliferation by 90.74%.Specifically,THAD induced significantly mitochondrial-dependent apoptosis via increasing mitochondrial membranes damage and subsequent G1 phase arrest,as evidenced by the decreased levels of pro-caspase-3 and Bcl-2,along with the increased levels of Bax and cleaved poly(ADP-ribose)polymerase(PARP).Furthermore,THAD inhibited protein kinase B(AKT)phosphorylation,leading to a decrease of c-Myc expression in response to a negative growth regulator.In the human acute myeloid leukemia cells(MOLM13)cell-bearing mouse model,THAD significantly inhibited AML cell infiltration and proliferation in both bone marrow and liver,effectively suppressing AML progression.Collectively,THAD demonstrated enhanced anti-AML effects by promoting apoptosis,offering a promising targeted self-delivery strategy for combination chemotherapy in AML treatment.
基金the National Natural Science Foundation of China(22137003 and 21922406)Natural Science Foundation of Jiangsu Province(BK20200301 and BK20190055)the Fundamental Research Funds for the Central Universities(020514380251)are acknowledged.
文摘Fluorogenic probes with"off-on"fluorescence signals have emerged as powerful tools for biosensing and bioimaging of biomolecules in living systems.Conventional single-target probes,however,often suffer from false-positive signals due to non-specific activation in non-target tissues or the diffusion of activated fluorescent products.To address these limitations,dual-targeted fluorogenic probes(DTFPs)have been developed,which simultaneously target two biomarkers to enhance detection specificity and minimize false-positive outcomes.DTFPs are designed to activate or retain fluorescence only when both biomarkers are present within a targeted region,enabling precise in vivo imaging of pathological conditions such as tumors and inflammation.This review highlights recent advances in DTFP development,focusing on their design principles,activation mechanisms,and applications in biosensing and bioimaging.We also discuss current challenges and future directions for DTFP research,aiming to inspire the design of next-generation probes with improved accuracy and specificity.By providing a comprehensive overview of DTFPs,this review seeks to advance their potential for transformative applications in biomedical imaging and diagnostics.
基金supported by Interdisciplinary Innova-tion Project of“Bioarchaeology Laboratory”of Jilin University,China,and“MedicineþX”Interdisciplinary Innovation Team of Norman Bethune Health Science Center of Jilin University,China(Grant No.:2022JBGS05).
文摘Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)mutations are influenced by random and uncontrollable factors,and the risk of the next widespread epidemic remains.Dual-target drugs that synergistically act on two targets exhibit strong therapeutic effects and advantages against mutations.In this study,a novel computational workflow was developed to design dual-target SARS-CoV-2 candidate inhibitors with the Envelope protein and Main protease selected as the two target proteins.The drug-like molecules of our self-constructed 3D scaffold database were used as high-throughput molecular docking probes for feature extraction of two target protein pockets.A multi-layer perceptron(MLP)was employed to embed the binding affinities into a latent space as conditional vectors to control conditional distribution.Utilizing a conditional generative neural network,cG-SchNet,with 3D Euclidean group(E3)symmetries,the conditional probability distributions of molecular 3D structures were acquired and a set of novel SARS-CoV-2 dual-target candidate inhibitors were generated.The 1D probability,2D joint probability,and 2D cumulative probability distribution results indicate that the generated sets are significantly enhanced compared to the training set in the high binding affinity area.Among the 201 generated molecules,42 molecules exhibited a sum binding affinity exceeding 17.0 kcal/mol while 9 of them having a sum binding affinity exceeding 19.0 kcal/mol,demonstrating structure diversity along with strong dual-target affinities,good absorption,distribution,metabolism,excretion,and toxicity(ADMET)properties,and ease of synthesis.Dual-target drugs are rare and difficult to find,and our“high-throughput docking-multi-conditional generation”workflow offers a wide range of options for designing or optimizing potent dual-target SARS-CoV-2 inhibitors.
基金supported by the National Natural Science Foundation of China(51873150,51573128).
