RESUMO
As a ROS scavenger, resveratrol exerts a neuroprotective effect by polarizing the M1 microglia to the anti-inflammatory M2 phenotype for ischemic stroke treatment. However, the obstruction of the blood-brain barrier (BBB) seriously impairs the efficacy of resveratrol. Herein, we develop a stepwise targeting nanoplatform for enhanced ischemic stroke therapy, which is fabricated by pH-responsive poly(ethylene glycol)-acetal-polycaprolactone-poly(ethylene glycol) (PEG-Acetal-PCL-PEG) and modified with cRGD and triphenylphosphine (TPP) on a long PEG chain and a short PEG chain, respectively. The as-designed micelle system features effective BBB penetration through cRGD-mediated transcytosis. Once entering the ischemic brain tissues and endocytosed by microglia, the long PEG shell can be detached from the micelles in the acidic lysosomes, subsequently exposing TPP to target mitochondria. Thus, the micelles can effectively alleviate oxidative stress and inflammation by enhanced delivery of resveratrol to microglia mitochondria, reversing the microglia phenotype through the scavenging of ROS. This work offers a promising strategy to treat ischemia-reperfusion injury.
Assuntos
AVC Isquêmico , Micelas , Humanos , Espécies Reativas de Oxigênio , Acetais , Resveratrol/farmacologia , Resveratrol/uso terapêutico , Polímeros/uso terapêutico , Polietilenoglicóis/uso terapêutico , Estresse Oxidativo , Inflamação/tratamento farmacológicoRESUMO
Sepsis is one of the leading causes of death worldwide. The disease progression of sepsis is very fast, and there is a 7-9% increase in mortality every hour. Therefore, rapid and sensitive detection of pathogenic bacteria is crucial for the timely treatment of sepsis as well as the reduction of mortality. Herein, we present a sensitive near-infrared (NIR) fluorescence identification and a rapid magnetic capture based on bioorthogonal nanoprobes for the detection of multiple bacteria in whole blood. The nanoprobes with NIR fluorescence/magnetic properties were modified with dibenzocyclooctyne groups and used to capture and recognize the bacteria via bioorthogonal reaction. The magnetic nanoprobes showed superparamagnetic properties with a saturation magnetization as high as 63 emu/g. Through clicking with the azide groups inserted on the bacteria walls by metabolic engineering, the bioorthogonal magnetic nanoprobes allow fast and broad-spectrum capture of both Gram-positive and Gram-negative bacteria. The bioorthogonal NIR fluorescent nanoprobes with a maximum emission at 900 nm can effectively avoid background interference, further enabling sensitive identification of the bacteria in whole blood. The detection limit was as low as 4 CFU/mL in less than 2.5 h and the nanoprobes were successfully applied to the detection of bacteria in blood samples from the patients with sepsis, showing the potential application in early sepsis diagnosis and clinical studies.
Assuntos
Nanopartículas , Sepse , Humanos , Fluorescência , Antibacterianos , Bactérias Gram-Negativas , Bactérias Gram-Positivas , Bactérias , Sepse/diagnósticoRESUMO
The abnormal pressure in tumor tissue is a significant limitation on the drug delivery efficiency of tumor therapy. This work reports a gradient-driven nanomotor as drug nanocarrier with the pressure-counterworking function. The dual-fuel nanomotors are formed by co-electrospinning of the photosensitive polymers with calcium peroxide (CaO2 ) and catalase (CAT), followed by ultraviolet (UV) irradiation and bovine serum albumin (BSA) incubation. The UV-responsive cleavage nanomotors can effectively release O2 molecules at the fractures as a driving force to increase the delivery speed and escape the phagocytosis of macrophage system in normal tissues. Furthermore, CAT catalyzes H2 O2 produced by CaO2 and the tumor interstitial fluids to provide stronger power for the nanomotors. Additionally, according to the analysis of directional motions of the nanomotors, the functional relationship between the rotational diffusion coefficient (DR ) and the physiological viscosity is constructed. The dual-fuel nanocarriers enable up to 13.25% of the injected dose (ID)/per gram tissue and significantly improve the penetration in deep tumor. It is of vital importance to design and obtain the adaptive pressure-gradient counterworking nanomotors, which can effectively improve the drug delivery efficiency in vitro and in vivo.
