Dual-targeting nanovesicles enhance specificity to dynamic tumor cells in vitro and in vivo via manipulation of αvβ3-ligand binding

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.

Membrane dual-targeting probes:A promising strategy for fluorescence-guided prostate cancer surgery and lymph node metastases detection

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.

Tumor and dendritic cell dual-targeting nanocarriers maximize the therapeutic potential of IDO1 inhibitor in vivo

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.

Novel PIKfyve/Tubulin Dual-target Inhibitor as a Promising Therapeutic Strategy for B-cell Acute Lymphoblastic Leukemia

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.

Dual-targeted treatment for inflammatory bowel disease:Whether fecal microbiota transplantation can be an important part of it

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.

Engineered a dual-targeting HA-TPP/A nanoparticle for combination therapy against KRAS-TP53 co-mutation in gastrointestinal cancers

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.

Comprehensive Online Management Based on Cloud Platform for Breast Cancer Patients Using Dual-Targeted Therapy with Macromolecular Monoclonal Antibodies

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.

Combination treatment of inflammatory bowel disease:Present status and future perspectives

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.

A dual-targeted multifunctional nanoformulation for potential prevention and therapy of Alzheimer’s disease

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.

Multidimensional autophagy nano-regulator boosts Alzheimer's disease treatment by improving both extra/intraneuronal homeostasis

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.

Targeted delivery of a STING agonist to brain tumors using bioengineered protein nanoparticles for enhanced immunotherapy

Immunotherapy is emerging as a powerful tool for combating many human diseases.However,the application of this life-saving treatment in serious brain diseases,including glioma,is greatly restricted.The major obstacle is the lack of effective technologies for transporting therapeutic agents across the blood-brain barrier(BBB)and achieving targeted delivery to specific cells once across the BBB.Ferritin,an iron storage protein,traverses the BBB via receptor-mediated transcytosis by binding to transferrin receptor 1(TfR1)overexpressed on BBB endothelial cells.Here,we developed bioengineered ferritin nanoparticles as drug delivery carriers that enable the targeted delivery of a small-molecule immunomodulator to achieve enhanced immunotherapeutic efficacy in an orthotopic glioma-bearing mouse model.We fused different glioma-targeting moieties on self-assembled ferritin nanoparticles via genetic engineering,and RGE fusion protein nanoparticles(RGE-HFn NPs)were identified as the best candidate.Furthermore,RGE-HFn NPs encapsulating a stimulator of interferon genes(STING)agonist(SR717@RGE-HFn NPs)maintained stable self-assembled structure and targeting properties even after traversing the BBB.In the glioma-bearing mouse model,SR717@RGE-HFn NPs elicited a potent local innate immune response in the tumor microenvironment,resulting in significant tumor growth inhibition and prolonged survival.Overall,this biomimetic brain delivery platform offers new opportunities to overcome the BBB and provides a promising approach for brain drug delivery and immunotherapy in patients with glioma.

An endoplasmic reticulum-targeted organic photothermal agent for enhanced cancer therapy

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.

Molecularly Engineered Aptamers Targeting Tumor Tissue and Cancer Cells for Efficient in Vivo Recognition and Enrichment

Molecular engineering of aptamers can confer exogenous biomedical properties that may be beneficial for various applications.In this study,a tumor-homing peptide modification strategy was developed to considerably enhance the accumulation and penetration abilities of the Sgc8c aptamer.Notably,the S2PM conjugate induced a much higher level of morphological variation in three-dimensional tumor microspheres(HCT116 cells)than in control groups,highlighting the importance of the homing and penetrating abilities derived from peptide.

Design, synthesis, and biological evaluation of quinazolin-4(3H)-one derivatives co-targeting poly (ADP-ribose) polymerase-1 and bromodomain containing protein 4 for breast cancer therapy

This study was aimed to design the first dual-target small-molecule inhibitor co-targeting poly(ADP-ribose)polymerase-1(PARP1)and bromodomain containing protein 4(BRD4),which had important cross relation in the global network of breast cancer,reflecting the synthetic lethal effect.A series of new BRD4 and PARP1 dual-target inhibitors were discovered and synthesized by fragmentbased combinatorial screening and activity assays that together led to the chemical optimization.Among these compounds,19 d was selected and exhibited micromole enzymatic potencies against BRD4 and PARP1,respectively.Compound 19 d was further shown to efficiently modulate the expression of BRD4 and PARP1.Subsequently,compound 19 d was found to induce breast cancer cell apoptosis and stimulate cell cycle arrest at G1 phase.Following pharmacokinetic studies,compound 19 d showed its antitumor activity in breast cancer susceptibility gene 1/2(BRCA1/2)wild-type MDA-MB-468 and MCF-7 xenograft models without apparent toxicity and loss of body weight.These results together demonstrated that a highly potent dual-targeted inhibitor was successfully synthesized and indicated that co-targeting of BRD4 and PARP1 based on the concept of synthetic lethality would be a promising therapeutic strategy for breast cancer.

Hardware Design and Test of a Gear-Shifting Control System of a Multi-gear Transmission for Electric Vehicles

The performance of electric vehicles is affected by the shift quality of multi-gear transmission.The realization of dual-target tracking control requires the transmission control unit(TCU)to accurately measure and process the input signals of the gear-shifting control system and precisely control the drive motor torque and the position of shift motors.An electric-vehicle-dedicated TCU was designed to meet the above design requirements.Its function modules included a single-chip control circuit,shift position signal sampling circuit,signal conditioning circuit of the rotational speed and angle,controller area network communication circuit,and shift motor drive circuit.A hardware-in-the-loop simulation test system showed that the TCU design scheme met measurement accuracy requirements and coordinated the actions of the shift actuator and motor control unit to achieve fast and smooth shifting before the road test.The power interruption time of the shifting process was within 350 ms.The reliability of the TCU design was further verified in a 150,000-km vehicle road test.