文摘Antioxidation and adjustable treatment strategies are critical for the effective treatment of Alzheimer’s disease(AD).Here,we design a dual-targeted Prussian blue nanoformulation(PTCN)that can cross the blood-brain barrier and target amyloid beta aggregates further exert antioxidant effects.An adjustable gradient dosing strategy with PTCN is used for the first time to design the preventive and therapeutic trials based on the severity of oxidative stress at different AD stages.The results show that PTCN could effectively ameliorate AD-related pathological processes,improve the cognitive decline,and rescue hippocampal atrophy of APP/PS1 mice in both preventive and therapeutic trials.Altogether,PTCN provided here is a successful combination of three traditional biomaterials with good biosafety,which has broad prospects for the early prevention,mild remission,and late treatment of AD,and is expected to be developed into personalized therapeutic drugs and healthcare products for clinical AD in the future.
基金funded by the University of Medicine and Pharmacy at Ho Chi Minh City under grant number 162/2019/HĐ-ĐHYD for Thanh-Dao Tran.
文摘Diabetes mellitus remains a major global health issue,and great attention is directed at natural therapeutics.This systematic review aimed to assess the potential of flavonoids as antidiabetic agents by investigating their inhibitory effects onα-glucosidase andα-amylase,two key enzymes involved in starch digestion.Six scientific databases(PubMed,Virtual Health Library,EMBASE,SCOPUS,Web of Science,and WHO Global Index Medicus)were searched until August 21,2022,for in vitro studies reporting IC50 values of purified flavonoids onα-amylase andα-glucosidase,along with corresponding data for acarbose as a positive control.A total of 339 eligible articles were analyzed,resulting in the retrieval of 1643 flavonoid structures.These structures were rigorously standardized and curated,yielding 974 unique compounds,among which 177 flavonoids exhibited inhibition of bothα-glucosidase andα-amylase are presented.Quality assessment utilizing a modified CONSORT checklist and structure-activity relationship(SAR)analysis were performed,revealing crucial features for the simultaneous inhibition of flavonoids against both enzymes.Moreover,the review also addressed several limitations in the current research landscape and proposed potential solutions.The curated datasets are available online at https://github.com/MedChemUMP/FDIGA.
基金funded by the National Natural Science Foundation of China(No.81770126,No.81900160,No.81800163,No.22025702,and No.91853203)the Fujian Natural Science Foundation of China(No.2020J011246 and No.2021J011359)+2 种基金the Foundation of Health and Family Planning Commission of Fujian Province of China(No.2020GGB054)the Xiamen Municipal Bureau of Science and Technology(No.3502Z20209003)the Fundamental Research Funds for the Central Universities of China(No.20720190101).
文摘Objective:In B-cell acute lymphoblastic leukemia(B-ALL),current intensive chemotherapies for adult patients fail to achieve durable responses in more than 50%of cases,underscoring the urgent need for new therapeutic regimens for this patient population.The present study aimed to determine whether HZX-02-059,a novel dual-target inhibitor targeting both phosphatidylinositol-3-phosphate 5-kinase(PIKfyve)and tubulin,is lethal to B-ALL cells and is a potential therapeutic for B-ALL patients.Methods:Cell proliferation,vacuolization,apoptosis,cell cycle,and in-vivo tumor growth were evaluated.In addition,Genome-wide RNA-sequencing studies were conducted to elucidate the mechanisms of action underlying the anti-leukemia activity of HZX-02-059 in B-ALL.Results:HZX-02-059 was found to inhibit cell proliferation,induce vacuolization,promote apoptosis,block the cell cycle,and reduce in-vivo tumor growth.Downregulation of the p53 pathway and suppression of the phosphoinositide 3-kinase(PI3K)/AKT pathway and the downstream transcription factors c-Myc and NF-κB were responsible for these observations.Conclusion:Overall,these findings suggest that HZX-02-059 is a promising agent for the treatment of B-ALL patients resistant to conventional therapies.