Assuntos
Sistemas de Liberação de Medicamentos , Líquido Extracelular , Preparações Farmacêuticas , PolímerosRESUMO
Aberrant energy metabolism not only endows tumor cells with unlimited proliferative capacity but also contributes to the establishment of the glucose-deficient/lactate-rich immunosuppressive tumor microenvironment (ITM) impairing antitumor immunity. Herein, a novel metabolic nanoregulator (D/B/CQ@ZIF-8@CS) was developed by enveloping 2-deoxy-d-glucose (2-DG), BAY-876, and chloroquine (CQ) into zeolitic imidazolate framework-8 (ZIF-8) to simultaneously deprive the energy/nutrition supply of tumor cells and relieve the ITM for synergetic tumor starvation-immunotherapy. Aerobic glycolysis, glucose uptake, and autophagy flux could be concurrently blocked by D/B/CQ@ZIF-8@CS, cutting off the nutrition/energy supply and the source of lactate. Furthermore, inhibition of glucose uptake and aerobic glycolysis could effectively reverse the glucose-deficient/lactate-rich ITM, thus functionally inactivating regulatory T cells and augmenting anti-CTLA-4 immunotherapy. Such a two-pronged strategy would provide new insights for the design of metabolic intervention-based synergistic cancer therapy.
Assuntos
Glicólise , Neoplasias , Linhagem Celular Tumoral , Metabolismo Energético , Glucose/metabolismo , Humanos , Terapia de Imunossupressão , Lactatos , Neoplasias/tratamento farmacológico , Microambiente TumoralRESUMO
A cancer vaccine has been widely applied in clinical tumor therapy as one of the main strategies of immunotherapy. However, the traditional cancer vaccine for a single antigen has a low benefit rate due to the individual differences in patients. Here, we report a R837-loaded poly(lactic-co-glycolic acid) nanovaccine coated with a calcinetin (CRT)-expressed cancer cell membrane antigen for immunotherapy. The cell membrane antigen that possessed a complete antigen array was obtained by inducing immunogenic cell death in vitro, avoiding the severe systemic toxicity of chemotherapy in vivo. The nanovaccine codelivers the adjuvant R837 and the Luc-4T1 membrane antigen, triggering a personalized immune response to the corresponding tumor. Moreover, the calcinetin exposed on the surface of the nanovaccine induces the active uptake of dendritic cells, consequently enhancing the antitumor effect. Meanwhile, the nanovaccine activates immune memory cells to provide long-term protection. Our work provides a new strategy for a clinical personalized antitumor vaccine.
Assuntos
Vacinas Anticâncer , Nanopartículas , Neoplasias , Animais , Membrana Celular , Células Dendríticas , Humanos , Imunoterapia , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias/tratamento farmacológicoRESUMO
The tumor immunosuppressive microenvironment greatly limits the efficacy of immunotherapy. Tumor-associated macrophages (TAMs) are the most abundant immunosuppressive cells in the tumor microenvironment, which can inhibit the tumor after converting it to an M1-like phenotype. In addition, immunogenic cell death (ICD) can increase the amount of T lymphocytes in tumors, activating antineoplastic immunity. Herein, tumor-associated macrophage polarization therapy supplemented with PLGA-DOX (PDOX)-induced ICD is developed for cancer treatment. The nanoparticles/bacteria complex (Ec-PR848) is fabricated for tumor targeting and TAM polarization, and PLGA-R848 (PR848) are attached to the surface of Escherichia coli (E. coli) MG1655 via electrostatic absorption. The toll-like receptor 7/8 (TLR7/8) agonist resiquimod (R848) and E. coli can greatly polarize M2 macrophages to M1 macrophages, while PDOX-induced ICD can also impair the immunosuppression of the tumor microenvironment. This strategy shows that tumor-associated macrophage polarization therapy combined with ICD induced by low-dose chemotherapeutic drugs can commendably enhance the efficacy of immunotherapy.
