Parkinson's disease(PD)is a debilitating and progressive neurodegenerative disorder with complex pathology and multiple membrane barriers that hinder drug delivery,resulting in the absence of ideal therapeutic dru...Parkinson's disease(PD)is a debilitating and progressive neurodegenerative disorder with complex pathology and multiple membrane barriers that hinder drug delivery,resulting in the absence of ideal therapeutic drugs with minimal side effects[1].Recently,natural medicine has garnered significant attention due to its remarkable efficacy and limited side effects.Icariin,a naturally occurring flavonoid,exhibits excellent potential as a therapeutic agent for neurodegenerative disease[2].However,its clinical application is limited by poor water solubility,low bioavailability,and high clearance rates.Here,an aqueous formulation of icariin/hydroxypropyl-β-cyclodextrin(HP-β-CD)supramolecular inclusion complex was obtained to optimize icariin properties.Furthermore,icariin cyclodextrin supramolecular inclusion complex based thermosensitive(icariin gels)was innovated.At lower temperatures,it remained in a liquid phase with high fluidity.Upon reaching the gelation temperature,it underwent a transition to a gel phase with significantly reduced fluidity,which may be suitable for the design of an intranasal delivery system for PD treatment.The innovative approach capitalizes on the exceptional characteristics of HP-β-CD,which was utilized to synergize with nasal delivery for targeted brain delivery and with icariin for PD treatment[3,4].展开更多
Chiral anticancer drugs are the subject of ongoing research due to their optical characterization and pharmacological effects.Achieving a single enantiomer of a chiral anticancer drug is arduous,but it can significant...Chiral anticancer drugs are the subject of ongoing research due to their optical characterization and pharmacological effects.Achieving a single enantiomer of a chiral anticancer drug is arduous,but it can significantly improve its pharmacokinetics for tumor therapy.Here,the chiral nanocatchers,known as Dbiotin-P5■MCC NCs,were designed and prepared based on host-vip self-assembly between D-biotin anchored pillar[5]arene(D-biotin-P5)and myristoyl chloride choline(MCC).D-Biotin-P5■MCC NCs featuring the chiral separation and enzyme-induced disassemble were evaluated for their ability to selectively capture and subsequently target the release of(R,R)-OXA enantiomers into tumor cells.Furthermore,the use of D-biotin-P5■MCC NCs has demonstrated a significant enhancement in the intracellular uptake of OXA,with the drug being efficiently released to MCF-7 breast cancer cells.This has led to a superior inhibitory effect on MCF-7 cells when compared to free OXA,while also reducing the cytotoxicity of the drug in HEK 293 human embryonic kidney cells.This research not only paves a promising way for the fabrication of chiral supramolecular nanocarriers but also holds the potential to improve the processes of chiral drug separation and targeted therapy.展开更多
High levels of tumor necrosis factor receptor type Il(TNFR2)are preferentially expressed by immunosuppressive CD4^(+)Foxp3^(+)regulatory T cells(T_(regs)),especially those present in the tumor microenvironment,as init...High levels of tumor necrosis factor receptor type Il(TNFR2)are preferentially expressed by immunosuppressive CD4^(+)Foxp3^(+)regulatory T cells(T_(regs)),especially those present in the tumor microenvironment,as initially reported by us.There is compelling evidence that targeting TNFR2 markedly enhances antitumor immune responses.Furthermore,a broad spectrum of human cancers also expresses TNFR2,while its expression by normal tissue is very limited.We thus hypothesized that TNFR2 may be harnessed for tumor-targeted delivery of chemotherapeutic agents.In this study,we performed a proof-of-concept study by constructing a TNFR2-targeted PEGylated poly(DL-lactic-co-glycolic acid)(PLGA-PEG)nanodrug delivery system[designated as TNFR2-PLGA-ADR(Adriamycin)].The results of in vitro study showed that this TNFR2-targeted delivery system had the properties in cellular binding and cytotoxicity toward mouse colon cancer cells.Further,upon intravenous injection,TNFR2-PLGA-ADR could efficiently accumulate in MC38 and CT26 mouse colon tumor tissues and preferentially bind with tumor-infiltrating T_(regs).Compared with ADR and ISO-PLGA-ADR,the in vivo antitumor effect of TNFR2-PLGA-ADR was markedly enhanced,which was associated with a decrease of TNFR2^(+)T_(regs) and an increase of IFNγ^(+)CD8^(+)cytotoxic T lymphocytes in the tumor tissue.Therefore,our results clearly show that targeting TNFR2 is a promising strategy for designing tumor-specific chemoimmunotherapeutic agent delivery system.展开更多
Addressing the urgent need for innovative depression treatments,this study heralds a breakthrough in major depressive disorder(MDD)therapy by intertwining clinical observations with neurobiological advancements.We ana...Addressing the urgent need for innovative depression treatments,this study heralds a breakthrough in major depressive disorder(MDD)therapy by intertwining clinical observations with neurobiological advancements.We analyzed brain-derived neurotrophic factor(BDNF)levels in serum exosomes from a diverse group of 60 individuals,including first-episode,drug-free MDD patients,medicated MDD patients,and healthy controls.Our results revealed a significant decrease in BDNF levels within MDD patients’exosomes,which notably increased post-medication,highlighting BDNF’s potential as a biomarker for both MDD diagnosis and treatment efficacy.Advancing these clinical findings,we developed RVG-modified exosomes engineered to overexpress BDNF(RVG-BDNF-Exos),designed to directly target neuronal cells.Our findings demonstrate that these engineered exosomes can successfully traverse the blood–brain barrier,targeting neurons in the hippocampus and prefrontal cortex.In our mouse model of depression induced by lipopolysaccharide,RVG-BDNF-Exos treatment led to a significant increase of BDNF in these key brain regions,crucial for mood regulation and neurogenesis.This intervention modulated the BDNF/TrkB/AKT signaling pathway,central to neural plasticity and implicated in depression’s pathogenesis.Behavioral assessments exhibited substantial improvements in depressive-like behaviors in mice treated with RVG-BDNF-Exos,including reduced immobility in Tail Suspension and Forced Swim Tests.Additionally,our treatment effectively decreased neuroinflammation,as evidenced by the reduction in microglia and astrocyte numbers.Moreover,RVG-BDNF-Exos treatment enhanced neurogenesis and regulated synaptic plasticity,as indicated by the increased expression of neuronal markers MAP2 and DCX,and synaptic proteins PSD95 and Syn-1.In conclusion,this study not only underscores the clinical potential of serum exosomal BDNF as a diagnostic and therapeutic marker for MDD but also demonstrates the efficacy of RVG-BDNF-Exos in alleviating depressive symptoms.Our findings pave the way for future targeted,personalized psychiatric treatments,offering a promising direction in MDD therapy.展开更多