基金financially supported by National Natural Science Foundation of China (Nos. 22074033, 22374035)。
文摘Micro RNA-133a(mi RNA-133a) and cardiac troponin I(c Tn I) are different-type crucial biomarkers of acute myocardial infarction(AMI), whose levels are great significance for AMI diagnosis and treatment. Herein,a novel photoelectrochemical-electrochemical(PEC-EC) dual-mode biosensing platform for dual-target assays of mi RNA-133a and c Tn I was developed. In which, a PEC-EC dual-mode sensing platform for mi RNA-133a was constructed based on the changes of the photocurrent inhibition effect and the electrochemical signal of Fc on the Fc-hairpin DNA probe(Fc-HP)/Zn Cd S-quantum dots(QDs)/ITO electrode. Furthermore, under magnetic separation and the specific interaction between c Tn I and its aptamer, the N-doped porous carbon-Zn O polyhedra(NPC-Zn O)-hemin-capture DNA probe hybrid(NH-CP) was obtained and introduced to the Fc-HP/Zn Cd S-QDs/ITO electrode via hybridization between NH-CP and Fc-HP. The hemin molecules encapsulated in NH-CP could effectively induce the photocurrent-polarity-switching of the FcHP/Zn Cd S-QDs/ITO electrode and generate a new electrochemical signal originating from hemin. Thus,c Tn I was assayed sensitively and selectively by the PEC-EC dual-mode biosensing platform. Here, Fc and hemin not only serve as the electrochemical indicators, but also respectively inhibit the photocurrent and switch the photocurrent polarity of Zn Cd S-QDs. Furthermore, the proposed biosensing platform could be easily expanded to the detection of other multiplex-type biomarkers via the change of the sequences of the related DNA probes, implying its significant potential in clinical diagnosis and biological analysis.
文摘The treatment of patients with inflammatory bowel disease(IBD),especially those with severe or refractory disease,represents an important challenge for the clinical gastroenterologist.It seems to be no exaggeration to say that in these patients,not only the scientific background of the gastroenterologist is tested,but also the abundance of“gifts”that he should possess(insight,intuition,determ-ination,ability to take initiative,etc.)for the successful outcome of the treatment.In daily clinical practice,depending on the severity of the attack,IBD is treated with one or a combination of two or more pharmaceutical agents.These combin-ations include not only the first-line drugs(e.g.,mesalazine,corticosteroids,antibiotics,etc)but also second-and third-line drugs(immunosuppressants and biologic agents).It is a fact that despite the significant therapeutic advances there is still a significant percentage of patients who do not satisfactorily respond to the treatment applied.Therefore,a part of these patients are going to surgery.In recent years,several small-size clinical studies,reviews,and case reports have been published combining not only biological agents with other drugs(e.g.,immunosuppressants or corticosteroids)but also the combination of two biologi-cal agents simultaneously,especially in severe cases.In our opinion,it is at least a strange(and largely unexplained)fact that we often use combinations of drugs in a given patient although studies comparing the simultaneous administration of two or more drugs with monotherapy are very few.As mentioned above,there is a timid tendency in the literature to combine two biological agents in severe cases unresponsive to the applied treatment or patients with severe extraintestinal manifestations.The appropriate dosage,the duration of the administration,the suitable timing for checking the clinical and laboratory outcome,as well as the treatment side-effects,should be the subject of intense clinical research shortly.In this editorial,we attempt to summarize the existing data regarding the already applied combination therapies and to humbly formulate thoughts and suggestions for the future application of the combination treatment of biological agents in a well-defined category of patients.We suggest that the application of biomarkers and artificial intelligence could help in establishing new forms of treatment using the available modern drugs in patients with IBD resistant to treatment.
基金support from the National Natural Science Foundation of China(22122701,22477054,22293050,91953201,92153303,22377050)the Excellent Research Program of Nanjing University(ZYJH004)the Natural Science Foundation of Jiangsu Province(BK20232020).
文摘Organelles are specialized areas where cells perform specific processes necessary for life and actively communicate with each other to keep the whole cell func-tioning.Disorders of the organelle networks are associated with multiple patho-logical processes.However,clearly and intuitively visualizing the highly dynamic interactions between ultrafine organelles is challenging.Fluorescence imaging technology provides opportunities due to the distinct advantages of facile,non-invasiveness and dynamic detection,making it particularly well-suited for appli-cations in uncovering the mysterious veil of organelle interactions.Regrettably,the lack of ideal fluorescence agents has always been an obstacle in imaging the intricate behaviors of organelles.In this review,we provide a systematic discussion on the existing dual-color and dual-targetable molecular sensors used in moni-toring organelle interactions,with a specific focus on their targeting strategies,imaging mechanisms and biological applications.Additionally,the current limi-tations and future development directions of dual-targetable probes and dual-emissives are briefly discussed.This review aims to provide guidance for re-searchers to develop more improved probes for studying organelle interactions in the biomedical field.