Assuntos
Nanopartículas , Neoplasias , Escherichia coli , Morte Celular Imunogênica , Imunoterapia , Neoplasias/tratamento farmacológico , Microambiente Tumoral , Macrófagos Associados a TumorRESUMO
Stapled α-helical peptides emerge as one of the attractive peptidomimetics which can efficiently penetrate the cell membrane to access intracellular targets. However, the incorporation of a highly lipophilic cross-link may lead to nonspecific membrane toxicity in certain cases. Here, we report a new class of thioether-tethered bicyclic α-helical peptide to mimic the highly constrained loop-helix structure of natural toxins with the dual-targeting ability for both cell-surface receptors and intracellular targets. The thioether cross-links are introduced to replace the redox-sensitive disulfide bonds in natural toxins via a photoinduced thiol-yne reaction followed by macrolactamization. As a proof of concept, αVß3 integrin targeting ligand was grafted into one of the macrocycles in the bicyclic scaffold, while a mitochondria-targeting proapoptotic motif was introduced into the other macrocycle stabilized by an i, i + 7 alkyl thioether cross-link to recapitulate its α-helical conformation. The obtained dual-targeting bicyclic α-helical BIRK peptides showed highly stable α-helical conformation in the presence of denaturants or under high temperature. Notably, BIRK peptides could induce selective cell death in αVß3 integrin-positive B16F10â¯cells by interfering with the bioenergetic functions of mitochondria. This work provides a new avenue to design and stabilize α-helical peptides in a highly constrained bicyclic loop-helix scaffold with dual functionality.
Assuntos
Peptídeos , Conformação Proteica em alfa-Hélice , Sequência de Aminoácidos , Conformação Molecular , PeptidomiméticosRESUMO
Typical glucose oxidase (GOx)-based starvation therapy is a promising strategy for tumor treatment; however, it is still difficult to achieve an effective therapeutic effect via a single starvation therapy. Herein, we designed a pH-sensitive polymeric vesicle (PV) self-assembled by histamine-modified chondroitin sulfate (CS-his) for codelivery of GOx and l-buthionine sulfoximine (BSO). GOx can consume glucose to induce the starvation therapy after the PVs reach cancer cell. Moreover, the product H2O2 will be reduced by a high concentration of glutathione (GSH) in the tumor cell, resulting in a reduction of the GSH content. The released BSO finally further reduced the GSH level. As a result, the signaling pathway of the ferroptosis will be activated. The in vivo results demonstrated that GOx/BSO@CS PVs exhibit a good inhibitory effect on the growth of 4T1 tumors in mice. Thus, this work provides a facile strategy to prepare pH-sensitive nanomedicine for synergistic starvation-ferroptosis therapy of tumor.
Assuntos
Ferroptose , Glucose Oxidase , Animais , Butionina Sulfoximina , Glutationa , Peróxido de Hidrogênio , Concentração de Íons de Hidrogênio , CamundongosRESUMO
Inspired by the superlubricated surface (SLS) of ice, which consists of an ultrathin and contiguous layer of surface-bound water, we built a SLS on the polycaprolactone (PCL)/poly(2-methacryloxyethylphosphorylcholine) (PMPC) composite nanofibrous membrane via electrospinning under controlled relative humidity (RH). The zwitterionic PMPC on the nanofiber provided a surface layer of bound water, thus generating a hydration lubrication surface. Prepared under 20% RH, electrospun PCL/PMPC nanofibers reached a minimum coefficient of friction (COF) of about 0.12 when the weight ratio of PMPC to PCL was 0.1. At a higher RH, a SLS with an ultralow COF of less than 0.05 was formed on the composite nanofibers. The high stability of the SLS hydration layer on the engineered nanofibrous membrane effectively inhibited fibroblast adhesion and markedly reduced tissue adhesion during tendon repair in vivo. This work demonstrates the great potential of this ice-inspired SLS approach in tissue adhesion-prevention applications.
