RESUMO
Introduction: Alzheimer's disease (AD), a neurodegenerative condition, stands as the most prevalent form of dementia. Its complex pathological mechanisms and the formidable blood-brain barrier (BBB) pose significant challenges to current treatment approaches. Oxidative stress is recognized as a central factor in AD, underscoring the importance of antioxidative strategies in its treatment. In this study, we developed a novel brain-targeted nanoparticle, Ce/Zr-MOF@Cur-Lf, for AD therapy. Methods: Layer-by-layer self-assembly technology was used to prepare Ce/Zr-MOF@Cur-Lf. In addition, the effect on the intracellular reactive oxygen species level, the uptake effect by PC12 and bEnd.3 cells and the in vitro BBB permeation effect were investigated. Finally, the mouse AD model was established by intrahippocampal injection of Aß1-42, and the in vivo biodistribution, AD therapeutic effect and biosafety of the nanoparticles were researched at the animal level. Results: As anticipated, Ce/Zr-MOF@Cur-Lf demonstrated efficient BBB penetration and uptake by PC12 cells, leading to attenuation of H2O2-induced oxidative damage. Moreover, intravenous administration of Ce/Zr-MOF@Cur-Lf resulted in rapid brain access and improvement of various pathological features of AD, including neuronal damage, amyloid-ß deposition, dysregulated central cholinergic system, oxidative stress, and neuroinflammation. Conclusion: Overall, Ce/Zr-MOF@Cur-Lf represents a promising approach for precise brain targeting and multi-target mechanisms in AD therapy, potentially serving as a viable option for future clinical treatment.
Assuntos
Doença de Alzheimer , Barreira Hematoencefálica , Cério , Curcumina , Estresse Oxidativo , Zircônio , Animais , Doença de Alzheimer/tratamento farmacológico , Células PC12 , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Zircônio/química , Zircônio/farmacocinética , Camundongos , Ratos , Curcumina/química , Curcumina/farmacocinética , Curcumina/farmacologia , Curcumina/administração & dosagem , Estresse Oxidativo/efeitos dos fármacos , Cério/química , Cério/farmacocinética , Cério/farmacologia , Cério/administração & dosagem , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/química , Distribuição Tecidual , Espécies Reativas de Oxigênio/metabolismo , Nanopartículas/química , Modelos Animais de Doenças , Estruturas Metalorgânicas/química , Estruturas Metalorgânicas/farmacocinética , Estruturas Metalorgânicas/farmacologia , Masculino , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Humanos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismoRESUMO
Lung cancer, predominantly non-small cell lung cancer (NSCLC), remains a significant global health challenge, with limited therapeutic options for patients with KRAS-mutated tumors. Herein, a copper-based metal-organic framework (Cu-MOF) was applied as a novel cuproptosis-mediated nanoplatform for lung cancer therapy. Cu-MOF would disassemble and liberate copper ions under the acidic microenvironment of lysosomes of cancer cells, initiating a cascade of cellular events. The released copper ions catalyzes the Fenton reaction, generating hydroxyl radicals that induce oxidative damage, leading to cytoskeletal disruption and activation of caspase-3, ultimately triggering apoptosis. Simultaneously, with the mediation of the key regulatory factor FDX1, we found that the copper ions binding to the mitochondrial protein DLAT could result in the loss of iron-sulfur cluster proteins and aggregation of lipoylated proteins, which culminated in proteotoxic stress-induced cuproptosis. The pronounced anti-tumor effects of Cu-MOF with apoptosis and cuproptosis were confirmed both in vitro and in vivo experiments. Such dual induction of apoptosis and cuproptosis by Cu-MOF presents a promising therapeutic strategy for NSCLC, particularly for KRAS-mutated tumors, and expands potential applications of Cu-based nanomateirals for other cancers.