This article provides a comprehensive review of various approaches to targeted drug delivery for liver cancer, an area of significant need due to the limited effectiveness of current treatments. The article begins by ...This article provides a comprehensive review of various approaches to targeted drug delivery for liver cancer, an area of significant need due to the limited effectiveness of current treatments. The article begins by highlighting the role of the liver in metabolism and discusses the high mortality associated with hepatocellular carcinoma (HCC). The shortcomings of traditional chemotherapy, such as multidrug resistance and off-target effects, necessitate the exploration of novel therapeutic strategies, with a focus on targeted approaches. The review details both passive and active targeting strategies. Passive targeting leverages the enhanced permeability and retention (EPR) effect and unique features of the tumor microenvironment, while active targeting employs specific ligands, such as peptides, antibodies, and proteins, to bind to overexpressed receptors on liver and tumor cells. The article further details many examples of active targeting using the asialoglycoprotein receptor (ASGPR), glycyrrhetinic acid (GA), transferrin receptor (TfR), and folate receptor (FR) on hepatocytes and tumor cells, demonstrating that there has been significant research effort put into this field. The importance of non-parenchymal cells in the liver is also discussed, and the article examines methods of targeting Kupffer cells, sinusoidal endothelial cells, and hepatic stellate cells for therapeutic benefit. The review goes on to cover the emerging field of subcellular targeting, including specific strategies to target the nucleus, mitochondria, and the endoplasmic reticulum/Golgi apparatus, noting that although there has been some progress, further research is needed in this area. The text finishes with a summary which acknowledges that while targeted therapies, including enzyme-activated prodrugs, such as Pradefovir, and other novel methods for drug delivery have shown significant promise, challenges remain in translating these therapies into clinical use due to limitations in understanding the sequential transport and the mechanisms of action. Ultimately, the article emphasizes the need for in-depth research to fully realize the potential of precision cancer therapies for liver cancer.展开更多
Background:Building upon our previous work that developed a folate receptor-mediated,euphaorbia factor L1-loaded PLGA microsphere system integrating active and magnetic targeting for theranostics,further investigation...Background:Building upon our previous work that developed a folate receptor-mediated,euphaorbia factor L1-loaded PLGA microsphere system integrating active and magnetic targeting for theranostics,further investigation into its in vivo pharmacokinetics and tissue distribution is warranted despite its demonstrated biocompatibility and safety.Methods:A UPLC-MS/MS method was established to determine the concentration of euphorbia sterol in rat plasma and mouse tissue homogenates,healthy male SD rats and KM mice were administered in groups,drug concentrations at different time points were determined,pharmacokinetic parameters were analyzed by DAS software,and data were processed by SAS software.Results:The proposed method met the requirements of biological sample detection.The plasma pharmacokinetics of rats showed that the drug concentration in the microsphere group was lower than that in the injection group,and the parameters such as mean residence time(MRT(0–t)),half-life(T1/2z)and apparent volume of distribution(Vz)were significantly different from those in the solution group.The distribution of mouse tissues showed that the drug concentrations in the liver and lung tissues of the microsphere preparation group were higher than those in the injection group,and the drug concentrations in the lung and liver tissues were more distributed.Conclusion:The targeted drug delivery system changed the pharmacokinetic behavior and tissue distribution of euphorbia sterol,slowed down plasma elimination,prolonged the half-life,and improved the targeting of drugs in lung and liver tissues and the magnetic targeting effect of lungs.展开更多
Antitumor nanomedicines are usually decorated with ligands to achieve multiple functions,such as targeting delivery,tissue penetration and enhanced cellular uptake.However,a single ligand with multiple functions is ge...Antitumor nanomedicines are usually decorated with ligands to achieve multiple functions,such as targeting delivery,tissue penetration and enhanced cellular uptake.However,a single ligand with multiple functions is generally preferred for use in practice.Herein,a versatile peptide,(HE)_(10)G_(5)R_(6)GDK(HE-RK),was engineered by integrating several motifs into a single sequence,including a masking segment(HE),a flexible linker(G_(5)),and a tumor-penetrating head(RK)which comprised a cell-penetrating peptide(R_(6))and a C-end Rule peptide(RGDK).The RK moiety in HE-RK was sequentially activated following the gradual charge reversal of HE to facilitate the accumulation of its cargos in deep tumor tissue and the cytosol of cancer cells.Moreover,in our study,polymer micelles conjugated with the HE-RK peptide(PM-HE-RK)showed superior cellular internalization at pH 6.5 compared to pH 7.4 in vitro,as well as extended blood circulation time and improved tumor targeting and penetration in vivo.Furthermore,the paclitaxel-loaded micelles(PTX/PM-HERK)demonstrated considerable antitumor efficacy,with an 81.48%tumor inhibition rate in the 4T1 mouse model.Overall,the construction of this all-in-one multisegment peptide presents a synergistic and complementary approach to advancing multifunctional peptide ligand design.展开更多
Cellular senescence is the results of aging and age-related diseases,and the development of anti-aging methods may improve health and extend longevity.The natural flavonol fisetin has been shown to antagonize senescen...Cellular senescence is the results of aging and age-related diseases,and the development of anti-aging methods may improve health and extend longevity.The natural flavonol fisetin has been shown to antagonize senescence in vitro and increases longevity in vivo,but has poor water solubility and limited bioavailability.In this study,a food-grade and senescent cell-targeted delivery system for fisetin was developed based on whey protein isolate-galactooligosaccharides(WPI-GOS)Maillard conjugate,which could recognize senescence associatedβ-galactosidase in senescent cells.The fisetin nanoparticles possessed a high encapsulation efficiency,excellent dispersibility in water,good storage stability and well biocompatibility.Moreover,they could effectively accumulate and retain in senescent cells with excellent senescent cell-targeting efficacy,and inhibit the oxidative stress-induced cellular senescence in vitro.Thus,this novel nanoparticle system based on WPI-GOS Maillard conjugate showed promise to deliver hydrophobic bioactive ingredients like fisetin to senescent cells to improve their bioavailability and anti-senescence effect.展开更多
Drug therapy towards tumours often causes adverse effects because of their non-specific nature.Membrane-coated technology and membrane-coated nanoparticles provide an advanced and promising platform of targeted and sa...Drug therapy towards tumours often causes adverse effects because of their non-specific nature.Membrane-coated technology and membrane-coated nanoparticles provide an advanced and promising platform of targeted and safe delivery.By camouflaging the nanoparticles with natural derived or artificially modified cell membranes,the nano-payloads are bestowed with properties from cell membranes such as longer circulation,tumour or inflammation-targeting,immune stimulation,augmenting the performance of traditional therapeutics.In this review,we review the development of membrane coating technology,and summarise the technical details,physicochemical properties,and research status of membrane-coated nanoparticles from different sources in tumour treatment.Finally,we also look forward to the prospects and challenges of transforming membrane coating technology from experiment into clinical use.Taken together,membrane-coated nanoparticles are bound to become one of the most potential anti-tumour strategies in the future.展开更多
In this study,sodium alginate(SA),a non-toxic natural polysaccharide with good biocompatibility and biodegradability,was developed for targeted delivery of curcumin(CUR)in tumor therapy.The strategy is to sulfhydrylat...In this study,sodium alginate(SA),a non-toxic natural polysaccharide with good biocompatibility and biodegradability,was developed for targeted delivery of curcumin(CUR)in tumor therapy.The strategy is to sulfhydrylate the folic acid(FA)modified SA,and the CUR dissolved in ethyl acetate(EAC)phase is coated in microcapsules by a quick,efficient and environment-friendly sonochemical method.The EAC in the microcapsule core is volatile,which can be recycled and reused to reduce cost.The prepared mi-crocapsules(FA-RSMCs@CUR)exhibited similar toxicity to free curcumin in anti-tumour evaluation in vitro.FA-RSMCs@CUR also exhibited effective antibacterial properties in the antibacterial evaluation in vitro.It is expected to become a low-cost tumor targeting vector in the future,and has the potential to be promoted in clinical application.展开更多