Assuntos
Nanofibras , Fibroblastos/patologia , Humanos , Membranas Artificiais , Poliésteres , Tendões/patologia , Aderências Teciduais/patologia , Aderências Teciduais/prevenção & controle , Engenharia Tecidual , Alicerces TeciduaisRESUMO
The progress of antitumor immunotherapy is usually limited by tumor-associated macrophages (TAMs) that account for the highest proportion of immunosuppressive cells in the tumor microenvironment, and the TAMs can also be reversed by modulating the M2-like phenotype. Herein, a biomimetic polymer magnetic nanocarrier is developed with selectively targeting and polarizing TAMs for potentiating immunotherapy of breast cancer. This nanocarrier PLGA-ION-R837â@âM (PIRâ@âM) is achieved, first, by the fabrication of magnetic polymer nanoparticles (NPs) encapsulating Fe3 O4 NPs and Toll-like receptor 7 (TLR7) agonist imiquimod (R837) and, second, by the coating of the lipopolysaccharide (LPS)-âtreated macrophage membranes on the surface of the NPs for targeting TAMs. The intracellular uptake of the PIRâ@âM can greatly polarize TAMs from M2 to antitumor M1 phenotype with the synergy of Fe3 O4 NPs and R837. The relevant mechanism of the polarization is deeply studied through analyzing the mRNA expression of the signaling pathways. Different from previous reports, the polarization is ascribed to the fact that Fe3 O4 NPs mainly activate the IRF5 signaling pathway via iron ions instead of the reactive oxygen species-induced NF-κB signaling pathway. The anticancer effect can be effectively enhanced through potentiating immunotherapy by the polarization of the TAMs in the combination of Fe3 O4 NPs and R837.
Assuntos
Polímeros , Macrófagos Associados a Tumor , Biomimética , Humanos , Imunoterapia , Fatores Reguladores de Interferon , Fenômenos MagnéticosRESUMO
Combination chemotherapy with time-programmed administration of multiple drugs is a promising method for cancer treatment. However, realizing time-programmed release of combined drugs from a single carrier is still a great challenge in enhanced cancer therapy. Here, an implantable trilayer structured fiber device is developed to achieve time-programmed release of combined drugs for synergistic treatment of breast cancer. The fiber device is prepared by a modified microfluidic-electrospinning technique. The glycerol solution containing chemotherapy agent doxorubicin (Dox) forms the internal periodic cavities of the fiber, and poly(l-lactic acid) and poly(ε-caprolactone) containing the angiogenesis inhibitor apatinib (Apa) form the double walls of the fiber. Rapid release of Dox can be obtained by adjusting the wall thickness of the cavities, meanwhile sustained release of Apa is achieved through the slow degradation of the fiber matrix. After the fiber device is implanted subcutaneously near to the implanted solid tumor of mice, an excellent synergistic therapeutic effect is achieved through time-programmed release of the combined dual drugs. The fiber device provides a platform to sequentially co-deliver dual or multiple drugs for enhanced combined therapeutic efficacy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias da Mama , Preparações de Ação Retardada , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Doxorrubicina/administração & dosagem , Feminino , Humanos , Células MCF-7 , Camundongos , Piridinas/administração & dosagemRESUMO
BACKGROUND: The erythropoietin-producing hepatocellular (Eph) receptor A5 (EphA5) has been found to be overexpressed in some malignant tumors and is associated with disease prognosis. However, the role of EphA5 in esophageal squamous cell carcinoma (ESCC) is not clear. METHODS: In the present study, we measured the expression of EphA5 in ESCC tissues and cell lines including KYSE150 and KYSE450 cells. siRNA transfection was used to interfere with EphA5 expression in ESCC cell lines. Cell viability, colony formation, scratch and invasion assays were performed to explore the roles of EphA5 in ESCC cell lines. Flow cytometry analysis was performed to investigate whether EphA5 could affect the cell apoptosis and cycle. The biomarkers related to epithelial-mesenchymal transition (EMT) and molecules associated with Wnt/ßcatenin signaling were also measured by western blot and immunofluorescence. RESULTS: The protein and mRNA expression of EphA5 were significantly higher in fresh ESCC tissues and cell lines compared with normal control groups and human normal esophageal epithelial cells (HEEC). The cell viability assay and colony formation assay revealed that EphA5 knockdown enhanced the proliferation of KYSE150 and KYSE450 cells in vitro. The invasion and migration of ESCC cells were accelerated after EphA5 knockdown. The expression of EMT biomarkers was altered in ESCC cells transfected with siRNA targeting EphA5. Moreover, EphA5 downregulation enhanced the protein levels of ßcatenin and p-GSK-3ßSer9, which play a key role in the Wnt/ßcatenin pathway. CONCLUSIONS: EphA5 knockdown promotes the proliferation of esophageal squamous cell carcinoma,enhances invasion and migration ability via epithelial-mesenchymal transition through activating Wnt/ßcatenin pathway.