Assuntos
Apoptose , Cobre , Neoplasias Pulmonares , Estruturas Metalorgânicas , Cobre/química , Cobre/farmacologia , Estruturas Metalorgânicas/química , Estruturas Metalorgânicas/farmacologia , Humanos , Apoptose/efeitos dos fármacos , Animais , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Camundongos , Linhagem Celular Tumoral , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Antineoplásicos/farmacologia , Antineoplásicos/química , Camundongos Nus , Camundongos Endogâmicos BALB CRESUMO
Rationale: Theranostic nanoplatforms exert a vital role in facilitating concurrent real-time diagnosis and on-demand treatment of diseases, thereby making contributions to the improvement of therapeutic efficacy. Nevertheless, the structural intricacy and the absence of well-defined integration of dual functionality persist as challenges in the development of theranostic nanoplatforms. Methods: We develop an atomically precise theranostic nanoplatform based on metal-organic cage (MOC) to provide magnetic resonance imaging (MRI) guided chemodynamic therapy (CDT) for cancer therapy and assess the theranostic performance both in vitro and in vivo. Through UV-vis spectroscopy, electron paramagnetic resonance (EPR), confocal microscopy, flow cytometry, immunofluorescence staining, and western blotting, the ability of MOC-Mn to generate â¢OH and the subsequent inhibition of HeLa cells was confirmed. Results: The MOC-Mn composed of manganese and calixarene was successfully synthesized and comprehensively characterized. The catalytic activity of manganese within MOC-Mn facilitated the efficient generation of hydroxyl radicals (â¢OH) through a Fenton-like reaction, leveraging the high concentrations of hydrogen peroxide in the tumor microenvironment (TME). Additionally, its capacity to prolong the T1 relaxation time and augment the MR signal was observed. The theranostic efficacy was verified via rigorous in vitro and in vivo experiments, indicating that MOC-Mn offered clearer visualization of tumor particulars and substantial suppression of tumor growth. Conclusion: This study showcases a precise MRI-guided CDT theranostic nanoplatform for cancer therapy, thereby promoting the advancement of precise nanomedicine and structure-function research.
Assuntos
Imageamento por Ressonância Magnética , Nanomedicina Teranóstica , Nanomedicina Teranóstica/métodos , Humanos , Animais , Células HeLa , Imageamento por Ressonância Magnética/métodos , Camundongos , Manganês/química , Camundongos Nus , Feminino , Radical Hidroxila/metabolismo , Radical Hidroxila/química , Neoplasias/tratamento farmacológico , Neoplasias/diagnóstico por imagem , Camundongos Endogâmicos BALB C , Estruturas Metalorgânicas/química , Estruturas Metalorgânicas/farmacologia , Nanopartículas/químicaRESUMO
Introduction: Photodynamic therapy (PDT) has attracted increasing attention in the clinical treatment of epidermal and luminal tumors. However, the PDT efficacy in practice is severely impeded by tumor hypoxia and the adverse factors associated with hydrophobic photosensitizers (PSs), including low delivery capacity, poor photoactivity and limited ROS diffusion. In this study, Pt nanozymes decorated two-dimensional (2D) porphyrin metal-organic framework (MOF) nanosheets (PMOF@HA) were fabricated and investigated to conquer the obstacles of PDT against hypoxic tumors. Materials and Methods: PMOF@HA was synthesized by the coordination of transition metal iron (Zr4+) and PS (TCPP), in situ generation of Pt nanozyme and surface modification with hyaluronic acid (HA). The abilities of hypoxic relief and ROS generation were evaluated by detecting the changes of O2 and 1O2 concentration. The cellular uptake was investigated using flow cytometry and confocal laser scanning microscopy. The SMMC-7721 cells and the subcutaneous tumor-bearing mice were used to demonstrate the PDT efficacy of PMOF@HA in vitro and in vivo, respectively. Results: Benefiting from the 2D structure and inherent properties of MOF materials, the prepared PMOF@HA could not only serve as nano-PS with high PS loading but also ensure the rational distance between PS molecules to avoid aggregation-induced quenching, enhance the photosensitive activity and promote the rapid diffusion of generated radical oxide species (ROS). Meanwhile, Pt nanozymes with catalase-like activity effectively catalyzed intratumoral overproduced H2O2 into O2 to alleviate tumor hypoxia. Additionally, PMOF@HA, with the help of externally coated HA, significantly improved the stability and increased the cell uptake by CD44 overexpressed tumor cells to strengthen O2 self-supply and PDT efficacy. Conclusion: This study provided a new strategy of integrating 2D porphyrin MOF nanosheets with nanozymes to conquer the obstacles of PDT against hypoxic tumors.