Herpes simplex virus thymidine kinase(HSVtk)gene therapy is a promising strategy for glioblastoma therapy.However,delivery of plasmid DNA(pDNA)encoding HSVtk into the brain by systemic administration is a challenge si...Herpes simplex virus thymidine kinase(HSVtk)gene therapy is a promising strategy for glioblastoma therapy.However,delivery of plasmid DNA(pDNA)encoding HSVtk into the brain by systemic administration is a challenge since pDNA can hardly penetrate the bloodbrain barrier.In this study,an exosome-membrane(EM)and polymer-based hybrid complex was developed for systemic delivery of pDNA into the brain.Histidine/arginine-linked polyamidoamine(PHR)was used as a carrier.PHR binds to pDNA by electrostatic interaction.The pDNA/PHR complex was mixed with EM and subjected to extrusion to produce pDNA/PHR-EM hybrid complex.For glioblastoma targeting,T7 peptide was attached to the pDNA/PHR-EM complex.Both pDNA/PHR-EM and T7-decorated pDNA/PHR-EM(pDNA/PHREM-T7)had a surface charge of–5 mV and a size of 280 nm.Transfection assays indicated that pDNA/PHR-EM-T7 enhanced the transfection to C6 cells compared with pDNA/PHREM.Intravenous administration of pHSVtk/PHR-EM-T7 showed that pHSVtk/PHR-EM and pHSVtk/PHR-EM-T7 delivered pHSVtk more efficiently than pHSVtk/lipofectamine and pHSVtk/PHR into glioblastoma in vivo.pHSVtk/PHR-EM-T7 had higher delivery efficiency than pHSVtk/PHR-EM.As a result,the HSVtk expression and apoptosis levels in the tumors of the pHSVtk/PHR-EM-T7 group were higher than those of the other control groups.Therefore,the pDNA/PHR-EM-T7 hybrid complex is a useful carrier for systemic delivery of pHSVtk to glioblastoma.展开更多
The prospect of employing chemoimmunotherapy targeted towards the endoplasmic reticulum(ER)presents an opportunity to amplify the synergistic effects of chemotherapy and immunotherapy.In this study,we initially valida...The prospect of employing chemoimmunotherapy targeted towards the endoplasmic reticulum(ER)presents an opportunity to amplify the synergistic effects of chemotherapy and immunotherapy.In this study,we initially validated celastrol(CEL)as an inducer of immunogenic cell death(ICD)by promoting ER stress and autophagy in colorectal cancer(CRC)cells.Subsequently,an ER-targeted strategy was posited,involving the codelivery of CEL with PD-L1 small interfering RNAs(siRNA)using KDEL peptide-modified exosomes derived from milk(KME),to enhance chemoimmunotherapy outcomes.Our findings demonstrate the efficient transportation of KME to the ER via the Golgi-to-ER pathway.Compared to their non-targeting counterparts,KME exhibited a significant augmentation of the CEL-induced ICD effect.Additionally,it facilitated the release of danger signaling molecules(DAMPs),thereby stimulating the antigen-presenting function of dendritic cells and promoting the infiltration of T cells into the tumor.Concurrently,the ER-targeted delivery of PD-L1 siRNA resulted in the downregulation of both intracellular and membrane PD-L1 protein expression,consequently fostering the proliferation and activity of CD8^(+)T cells.Ultimately,the ER-targeted formulation exhibited enhanced anti-tumor efficacy and provoked anti-tumor immune responses against orthotopic colorectal tumors in vivo.Collectively,a robust ER-targeted delivery strategy provides an encouraging approach for achieving potent cancer chemoimmunotherapy.展开更多
Stroke is the second leading cause of death and the primary cause of permanent disability worldwide.Ischemic stroke(IS)accounts for 87%of all strokes globally and is characterized by the occlusion of cerebral vasculat...Stroke is the second leading cause of death and the primary cause of permanent disability worldwide.Ischemic stroke(IS)accounts for 87%of all strokes globally and is characterized by the occlusion of cerebral vasculature due to embolic presence.Clinical treatments for IS include enzymatic thrombolysis,mechanical thrombectomy,and neuroprotection.However,these approaches have obvious limitations.First,early vascular recanalization leads to secondary cascade injuries and a high risk of hemorrhagic transformation,resulting in poor clinical outcomes for patients with IS.In addition,neuroprotective agents often fail to achieve satisfactory clinical efficacy due to inadequate drug concentrations and off-target effects[1].Targeted stimuli-responsive nanoformulations for thrombolysis and neuroprotection have been developed to address these limitations in current clinical treatments.These nanoformulations are based on IS-specific thrombus-associated receptors and the pathological microenvironments,showing great promise in treating IS(Figure A).展开更多
As one of the most common gynecological malignancies,peritoneal metastasis is a common feature and cause of high mortality in ovarian cancer(OC).Currently,the standard treatment for OC and its peritoneal metastasis is...As one of the most common gynecological malignancies,peritoneal metastasis is a common feature and cause of high mortality in ovarian cancer(OC).Currently,the standard treatment for OC and its peritoneal metastasis is maximal cytoreductive surgery(CRS)combined with platinum-based chemotherapy.Compared with intravenous chemotherapy,traditional intraperitoneal(IP)chemotherapy exhibits obvious pharmacokinetic(PK)advantages and systemic safety and has shown significant survival benefits in several clinical studies of OC patients.However,there remain several challenges in traditional IP chemotherapy,such as insufficient drug retention,a lack of tumor targeting,inadequate drug penetration,gastrointestinal toxicity,and limited inhibition of tumor metastasis and chemoresistance.Nanomedicine-based IP targeting delivery systems,through specific drug carrier design with tumor cells and tumor environment(TME)targeting,make it possible to overcome these challenges and maximize local therapy efficacy while reducing side effects.In this review article,the rationale and challenges of nanomedicine-based IP chemotherapies,as well as their in vivo fate after IP administration,which are crucial for their rational design and clinical translation,are firstly discussed.Then,current strategies for nanomedicine-based targeting delivery systems and the relevant clinical trials in IP chemotherapy are summarized.Finally,the future directions of the nanomedicine-based IP targeting delivery system for OC and its peritoneal metastasis are proposed,expecting to improve the clinical development of IP chemotherapy.展开更多
Thymoquinone(TQ)and gallic acid(GA)are known for counter-tumorigenic characteristics.GA inhibits cancer cell proliferation by interfering with many apoptotic signaling pathways,producing more reactive oxygen species(R...Thymoquinone(TQ)and gallic acid(GA)are known for counter-tumorigenic characteristics.GA inhibits cancer cell proliferation by interfering with many apoptotic signaling pathways,producing more reactive oxygen species(ROS),focusing on the cell cycle,and suppressing the expression of oncogenes and matrix metalloproteinases(MMPs).In this study,TQ(after reducing to thymohydroquinone)and GA are esterified to form thymohydroquinyl gallate(a prodrug).Thymohydroquinyl gallate(THQG)possesses enhanced antineoplastic efficacy and targeted delivery potential.The chemical and spectroscopic analysis confirms ester synthesis.Gold nanoparticles(AuNPs)are employed as nanocarriers due to their physicochemical and optical characteristics,biocompatibility,and low toxicity.As an efficient drug transporter,(AuNPs) shield conjugated drugs from enzymatic digestion.The prodrug acts as a reducing agent for Au metal atoms and is loaded onto it after reduction.The nano drug is radiolabeled with 99mTc and 131I to monitor the drug biodistribution in animals using a gamma camera and single-photon emission computerized tomography(SPECT).131I is an antineoplastic that helps enhance the drug's efficiency.Chromatographic results reveal promising radiolabeling percentages.In vitro,drug release shows sustained release at pH~5.8.In vitro 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide(MTT)cytotoxicity assay reveals drug potency on CAL 27 and MCF 7 cell lines.展开更多