RESUMO
A trade-off between minimized premature leakage and rapid cargo release on demand is an intractable obstacle faced by smart delivery systems that restrains them from lab to market. To address this dilemma, dynamic hybrid colloidosomes relying on strong yet reversible electrostatic interactions are developed, simply through one-pot cooperative self-assembly of silica nanoparticles and fluorescent carbon dots at the interface of emulsion droplets. Specifically, pH-driven charge reversal of zwitterionic carbon dots leads to immediate electrostatic conversion between the two building blocks from attraction to repulsion. This makes robust locking and instantaneous breakdown of the colloidosomes subtly balanced, thus enabling low off-state leakage (10.5% over 7 days) while ultrafast on-state release (>90% within 5 min) upon an acidic stimulus. We envision that such biocompatible, traceable, and smart colloidosomes will offer unique opportunities for broad applications as on-demand release is desired.
Assuntos
Coloides/química , Sistemas de Liberação de Medicamentos , Nanopartículas/química , Emulsões/química , Concentração de Íons de Hidrogênio , Tamanho da Partícula , Porosidade , Dióxido de Silício/química , Eletricidade EstáticaRESUMO
Multiple drug resistance (MDR) of cancer cells is a major cause of chemotherapy failure. It is currently a great challenge to develop a direct and effective strategy for continuously inhibiting the P-glycoprotein (P-gp) drug pump of MDR tumor cells, thus enhancing the intracellular concentration of the therapeutic agent for effectively killing MDR tumor cells. Here, a new implantable hierarchical-structured ultrafine fiber device is developed via a microfluidic-electrospinning technology for localized codelivery of doxorubicin (DOX) and apatinib (AP). An extremely high encapsulation efficiency of ≈99% for the dual drugs is achieved through this strategy. The release of the loaded dual drugs can be controlled in a programmable release model with a rapid release of the micelles, while AP is slowly released. The sustained release of AP can continuously inhibit the P-gp drug pump of MDR tumor cells, increasing the intracellular DOX accumulation. The in vivo DOX biodistribution displays that the DOX accumulation in the tumor tissues achieves 17.82% after implanting the fiber device for 72 h, which is 6.36-fold higher than that of the intravenously injected DOX. Importantly, the fiber device shows an excellent antitumor effect on MDR tumor-bearing mice with low systemic toxicity.
Assuntos
Doxorrubicina/administração & dosagem , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Piridinas/administração & dosagem , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Linhagem Celular Tumoral , Doxorrubicina/uso terapêutico , Resistência a Múltiplos Medicamentos/genética , Resistencia a Medicamentos Antineoplásicos , Células Endoteliais/metabolismo , Feminino , Humanos , Células MCF-7 , Camundongos , Micelas , Piridinas/uso terapêuticoRESUMO
Mitochondrial-targeting therapy is an emerging strategy for enhanced cancer treatment. In the present study, a multistage targeting strategy using doxorubicin-loaded magnetic composite nanoparticles is developed for enhanced efficacy of photothermal and chemical therapy. The nanoparticles with a core-shell-SS-shell architecture are composed of a core of Fe3 O4 colloidal nanocrystal clusters, an inner shell of polydopamine (PDA) functionalized with triphenylphosphonium (TPP), and an outer shell of methoxy poly(ethylene glycol) linked to the PDA by disulfide bonds. The magnetic core can increase the accumulation of nanoparticles at the tumor site for the first stage of tumor tissue targeting. After the nanoparticles enter the tumor cells, the second stage of mitochondrial targeting is realized as the mPEG shell is detached from the nanoparticles by redox responsiveness to expose the TPP. Using near-infrared light irradiation at the tumor site, a photothermal effect is generated from the PDA photosensitizer, leading to a dramatic decrease in mitochondrial membrane potential. Simultaneously, the loaded doxorubicin can rapidly enter the mitochondria and subsequently damage the mitochondrial DNA, resulting in cell apoptosis. Thus, the synergism of photothermal therapy and chemotherapy targeting the mitochondria significantly enhances the cancer treatment.