基金supported by the National Natural Science Foundation of China(12202027,11932003 and 12332004)the Academic Excellence Foundation of BUAA for PhD Students.
文摘Optogenetic techniques provide precise control over the activity of specific neurons within the nucleus,offering more accurate regulatory effects compared to deep brain stimulation.The heterogeneity of the globus pallidus externa(GPe)has garnered wide attention,wherein significant differences in pathological changes emphasize its potential as a stimulation target with distinct mechanisms.A basal ganglia-thalamus(BG-Th)network model incorporating heterogeneous GPe is developed to explore potential optogenetic stimulation targets for treating Parkinson's disease(PD).Initially,the modulation mechanisms of single-target optogenetic stimulation on the abnormal rhythmic oscillations of BG nuclei are examined.Excitation of D1 medium spine neuron(MSN),calcium-binding protein parvalbumin(PV)GPe,and inhibition of globus pallidus interna(GPi)can effectively suppress synchronous bursting activity in GPi,while excitation of GPi promotes high-frequency discharge to disrupt beta oscillations.Furthermore,dual-target optogenetic stimulation strategies are devised to reduce energy consumption.Results show that targets with similar mechanisms exhibit additive effects,whereas targets with opposing mechanisms lead to cancellation.The underlying effective mechanisms of dual-target strategies are:enhancing the inhibitory input to GPi thus inhibiting the activity of GPi,or disrupting beta oscillations by restoring high-frequency discharges in GPi.The strategy composed of exciting D1 MSN and inhibiting GPi requires the minimum total light intensity among single-target and dual-target strategies in our simulation.Furthermore,simultaneously enhancing PV GPe and inhibiting D2 MSN achieves the greatest reduction in total energy consumption(40.8%reduction),compared to only enhancing PV GPe.The findings unveil effective circuit mechanisms of optogenetic stimulation and provide novel insights for designing precise regulatory strategies for PD.
基金supported by the National Natural Science Foundation of China(22107080 and 82300113).
文摘Glioma represents the most prevalent malignant tumor of the central nervous system,with chemotherapy serving as an essential adjunctive treatment.However,most chemotherapeutic agents exhibit limited ability to penetrate the blood-brain barrier(BBB).This study introduced a novel dualtargeting strategy for glioma therapy by modulating the formation of nanobody-driven protein coronas to enhance the brain and tumor-targeting efficiency of hydrophobic cisplatin prodrug-loaded lipid nanoparticles(C8Pt-Ls).Specifically,nanobodies(Nbs)with fibrinogen-binding capabilities were conjugated to the surface of C8Pt-Ls,resulting in the generation of Nb-C8Pt-Ls.Within the bloodstream,Nb-C8Pt-Ls could bound more fibrinogen,forming the protein corona that specifically interacted with LRP-1,a receptor highly expressed on the BBB.This interaction enabled a“Hitchhiking Effect”mechanism,facilitating efficient trans-BBB transport and promoting effective brain targeting.Additionally,the protein corona interacted with LRP-1,which is also overexpressed in glioma cells,achieving precise tumor targeting.Computational simulations and SPR detection clarified the molecular interaction mechanism of the Nb-fibrinogen-(LRP-1)complex,confirming its binding specificity and stability.Our results demonstrated that this strategy significantly enhanced C8Pt accumulation in brain tissues and tumors,induced apoptosis in glioma cells,and improved therapeutic efficacy.This study provides a novel framework for glioma therapy and underscores the potential of protein corona modulation-based dual-targeting strategies in advancing treatments for brain tumors.