Targeted delivery of therapeutics for spinal cord injury(SCI)has been a long-term challenge due to the complexity of the pathological procession.Macrophage,as an immune cell,can selectively accumulate at the trauma si...Targeted delivery of therapeutics for spinal cord injury(SCI)has been a long-term challenge due to the complexity of the pathological procession.Macrophage,as an immune cell,can selectively accumulate at the trauma site after SCI.This intrinsic targeting,coupled with good immune-escaping capacity makes macrophages an ideal source of biomimetic delivery carrier for SCI.Worth mentioning,macrophages have multiple polarization states,which may not be ignored when designing macrophage-based delivery systems.Herein,we fabricated macrophage membrane-camouflaged liposomes(RM-LIPs)and evaluated their abilities to extend drug circulation time and target the injured spinal cord.Specially,we detected the expression levels of the two main targeted receptors Mac-1 and integrinα4 in three macrophage subtypes,including unactivated(M0)macrophages,classically activated(M1)macrophages and alternatively activated(M2)macrophages,and compared targeting of these macrophage membrane-coated nanoparticles for SCI.The macrophage membrane camouflage decreased cellular uptake of liposomes in RAW264.7 immune cells and strengthened binding of the nanoparticle to the damaged endothelial cells in vitro.RM-LIPs can prolong drug circulation time and actively accumulate at the trauma site of the spinal cord in vivo.Besides,RM-LIPs loaded with minocycline(RM-LIP/MC)showed a comprehensive therapeutic effect on SCI mice,and the anti-pyroptosis was found to be a novel mechanism of RM-LIP/MC treatment of SCI.Moreover,the levels of Mac-1 and integrinα4 in macrophages and the targeting of RM-LIP for SCI were found to be independent of macrophage polarization states.Our study provided a biomimetic strategy via the biological properties of macrophages for SCI targeting and treatment.展开更多
Exosome is an excellent vesicle for in vivo delivery of therapeutics,including RNAi and chemical drugs.The extremely high efficiency in cancer regression can partly be attributed to its fusion mechanism in delivering ...Exosome is an excellent vesicle for in vivo delivery of therapeutics,including RNAi and chemical drugs.The extremely high efficiency in cancer regression can partly be attributed to its fusion mechanism in delivering therapeutics to cytosol without endosome trapping.However,being composed of a lipidbilayer membrane without specific recognition capacity for aimed-cells,the entry into nonspecific cells can lead to potential side-effects and toxicity.Applying engineering approaches for targeting-capacity to deliver therapeutics to specific cells is desirable.Techniques with chemical modification in vitro and genetic engineering in cells have been reported to decorate exosomes with targeting ligands.RNA nanoparticles have been used to harbor tumor-specific ligands displayed on exosome surface.The negative charge reduces nonspecific binding to vital cells with negatively charged lipid-membrane due to the electrostatic repulsion,thus lowering the side-effect and toxicity.In this review,we focus on the uniqueness of RNA nanoparticles for exosome surface display of chemical ligands,small peptides or RNA aptamers,for specific cancer targeting to deliver anticancer therapeutics,highlighting recent advances in targeted delivery of siRNA and miRNA that overcomes the previous RNAi delivery roadblocks.Proper understanding of exosome engineering with RNA nanotechnology promises efficient therapies for a wide range of cancer subtypes.展开更多
In order to enhance the efficiency and specificity of anticancer drug delivery and realize intelligently controlled release,a new multi-functional nanoparticle drug carrier was synthesized.The drug carrier was prepare...In order to enhance the efficiency and specificity of anticancer drug delivery and realize intelligently controlled release,a new multi-functional nanoparticle drug carrier was synthesized.The drug carrier was prepared by functionalizing multi-walled carbon nanotubes(MWCNTs) with polyethylenimines(PEI),fluorescein isothiocyanate(FITC) and glycyrrhizic acid(GL).After detailed characterization,doxorubicin(DOX) was loaded onto the obtained MWCNT composites through π-π stacking interactions.The drug loading capacity of the GL-functionalized material was up to 92%,and the release behavior was significantly pH-sensitive.Release at pH = 5.8(typical of the tumor cell microenvironment) was much more rapid and reached a greater extent than release under normal physiological conditions(pH = 7.4).The modified MWCNTs had high biocompatibility with the liver cancer cell line SMMC-7721,but were able to induce cell death after 24 h incubation if loaded with DOX.Tests with shorter incubation time(2 h) were undertaken to investigate the selectivity of the MWCNT composites,showed that the nanocomposites could specifically target cancer cells.The above results suggest that the functionalized carbon nanotubes-based material has potential applications for targeted delivery and controlled release of anticancer drug.展开更多
Selective occlusion of tumor vasculature has proven to be an effective strategy for cancer therapy.Among vascular coagulation agents,the extracellular domain of coagulation-inducing protein tissue factor,truncated tis...Selective occlusion of tumor vasculature has proven to be an effective strategy for cancer therapy.Among vascular coagulation agents,the extracellular domain of coagulation-inducing protein tissue factor,truncated tissue factor(tTF),is the most widely used.Since the truncated protein exhibits no coagulation activity and is rapidly cleared in the circulation,free tTF cannot be used for cancer treatment on its own but must be combined with other moieties.We here developed a novel,tumor-specific tTF delivery system through coupling tTF with the DNA aptamer,AS1411,which selectively binds to nucleolin receptors overexpressing on the surface of tumor vascular endothelial cells and is specifically cytotoxic to target cells.Systemic administration of the tTF-AS1411 conjugates into tumor-bearing animals induced intravascular thrombosis solely in tumors,thus reducing tumor blood supply and inducing tumor necrosis without apparent side effects.This conjugate represents a uniquely attractive candidate for the clinical translation of vessel occlusion agent for cancer therapy.展开更多
The lymphatic system has an important defensive role in the human body. The metastasis of most tumors initially spreads through the surrounding lymphatic tissue and eventually forms lymphatic metastatic tumors; the tu...The lymphatic system has an important defensive role in the human body. The metastasis of most tumors initially spreads through the surrounding lymphatic tissue and eventually forms lymphatic metastatic tumors; the tumor cells may even transfer to other organs to form other types of tumors. Clinically, lymphatic metastatic tumors develop rapidly. Given the limitations of surgical resection and the low effectiveness of radiotherapy and chemotherapy, the treatment of lymphatic metastatic tumors remains a great challenge. Lymph node metastasis may lead to the further spread of tumors and may be predictive of the endpoint event. Under these circumstances, novel and effective lymphatic targeted drug delivery systems have been explored to improve the specificity of anticancer drugs to tumor cells in lymph nodes. In this review, we summarize the principles of lymphatic targeted drug delivery and discuss recent advances in the development of lymphatic targeted carriers.展开更多
基金supported by the National Natural Science Foundation of China(Grant No.:82104399)the Science and Technology Project of Haihe Laboratory of Modern Chinese Medicine,China(Grant No.:22HHZYSS00001).