Assuntos
Nanopartículas/química , Fármacos Fotossensibilizantes/química , Fototerapia/métodos , Indóis/química , Mitocôndrias/metabolismo , Compostos Organofosforados/química , Polímeros/químicaRESUMO
Compressed monodisperse emulsions in confined space exhibit highly ordered structures. The influence of the volume fraction and the confinement geometry on the organized structures is investigated and the mechanism by which structural transition occurs is studied. Based on the understanding of ordering behavior of compressed emulsions, a simple and high-throughput method to fabricate monodisperse polyhedral microgels using the emulsions as the template is developed. By controlling the geometry of the confined spaces, a variety of shapes such as hexagonal prism, Fejes Toth honeycomb prism, truncated octahedron, pyritohedron, and truncated hexagonal trapezohedron are implemented. Moreover, the edge sharpness of each shape is controllable by adjusting the drop volume fraction. This design principle can be readily extended to other shapes and materials, and therefore provides a useful means to create polyhedral microparticles for both fundamental study and practical applications.
RESUMO
The development of a nanocarrier delivery system having both sufficient stability in blood circulation and a rapid drug release profile at target sites remains a major challenge in cancer therapy. Here, a multifunctional star-shaped micellar system with a precisely spatiotemporal control of releasing encapsulated agents is developed by mixing a photoinitiated crosslinking amphiphilic copolymer with a phenylboronic acid (PBA)-functionalized redox-sensitive amphiphilic copolymer for the first time. The combination of the functional polymers effectively resolves the contradiction that the micellar system cannot release the rapid drug release in cells when it possesses an extreme stability that is often required in blood circulation. In this system, the inner core polymers are photo-crosslinked, endowing a stable micelle matrix structure; the end groups of the hydrophilic segments are decorated with PBA ligands, providing an active targeting ability; disulfide bonds in the micellar matrix impart a redox-responsive trigger for the prompt intracellular release of drugs. As a result, with a relatively low DOX dosage (2 mg kg(-1) per injection) the in vivo antitumor effect on H22-bearing BALB/c mice shows that the micelles have a high therapeutic efficacy against solid tumors while minimal side effects against normal tissues.
Assuntos
Liberação Controlada de Fármacos , Nanopartículas/química , Nanotecnologia/métodos , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Ácidos Borônicos/química , Caproatos/química , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Endocitose/efeitos dos fármacos , Células Hep G2 , Humanos , Lactonas/química , Camundongos Endogâmicos BALB C , Micelas , Polietilenoglicóis/síntese química , Polietilenoglicóis/química , Espectroscopia de Prótons por Ressonância Magnética , Distribuição Tecidual/efeitos dos fármacosRESUMO
Regulation of the growth of vascular endothelial cells (ECs) and smooth muscle cells (SMCs) with artificial vascular grafts at vascularization is well-known to regenerate functional blood vessels for treating cardiovascular disease; however, little research has been published on this subject. Here, a novel polymer vascular graft is presented, whose inner surface contains an assembled circular microgroove pattern decorated with a combination of concentric circular microgrooves and radial, straight microgrooves inspired by the orientation of SMCs and ECs in natural tissues. The surface micropatterns can produce dynamically tunable variations via the thermally switched shape memory. The results from the in vitro EC/SMC co-cultures reveal that the surface micropatterns have a great capacity to regulate the specific distribution of ECs/SMCs because the ECs grow along the radial, straight microgrooves and the SMCs grow along concentric circular microgrooves. The in vivo vascularization is further analyzed by implanting the vascular graft in the rabbit carotid artery. Both histological analysis and immunofluorescence staining demonstrate that it is capable of highly effectively capturing ECs and SMCs in the blood and subsequent regeneration of new blood vessels. Therefore, this study opens a new possibility for regenerating neovessels to replace and repair damaged vessels for cardiovascular diseases treatment.