基金supported by National Natural Science Foundation of China (Nos.21927811,21874086 and 21775094)National Key R&D Program of China (No.2019YFA0210100)Youth Innovation Science and Technology Program of Higher Education Institution of Shandong Province (No.2019KJC022)。
文摘Developing selectively targeted photothermal agents to reduce side effects in photothermal therapy remains a great challenge. Inspired by the key role of endoplasmic reticulum in the protein synthesis and intracellular signal transduction, particularly for the immunogenic cell death induced by endoplasmic reticulum stress, we developed an endoplasmic reticulum-targeted organic photothermal agent(Ts-PTRGD) for enhancing photothermal therapy of tumor. The photothermal agent was covalently attached with 4-methylbenzenesulfonamide and cyclic Arg-Gly-Asp(c RGD) peptide for realizing the targeting of endoplasmic reticulum and tumor cell. Owing to its amphiphilic properties, it readily self-assembles in water to form nanoparticles. The photothermal agent possesses excellent photophysical properties and biological compatibility. In vitro and in vivo experiments demonstrate that it can actively target endoplasmic reticulum and effectively ablate tumor with near-infrared laser.
基金supported by the National Key Research and Development Plan(2022YFC3401000)National Natural Science Foundation of China(81871994,82022037,T2222014 and 32071398)+2 种基金Guangdong Provincial Natural Science Foundation(2019B151502063)Guangdong Basic and Applied Basic Research Foundation(2021B1515230009)Key Research and Development Plan of Guangdong Province(2020B0101030006,2020B1515120096 and 2022B0202010002).
文摘KRAS-TP53 co-mutation is strongly associated with poor prognosis and high malignancy in gastrointestinal cancers.Therefore,a novel approach to oncotherapy may lie in combination therapy targeting both KRAS and TP53.Herein,we present a novel self-assembled nanoparticle(HA-TPP/A)that are functionalized nano-carrier hyaluronic acid(HA)-TPP conjugate(HA-TPP)to degrade mutant p53 proteins(mutp53)and co-deliver AMG510 for treating KRAS-TP53 co-alteration of gastrointestinal cancers by inhibiting the mutant KRAS and mutp53 signaling pathways.The HA-TPP/A nanoparticles led to ubiquitination-dependent proteasomal degradation of mutp53 by targeting damage to mitochondria.Furthermore,these nanoparticles abrogated the gain-of-function(GOF)phenotypes of mutp53 and increased sensitivity to AMG510-induced cell killing,thereby reducing cell proliferation and migration in gastrointestinal cancer with KRAS-TP53 co-mutation.The co-loaded HA-TPP/A nanoparticles demonstrated remarkable therapeutic efficacy in a tumor-bearing mouse model,particularly in KRAS-TP53 double mutant expressing cancer cells,compared with single drug and combined free drug groups.Notably,HA-TPP/A is the first reported nanoparticle with an ability to co-target KRAS-TP53,providing a promising approach for therapy in highly malignant gastrointestinal tumors and potentially expanding clinical indications for AMG510 targeted therapies in gastrointestinal tumors.
基金supported by the National Key R&D Program of China(2017YFA0205600)the National Science Foundation of China(81690264,81821004,81703441 and 81872809)
文摘The dynamic or flowing tumor cells just as leukemia cells and circulating tumor cells face a microenvironment difference from the solid tumors,and the related targeting nanomedicines are rarely reported.The existence of fluidic shear stress in blood circulation seems not favorable for the binding of ligand modified nanodrugs with their target receptor.Namely,the binding feature is very essential in this case.Herein,we utilized HSPC,PEG-DSPE,cholesterol and two avb3 ligands(RGDm7 and DT4)with different binding rates to build dual-targeting nanovesicles,in an effort to achieve a"fast-binding/slow-unbinding"function.It was demonstrated that the dual-targeting nanovesicles actualized effi-cient cellular uptake and antitumor effect in vitro both for static and dynamic tumor cells.Besides,the potency of the dual-targeting vesicles for flowing tumor cells was better than that for static tumor cells.Then,a tumor metastasis mice model and a leukemia mice model were established to detect the killing ability of the drug-loaded dual-targeting vesicles to dynamic tumor cells in vivo.The therapy efficacy of the dual-targeting system was higher than other controls including single-targeting ones.Generally,it seems possible to strengthen drug-targeting to dynamic tumor cells via the control of ligandereceptor interaction.
基金supported by the National Natural Science Foundation of China(NSFC)projects(22122705,22077139 and 81972400)CAMS Innovation Fund for Medical Sciences(CIFMS)(2021-I2M-1-054 and 2021-I2M-1-015)Beijing Outstanding Young Scientist Program(BJJWZYJH01201910023028,China).