文摘Parkinson's disease(PD)is a debilitating and progressive neurodegenerative disorder with complex pathology and multiple membrane barriers that hinder drug delivery,resulting in the absence of ideal therapeutic drugs with minimal side effects[1].Recently,natural medicine has garnered significant attention due to its remarkable efficacy and limited side effects.Icariin,a naturally occurring flavonoid,exhibits excellent potential as a therapeutic agent for neurodegenerative disease[2].However,its clinical application is limited by poor water solubility,low bioavailability,and high clearance rates.Here,an aqueous formulation of icariin/hydroxypropyl-β-cyclodextrin(HP-β-CD)supramolecular inclusion complex was obtained to optimize icariin properties.Furthermore,icariin cyclodextrin supramolecular inclusion complex based thermosensitive(icariin gels)was innovated.At lower temperatures,it remained in a liquid phase with high fluidity.Upon reaching the gelation temperature,it underwent a transition to a gel phase with significantly reduced fluidity,which may be suitable for the design of an intranasal delivery system for PD treatment.The innovative approach capitalizes on the exceptional characteristics of HP-β-CD,which was utilized to synergize with nasal delivery for targeted brain delivery and with icariin for PD treatment[3,4].
基金supported by the National Natural Science Foundations of China(Nos.22464022,22461048,and 22364023)Scientific Research Fund Project of Yunnan Education Department(No.2023j0204)+3 种基金Yunnan Normal University Doctoral Research Initiation Program(No.01100205020503180)Xing Dian Talent Support Program Foundations(No.01100208019916016)Yunnan Normal University Graduate Research Innovation Fund Project(No.YJSJJ23-B87)Yunnan Basic Research Funding Program(Nos.202401AT070128,202301AT070074,and 202201AU070056)。
文摘Chiral anticancer drugs are the subject of ongoing research due to their optical characterization and pharmacological effects.Achieving a single enantiomer of a chiral anticancer drug is arduous,but it can significantly improve its pharmacokinetics for tumor therapy.Here,the chiral nanocatchers,known as Dbiotin-P5■MCC NCs,were designed and prepared based on host-vip self-assembly between D-biotin anchored pillar[5]arene(D-biotin-P5)and myristoyl chloride choline(MCC).D-Biotin-P5■MCC NCs featuring the chiral separation and enzyme-induced disassemble were evaluated for their ability to selectively capture and subsequently target the release of(R,R)-OXA enantiomers into tumor cells.Furthermore,the use of D-biotin-P5■MCC NCs has demonstrated a significant enhancement in the intracellular uptake of OXA,with the drug being efficiently released to MCF-7 breast cancer cells.This has led to a superior inhibitory effect on MCF-7 cells when compared to free OXA,while also reducing the cytotoxicity of the drug in HEK 293 human embryonic kidney cells.This research not only paves a promising way for the fabrication of chiral supramolecular nanocarriers but also holds the potential to improve the processes of chiral drug separation and targeted therapy.
基金funded by Macao Science and Technology Development Fund(FDCT,0007/2022/AKP,0099/2021/A2 and 005/2023/SKL)University of Macao(MYRG2022-00260-ICMS,CPG2024-00031-ICMS)the National Natural Science Foundation of China(No.82203012).
文摘High levels of tumor necrosis factor receptor type Il(TNFR2)are preferentially expressed by immunosuppressive CD4^(+)Foxp3^(+)regulatory T cells(T_(regs)),especially those present in the tumor microenvironment,as initially reported by us.There is compelling evidence that targeting TNFR2 markedly enhances antitumor immune responses.Furthermore,a broad spectrum of human cancers also expresses TNFR2,while its expression by normal tissue is very limited.We thus hypothesized that TNFR2 may be harnessed for tumor-targeted delivery of chemotherapeutic agents.In this study,we performed a proof-of-concept study by constructing a TNFR2-targeted PEGylated poly(DL-lactic-co-glycolic acid)(PLGA-PEG)nanodrug delivery system[designated as TNFR2-PLGA-ADR(Adriamycin)].The results of in vitro study showed that this TNFR2-targeted delivery system had the properties in cellular binding and cytotoxicity toward mouse colon cancer cells.Further,upon intravenous injection,TNFR2-PLGA-ADR could efficiently accumulate in MC38 and CT26 mouse colon tumor tissues and preferentially bind with tumor-infiltrating T_(regs).Compared with ADR and ISO-PLGA-ADR,the in vivo antitumor effect of TNFR2-PLGA-ADR was markedly enhanced,which was associated with a decrease of TNFR2^(+)T_(regs) and an increase of IFNγ^(+)CD8^(+)cytotoxic T lymphocytes in the tumor tissue.Therefore,our results clearly show that targeting TNFR2 is a promising strategy for designing tumor-specific chemoimmunotherapeutic agent delivery system.
基金supported by the National Natural Science Foundation of China(no.82071676).
文摘Addressing the urgent need for innovative depression treatments,this study heralds a breakthrough in major depressive disorder(MDD)therapy by intertwining clinical observations with neurobiological advancements.We analyzed brain-derived neurotrophic factor(BDNF)levels in serum exosomes from a diverse group of 60 individuals,including first-episode,drug-free MDD patients,medicated MDD patients,and healthy controls.Our results revealed a significant decrease in BDNF levels within MDD patients’exosomes,which notably increased post-medication,highlighting BDNF’s potential as a biomarker for both MDD diagnosis and treatment efficacy.Advancing these clinical findings,we developed RVG-modified exosomes engineered to overexpress BDNF(RVG-BDNF-Exos),designed to directly target neuronal cells.Our findings demonstrate that these engineered exosomes can successfully traverse the blood–brain barrier,targeting neurons in the hippocampus and prefrontal cortex.In our mouse model of depression induced by lipopolysaccharide,RVG-BDNF-Exos treatment led to a significant increase of BDNF in these key brain regions,crucial for mood regulation and neurogenesis.This intervention modulated the BDNF/TrkB/AKT signaling pathway,central to neural plasticity and implicated in depression’s pathogenesis.Behavioral assessments exhibited substantial improvements in depressive-like behaviors in mice treated with RVG-BDNF-Exos,including reduced immobility in Tail Suspension and Forced Swim Tests.Additionally,our treatment effectively decreased neuroinflammation,as evidenced by the reduction in microglia and astrocyte numbers.Moreover,RVG-BDNF-Exos treatment enhanced neurogenesis and regulated synaptic plasticity,as indicated by the increased expression of neuronal markers MAP2 and DCX,and synaptic proteins PSD95 and Syn-1.In conclusion,this study not only underscores the clinical potential of serum exosomal BDNF as a diagnostic and therapeutic marker for MDD but also demonstrates the efficacy of RVG-BDNF-Exos in alleviating depressive symptoms.Our findings pave the way for future targeted,personalized psychiatric treatments,offering a promising direction in MDD therapy.
文摘This article provides a comprehensive review of various approaches to targeted drug delivery for liver cancer, an area of significant need due to the limited effectiveness of current treatments. The article begins by highlighting the role of the liver in metabolism and discusses the high mortality associated with hepatocellular carcinoma (HCC). The shortcomings of traditional chemotherapy, such as multidrug resistance and off-target effects, necessitate the exploration of novel therapeutic strategies, with a focus on targeted approaches. The review details both passive and active targeting strategies. Passive targeting leverages the enhanced permeability and retention (EPR) effect and unique features of the tumor microenvironment, while active targeting employs specific ligands, such as peptides, antibodies, and proteins, to bind to overexpressed receptors on liver and tumor cells. The article further details many examples of active targeting using the asialoglycoprotein receptor (ASGPR), glycyrrhetinic acid (GA), transferrin receptor (TfR), and folate receptor (FR) on hepatocytes and tumor cells, demonstrating that there has been significant research effort put into this field. The importance of non-parenchymal cells in the liver is also discussed, and the article examines methods of targeting Kupffer cells, sinusoidal endothelial cells, and hepatic stellate cells for therapeutic benefit. The review goes on to cover the emerging field of subcellular targeting, including specific strategies to target the nucleus, mitochondria, and the endoplasmic reticulum/Golgi apparatus, noting that although there has been some progress, further research is needed in this area. The text finishes with a summary which acknowledges that while targeted therapies, including enzyme-activated prodrugs, such as Pradefovir, and other novel methods for drug delivery have shown significant promise, challenges remain in translating these therapies into clinical use due to limitations in understanding the sequential transport and the mechanisms of action. Ultimately, the article emphasizes the need for in-depth research to fully realize the potential of precision cancer therapies for liver cancer.
基金sponsored by the Fundamental Research Funds forthe Central Universities(No.2024-JYB-JBZD-047)High Level Key Discipline Construction of Traditional Chinese Medicine(zyyzdxk-2023272).
文摘Background:Building upon our previous work that developed a folate receptor-mediated,euphaorbia factor L1-loaded PLGA microsphere system integrating active and magnetic targeting for theranostics,further investigation into its in vivo pharmacokinetics and tissue distribution is warranted despite its demonstrated biocompatibility and safety.Methods:A UPLC-MS/MS method was established to determine the concentration of euphorbia sterol in rat plasma and mouse tissue homogenates,healthy male SD rats and KM mice were administered in groups,drug concentrations at different time points were determined,pharmacokinetic parameters were analyzed by DAS software,and data were processed by SAS software.Results:The proposed method met the requirements of biological sample detection.The plasma pharmacokinetics of rats showed that the drug concentration in the microsphere group was lower than that in the injection group,and the parameters such as mean residence time(MRT(0–t)),half-life(T1/2z)and apparent volume of distribution(Vz)were significantly different from those in the solution group.The distribution of mouse tissues showed that the drug concentrations in the liver and lung tissues of the microsphere preparation group were higher than those in the injection group,and the drug concentrations in the lung and liver tissues were more distributed.Conclusion:The targeted drug delivery system changed the pharmacokinetic behavior and tissue distribution of euphorbia sterol,slowed down plasma elimination,prolonged the half-life,and improved the targeting of drugs in lung and liver tissues and the magnetic targeting effect of lungs.
基金funded by the National Natural Science Foundation of China(22478438,32401048,and 82273882)the Science Fund for Distinguished Young Scholars of Jiangsu Province(BK20240098)the Special Research Fund from the State Key Laboratory of Natural Medicines at China Pharmaceutical University(SKLNMZZ2024JS19).
文摘Antitumor nanomedicines are usually decorated with ligands to achieve multiple functions,such as targeting delivery,tissue penetration and enhanced cellular uptake.However,a single ligand with multiple functions is generally preferred for use in practice.Herein,a versatile peptide,(HE)_(10)G_(5)R_(6)GDK(HE-RK),was engineered by integrating several motifs into a single sequence,including a masking segment(HE),a flexible linker(G_(5)),and a tumor-penetrating head(RK)which comprised a cell-penetrating peptide(R_(6))and a C-end Rule peptide(RGDK).The RK moiety in HE-RK was sequentially activated following the gradual charge reversal of HE to facilitate the accumulation of its cargos in deep tumor tissue and the cytosol of cancer cells.Moreover,in our study,polymer micelles conjugated with the HE-RK peptide(PM-HE-RK)showed superior cellular internalization at pH 6.5 compared to pH 7.4 in vitro,as well as extended blood circulation time and improved tumor targeting and penetration in vivo.Furthermore,the paclitaxel-loaded micelles(PTX/PM-HERK)demonstrated considerable antitumor efficacy,with an 81.48%tumor inhibition rate in the 4T1 mouse model.Overall,the construction of this all-in-one multisegment peptide presents a synergistic and complementary approach to advancing multifunctional peptide ligand design.
基金supported by Dalian Youth Science and Technology Star Project(2020RQ121)the National Science Fund for Distinguished Young Scholars of China(31925031)+1 种基金Doctoral Scientific Research Foundation of Liaoning Province(2020-BS-211)Liaoning Province Education Administration(J2020101)。
文摘Cellular senescence is the results of aging and age-related diseases,and the development of anti-aging methods may improve health and extend longevity.The natural flavonol fisetin has been shown to antagonize senescence in vitro and increases longevity in vivo,but has poor water solubility and limited bioavailability.In this study,a food-grade and senescent cell-targeted delivery system for fisetin was developed based on whey protein isolate-galactooligosaccharides(WPI-GOS)Maillard conjugate,which could recognize senescence associatedβ-galactosidase in senescent cells.The fisetin nanoparticles possessed a high encapsulation efficiency,excellent dispersibility in water,good storage stability and well biocompatibility.Moreover,they could effectively accumulate and retain in senescent cells with excellent senescent cell-targeting efficacy,and inhibit the oxidative stress-induced cellular senescence in vitro.Thus,this novel nanoparticle system based on WPI-GOS Maillard conjugate showed promise to deliver hydrophobic bioactive ingredients like fisetin to senescent cells to improve their bioavailability and anti-senescence effect.
文摘Drug therapy towards tumours often causes adverse effects because of their non-specific nature.Membrane-coated technology and membrane-coated nanoparticles provide an advanced and promising platform of targeted and safe delivery.By camouflaging the nanoparticles with natural derived or artificially modified cell membranes,the nano-payloads are bestowed with properties from cell membranes such as longer circulation,tumour or inflammation-targeting,immune stimulation,augmenting the performance of traditional therapeutics.In this review,we review the development of membrane coating technology,and summarise the technical details,physicochemical properties,and research status of membrane-coated nanoparticles from different sources in tumour treatment.Finally,we also look forward to the prospects and challenges of transforming membrane coating technology from experiment into clinical use.Taken together,membrane-coated nanoparticles are bound to become one of the most potential anti-tumour strategies in the future.
基金supported by the Pharmaceutical Health Industry Development Special Project of the Science and Technology Department of Jilin Province,China(grant No.20210401172YY)Interdisciplinary Research Funding Program for Doctoral Students of jilin University(grant No.101832020DjX026).
文摘In this study,sodium alginate(SA),a non-toxic natural polysaccharide with good biocompatibility and biodegradability,was developed for targeted delivery of curcumin(CUR)in tumor therapy.The strategy is to sulfhydrylate the folic acid(FA)modified SA,and the CUR dissolved in ethyl acetate(EAC)phase is coated in microcapsules by a quick,efficient and environment-friendly sonochemical method.The EAC in the microcapsule core is volatile,which can be recycled and reused to reduce cost.The prepared mi-crocapsules(FA-RSMCs@CUR)exhibited similar toxicity to free curcumin in anti-tumour evaluation in vitro.FA-RSMCs@CUR also exhibited effective antibacterial properties in the antibacterial evaluation in vitro.It is expected to become a low-cost tumor targeting vector in the future,and has the potential to be promoted in clinical application.
基金supported by the Individual Basic Science&Engineering Research Program(NRF-2022R1A2B5B01001920)through the National Research Foundation,funded by the Ministry of Science and ICT in Korea.