文摘Fluorescence-guided surgery(FGS)with tumor-targeted imaging agents,particularly those using the near-infrared wavelength,has emerged as a real-time technique to highlight the tumor location and margins during a surgical procedure.For accurate visualization of prostate cancer(PCa)boundary and lymphatic metastasis,we developed a new approach involving an efficient self-quenched near-infrared fluorescence probe,Cy-KUE-OA,with dual PCa-membrane affinity.Cy-KUE-OA specifically targeted the prostate-specific membrane antigen(PSMA),anchored into the phospholipids of the cell membrane of PCa cells and consequently showed a strong Cy7-de-quenching effect.This dual–membrane-targeting probe allowed us to detect PSMA-expressing PCa cells both in vitro and in vivo and enabled clear visualization of the tumor boundary during fluorescence-guided laparoscopic surgery in PCa mouse models.Furthermore,the high PCa preference of Cy-KUE-OA was confirmed on surgically resected patient specimens of healthy tissues,PCa,and lymph node metastases.Taken together,our results serve as a bridge between preclinical and clinical research in FGS of PCa and lay a solid foundation for further clinical research.
基金support from the National Natural Science Foundation of China(Nos.81773648 and 81973267)the Zhejiang Provincial Natural Science Foundation of China(Nos.LD19H300001 and LQ20H300004).
文摘Researches on indoleamine-2,3-dioxygenase-1(IDO1),a neoplastic pathogenesis-related protein,have provided a new angle of view to regulate malignancy-related immunosuppression.However,the therapeutic efficacy of IDO1 inhibitors is subject to key limitations as both cancer and dendritic cells tend to be trapped in the IDO1-mediated immune dysfunction,which poses challenges to the inhibitory potency of drug regimens in multiple targets.Here,we report on the fabrication technique of a biomimetic nanocarrier that is endowed with the whole array of cancer cell membrane proteins for encapsulating the most used IDO1 probe indoximod(IND).By fully utilizing the homologous adhesion proteins and antigenic motifs on cytomembrane,these nanoparticulate particles are capable of infiltrating tumors and actively accumulating in cancer and dendritic cells,as well as hitching a ride on dendritic cells to tumor-draining lymph nodes.Ultimately,by increasing the distribution of drugs in both tumor cells and dendritic cells in tumor-draining lymph nodes,these formulations greatly enhance the efficacy of IND without the aid of chemotherapeutic drugs,achieving substantial control of tumor growth.Overall,this leverage of bionanotechnology maximizes the therapeutic potential of IND and can provide a theoretical reference for the clinical application of IDO1 inhibitors.
基金supported by National Natural Science Foundation of China(Nos.82073780 and 82273868,China)Shanghai Municipal Natural Science Foundation(No.19ZR1406200,China)。
文摘Intraneuronal dysproteostasis and extraneuronal microenvironmental abnormalities in Alzheimer’s disease(AD)collectively culminate in neuronal deterioration.In the context of AD,autophagy dysfunction,a multi-link obstacle involving autophagy downregulation and lysosome defects in neurons/microglia is highly implicated in intra/extraneuronal pathological processes.Therefore,multidimensional autophagy regulation strategies co-manipulating“autophagy induction”and“lysosome degradation”in dual targets(neuron and microglia)are more reliable for AD treatment.Accordingly,we designed an RP-1 peptide-modified reactive oxygen species(ROS)-responsive micelles(RT-NM)loading rapamycin or gypenoside XVII.Guided by RP-1 peptide,the ligand of receptor for advanced glycation end products(RAGE),RT-NM efficiently targeted neurons and microglia in AD-affected region.This nanocombination therapy activated the whole autophagy-lysosome pathway by autophagy induction(rapamycin)and lysosome improvement(gypenoside XVII),thus enhancing autophagic degradation of neurotoxic aggregates and inflammasomes,and promoting Aβ phagocytosis.Resultantly,it decreased aberrant protein burden,alleviated neuroinflammation,and eventually ameliorated memory defects in 3×Tg-AD transgenic mice.Our research developed a multidimensional autophagy nano-regulator to boost the efficacy of autophagy-centered AD therapy.