文摘Herpes simplex virus thymidine kinase(HSVtk)gene therapy is a promising strategy for glioblastoma therapy.However,delivery of plasmid DNA(pDNA)encoding HSVtk into the brain by systemic administration is a challenge since pDNA can hardly penetrate the bloodbrain barrier.In this study,an exosome-membrane(EM)and polymer-based hybrid complex was developed for systemic delivery of pDNA into the brain.Histidine/arginine-linked polyamidoamine(PHR)was used as a carrier.PHR binds to pDNA by electrostatic interaction.The pDNA/PHR complex was mixed with EM and subjected to extrusion to produce pDNA/PHR-EM hybrid complex.For glioblastoma targeting,T7 peptide was attached to the pDNA/PHR-EM complex.Both pDNA/PHR-EM and T7-decorated pDNA/PHR-EM(pDNA/PHREM-T7)had a surface charge of–5 mV and a size of 280 nm.Transfection assays indicated that pDNA/PHR-EM-T7 enhanced the transfection to C6 cells compared with pDNA/PHREM.Intravenous administration of pHSVtk/PHR-EM-T7 showed that pHSVtk/PHR-EM and pHSVtk/PHR-EM-T7 delivered pHSVtk more efficiently than pHSVtk/lipofectamine and pHSVtk/PHR into glioblastoma in vivo.pHSVtk/PHR-EM-T7 had higher delivery efficiency than pHSVtk/PHR-EM.As a result,the HSVtk expression and apoptosis levels in the tumors of the pHSVtk/PHR-EM-T7 group were higher than those of the other control groups.Therefore,the pDNA/PHR-EM-T7 hybrid complex is a useful carrier for systemic delivery of pHSVtk to glioblastoma.
基金the financial support from the National Science Fund of Distinguished Young Scholars(No.82025032,China)the National Natural Science Foundation of China(No.82073773,China)+5 种基金the Key Research Program of Chinese Academy of Sciences(No.ZDBS-ZRKJZ-TLC005,China)the"Open Competition to Select the Best Candidates"Key Technology Program for Nucleic Acid Drugs of NCTIB(No.NCTIB2022HS01006,China)Young Elite Scientists Sponsorship Program by CAST(No.2022QNRC001,China)Shanghai Action Plan for Science,Technology,and Innovation(No.23HC1401200,China)Shanghai Post-doctoral Excellence Program(No.2022693,China)Shanghai Institute of Materia Medica,Chinese Academy of Sciences(No.SIMM0220232001,China).
文摘The prospect of employing chemoimmunotherapy targeted towards the endoplasmic reticulum(ER)presents an opportunity to amplify the synergistic effects of chemotherapy and immunotherapy.In this study,we initially validated celastrol(CEL)as an inducer of immunogenic cell death(ICD)by promoting ER stress and autophagy in colorectal cancer(CRC)cells.Subsequently,an ER-targeted strategy was posited,involving the codelivery of CEL with PD-L1 small interfering RNAs(siRNA)using KDEL peptide-modified exosomes derived from milk(KME),to enhance chemoimmunotherapy outcomes.Our findings demonstrate the efficient transportation of KME to the ER via the Golgi-to-ER pathway.Compared to their non-targeting counterparts,KME exhibited a significant augmentation of the CEL-induced ICD effect.Additionally,it facilitated the release of danger signaling molecules(DAMPs),thereby stimulating the antigen-presenting function of dendritic cells and promoting the infiltration of T cells into the tumor.Concurrently,the ER-targeted delivery of PD-L1 siRNA resulted in the downregulation of both intracellular and membrane PD-L1 protein expression,consequently fostering the proliferation and activity of CD8^(+)T cells.Ultimately,the ER-targeted formulation exhibited enhanced anti-tumor efficacy and provoked anti-tumor immune responses against orthotopic colorectal tumors in vivo.Collectively,a robust ER-targeted delivery strategy provides an encouraging approach for achieving potent cancer chemoimmunotherapy.
文摘Stroke is the second leading cause of death and the primary cause of permanent disability worldwide.Ischemic stroke(IS)accounts for 87%of all strokes globally and is characterized by the occlusion of cerebral vasculature due to embolic presence.Clinical treatments for IS include enzymatic thrombolysis,mechanical thrombectomy,and neuroprotection.However,these approaches have obvious limitations.First,early vascular recanalization leads to secondary cascade injuries and a high risk of hemorrhagic transformation,resulting in poor clinical outcomes for patients with IS.In addition,neuroprotective agents often fail to achieve satisfactory clinical efficacy due to inadequate drug concentrations and off-target effects[1].Targeted stimuli-responsive nanoformulations for thrombolysis and neuroprotection have been developed to address these limitations in current clinical treatments.These nanoformulations are based on IS-specific thrombus-associated receptors and the pathological microenvironments,showing great promise in treating IS(Figure A).
基金supported by the National Key R&D Program of China(No.2020YFE0201700)the Liaoning Revitalization Talents Program(No.XLYC1908031)。
文摘As one of the most common gynecological malignancies,peritoneal metastasis is a common feature and cause of high mortality in ovarian cancer(OC).Currently,the standard treatment for OC and its peritoneal metastasis is maximal cytoreductive surgery(CRS)combined with platinum-based chemotherapy.Compared with intravenous chemotherapy,traditional intraperitoneal(IP)chemotherapy exhibits obvious pharmacokinetic(PK)advantages and systemic safety and has shown significant survival benefits in several clinical studies of OC patients.However,there remain several challenges in traditional IP chemotherapy,such as insufficient drug retention,a lack of tumor targeting,inadequate drug penetration,gastrointestinal toxicity,and limited inhibition of tumor metastasis and chemoresistance.Nanomedicine-based IP targeting delivery systems,through specific drug carrier design with tumor cells and tumor environment(TME)targeting,make it possible to overcome these challenges and maximize local therapy efficacy while reducing side effects.In this review article,the rationale and challenges of nanomedicine-based IP chemotherapies,as well as their in vivo fate after IP administration,which are crucial for their rational design and clinical translation,are firstly discussed.Then,current strategies for nanomedicine-based targeting delivery systems and the relevant clinical trials in IP chemotherapy are summarized.Finally,the future directions of the nanomedicine-based IP targeting delivery system for OC and its peritoneal metastasis are proposed,expecting to improve the clinical development of IP chemotherapy.
文摘Thymoquinone(TQ)and gallic acid(GA)are known for counter-tumorigenic characteristics.GA inhibits cancer cell proliferation by interfering with many apoptotic signaling pathways,producing more reactive oxygen species(ROS),focusing on the cell cycle,and suppressing the expression of oncogenes and matrix metalloproteinases(MMPs).In this study,TQ(after reducing to thymohydroquinone)and GA are esterified to form thymohydroquinyl gallate(a prodrug).Thymohydroquinyl gallate(THQG)possesses enhanced antineoplastic efficacy and targeted delivery potential.The chemical and spectroscopic analysis confirms ester synthesis.Gold nanoparticles(AuNPs)are employed as nanocarriers due to their physicochemical and optical characteristics,biocompatibility,and low toxicity.As an efficient drug transporter,(AuNPs) shield conjugated drugs from enzymatic digestion.The prodrug acts as a reducing agent for Au metal atoms and is loaded onto it after reduction.The nano drug is radiolabeled with 99mTc and 131I to monitor the drug biodistribution in animals using a gamma camera and single-photon emission computerized tomography(SPECT).131I is an antineoplastic that helps enhance the drug's efficiency.Chromatographic results reveal promising radiolabeling percentages.In vitro,drug release shows sustained release at pH~5.8.In vitro 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide(MTT)cytotoxicity assay reveals drug potency on CAL 27 and MCF 7 cell lines.
基金supported by the National Natural Science Foundation of China(No.81673376)the National Natural Science Foundation of Chongqing(cstc2015jcyj BX0100)the project for innovative Research Group at Higher Educational Institutions in Chongqing(CXQT20006)。
文摘Targeted delivery of therapeutics for spinal cord injury(SCI)has been a long-term challenge due to the complexity of the pathological procession.Macrophage,as an immune cell,can selectively accumulate at the trauma site after SCI.This intrinsic targeting,coupled with good immune-escaping capacity makes macrophages an ideal source of biomimetic delivery carrier for SCI.Worth mentioning,macrophages have multiple polarization states,which may not be ignored when designing macrophage-based delivery systems.Herein,we fabricated macrophage membrane-camouflaged liposomes(RM-LIPs)and evaluated their abilities to extend drug circulation time and target the injured spinal cord.Specially,we detected the expression levels of the two main targeted receptors Mac-1 and integrinα4 in three macrophage subtypes,including unactivated(M0)macrophages,classically activated(M1)macrophages and alternatively activated(M2)macrophages,and compared targeting of these macrophage membrane-coated nanoparticles for SCI.The macrophage membrane camouflage decreased cellular uptake of liposomes in RAW264.7 immune cells and strengthened binding of the nanoparticle to the damaged endothelial cells in vitro.RM-LIPs can prolong drug circulation time and actively accumulate at the trauma site of the spinal cord in vivo.Besides,RM-LIPs loaded with minocycline(RM-LIP/MC)showed a comprehensive therapeutic effect on SCI mice,and the anti-pyroptosis was found to be a novel mechanism of RM-LIP/MC treatment of SCI.Moreover,the levels of Mac-1 and integrinα4 in macrophages and the targeting of RM-LIP for SCI were found to be independent of macrophage polarization states.Our study provided a biomimetic strategy via the biological properties of macrophages for SCI targeting and treatment.
基金supported in part by NIH grants U01CA207946 and R01EB019036 to Peixuan Guo and NIH grant R01CA257961 to Dan Shu and Daniel W.Binzelfunded by the CM Chen Foundationsupported in part by Grant P30CA016058,National Cancer Institute,Bethesda,MD。
文摘Exosome is an excellent vesicle for in vivo delivery of therapeutics,including RNAi and chemical drugs.The extremely high efficiency in cancer regression can partly be attributed to its fusion mechanism in delivering therapeutics to cytosol without endosome trapping.However,being composed of a lipidbilayer membrane without specific recognition capacity for aimed-cells,the entry into nonspecific cells can lead to potential side-effects and toxicity.Applying engineering approaches for targeting-capacity to deliver therapeutics to specific cells is desirable.Techniques with chemical modification in vitro and genetic engineering in cells have been reported to decorate exosomes with targeting ligands.RNA nanoparticles have been used to harbor tumor-specific ligands displayed on exosome surface.The negative charge reduces nonspecific binding to vital cells with negatively charged lipid-membrane due to the electrostatic repulsion,thus lowering the side-effect and toxicity.In this review,we focus on the uniqueness of RNA nanoparticles for exosome surface display of chemical ligands,small peptides or RNA aptamers,for specific cancer targeting to deliver anticancer therapeutics,highlighting recent advances in targeted delivery of siRNA and miRNA that overcomes the previous RNAi delivery roadblocks.Proper understanding of exosome engineering with RNA nanotechnology promises efficient therapies for a wide range of cancer subtypes.
基金Science and Technology Commission of Shanghai Municipality,China(No.16410723700)"111 Project" Biomedical Textile Materials Science and Technology,China(No.B07024)the UK-China Joint Laboratory for Therapeutic Textiles
文摘In order to enhance the efficiency and specificity of anticancer drug delivery and realize intelligently controlled release,a new multi-functional nanoparticle drug carrier was synthesized.The drug carrier was prepared by functionalizing multi-walled carbon nanotubes(MWCNTs) with polyethylenimines(PEI),fluorescein isothiocyanate(FITC) and glycyrrhizic acid(GL).After detailed characterization,doxorubicin(DOX) was loaded onto the obtained MWCNT composites through π-π stacking interactions.The drug loading capacity of the GL-functionalized material was up to 92%,and the release behavior was significantly pH-sensitive.Release at pH = 5.8(typical of the tumor cell microenvironment) was much more rapid and reached a greater extent than release under normal physiological conditions(pH = 7.4).The modified MWCNTs had high biocompatibility with the liver cancer cell line SMMC-7721,but were able to induce cell death after 24 h incubation if loaded with DOX.Tests with shorter incubation time(2 h) were undertaken to investigate the selectivity of the MWCNT composites,showed that the nanocomposites could specifically target cancer cells.The above results suggest that the functionalized carbon nanotubes-based material has potential applications for targeted delivery and controlled release of anticancer drug.
基金supported by grants from the National R&D Program of China(2018YFE0205300,2018YFA0208900)the National Natural Science Foundation of China(81871489,91859118,31730032,31700870,31470969,31661130152)+2 种基金the National Distinguished Young Scientist program(31325010,China)the K.C.Wong Education Foundation(GJTD-2018-03,China)the Beijing Municipal Natural Science Foundation(7182126,China)
文摘Selective occlusion of tumor vasculature has proven to be an effective strategy for cancer therapy.Among vascular coagulation agents,the extracellular domain of coagulation-inducing protein tissue factor,truncated tissue factor(tTF),is the most widely used.Since the truncated protein exhibits no coagulation activity and is rapidly cleared in the circulation,free tTF cannot be used for cancer treatment on its own but must be combined with other moieties.We here developed a novel,tumor-specific tTF delivery system through coupling tTF with the DNA aptamer,AS1411,which selectively binds to nucleolin receptors overexpressing on the surface of tumor vascular endothelial cells and is specifically cytotoxic to target cells.Systemic administration of the tTF-AS1411 conjugates into tumor-bearing animals induced intravascular thrombosis solely in tumors,thus reducing tumor blood supply and inducing tumor necrosis without apparent side effects.This conjugate represents a uniquely attractive candidate for the clinical translation of vessel occlusion agent for cancer therapy.
基金supported by the Specialized Research Fund for the Doctoral Program of Higher Education (No. 20110071130011)the National Science and Technology Major Project (No. 2012ZX09304004)
文摘The lymphatic system has an important defensive role in the human body. The metastasis of most tumors initially spreads through the surrounding lymphatic tissue and eventually forms lymphatic metastatic tumors; the tumor cells may even transfer to other organs to form other types of tumors. Clinically, lymphatic metastatic tumors develop rapidly. Given the limitations of surgical resection and the low effectiveness of radiotherapy and chemotherapy, the treatment of lymphatic metastatic tumors remains a great challenge. Lymph node metastasis may lead to the further spread of tumors and may be predictive of the endpoint event. Under these circumstances, novel and effective lymphatic targeted drug delivery systems have been explored to improve the specificity of anticancer drugs to tumor cells in lymph nodes. In this review, we summarize the principles of lymphatic targeted drug delivery and discuss recent advances in the development of lymphatic targeted carriers.