Assuntos
Ácido Hialurônico , Estruturas Metalorgânicas , Fotoquimioterapia , Fármacos Fotossensibilizantes , Porfirinas , Hipóxia Tumoral , Fotoquimioterapia/métodos , Estruturas Metalorgânicas/química , Estruturas Metalorgânicas/farmacologia , Animais , Camundongos , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/administração & dosagem , Linhagem Celular Tumoral , Humanos , Hipóxia Tumoral/efeitos dos fármacos , Ácido Hialurônico/química , Ácido Hialurônico/farmacologia , Porfirinas/química , Porfirinas/farmacologia , Porfirinas/farmacocinética , Porfirinas/administração & dosagem , Espécies Reativas de Oxigênio/metabolismo , Platina/química , Platina/farmacologia , Nanoestruturas/química , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias/tratamento farmacológico , Sobrevivência Celular/efeitos dos fármacosRESUMO
Due to their rapid spread, high variability, and drug-resistant strains, new viral infections are continuously emerging. A lack of effective antiviral drugs and vaccines, resulting in disease and death, has significant socioeconomic consequences. Hemoperfusion can effectively adsorb and remove toxins from the blood, thus purifying the blood and serving as an acute treatment. Therefore, the aim of this study was to construct adsorbents to selectively remove viruses from the blood to quickly treat pathogen infection. We reported on new metal-organic framework (MOF)-polymer beads based on MIL-53(Al) and cellulose acetate (CNC), which were prepared by a one-step phase inversion method and applied as a viral hemo-adsorbent for the first time. The characterization results demonstrated that MIL-53(Al) was well dispersed in the CNC matrix. The adsorption results demonstrated that the capture efficiency of the human immunodeficiency virus (HIV) could exceed 99.93%, and the corresponding infectious titer decreased by approximately 103 times in clinical application. Moreover, CNC/MIL-53 exhibited low hemolysis ratios and good anticoagulant properties. Furthermore, molecular dynamics simulations revealed that the interplay of hydrogen bonding was the governing physisorption mechanism. Overall, CNC/MIL-53 could serve as a new type of hemoperfusion adsorbent for virus removal from blood and provide a new treatment pathway to mitigate epidemics.
Assuntos
Celulose , Estruturas Metalorgânicas , Celulose/química , Celulose/análogos & derivados , Estruturas Metalorgânicas/química , Estruturas Metalorgânicas/farmacologia , Adsorção , Humanos , Porosidade , Simulação de Dinâmica Molecular , Hemoperfusão/métodos , AnimaisRESUMO
The combination of chemotherapy and photodynamic therapy (PDT), enabled by core-shell nano-platforms, is a promising method to improve cancer therapy by overcoming hypoxia and boosting drug penetration in breast tumor. Core-shell magnetic (iron oxide: Fe3O4)@platinum-metal organic framework/epirubicin (abbreviated as M@Pt-MOF/EPI) nano-platform is considered an effective cancer therapeutic agent. Relatively small particle size, round shape, and specific response to pH, are the key features of these nanomaterials to be used as promising therapeutic agents. Chemotherapy and photodynamic therapy, when applied in addition to the anticancer effects of nanomaterials, further enhance the therapeutic efficacy. The extensive use, utilization, and efficacy of Core-Shell Magnetic@Platinium-Metal Organic Framework/epirubicin Nano-Platforms for chemo-photodynamic combination therapy in the treatment of several cancers, including triple-negative breast cancer, are examined in this in-depth investigation.
Assuntos
Epirubicina , Fotoquimioterapia , Neoplasias de Mama Triplo Negativas , Humanos , Fotoquimioterapia/métodos , Epirubicina/uso terapêutico , Epirubicina/administração & dosagem , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Feminino , Estruturas Metalorgânicas/química , Estruturas Metalorgânicas/farmacologia , Antineoplásicos/uso terapêutico , Antineoplásicos/administração & dosagem , Terapia Combinada , Platina/uso terapêutico , Platina/farmacologiaRESUMO
Immunotherapy has shown marked progress in promoting systemic anti-colorectal cancer (CRC) clinical effects. For further effectively sensitizing CRC to immunotherapy, we have engineered a pH-sensitive zeolitic imidazolate framework-8 (CS/NPs), capable of efficient cGAS-STING pathway activation and immune checkpoint blockade, by encapsulating the chemotherapeutic mitoxantrone (MTX) and immunomodulator thymus pentapeptide (TP5) and tailoring with tumor-targeting chondroitin sulfate (CS). In this nanoframework, CS endows CS/NPs with specific tumor-targeting activity and reduced systemic toxicity. Of note, the coordinated Zn2+ disrupts glycolytic processes and downregulates the expression of glucose transporter type 1 (GLUT1), thus depriving the cancer cells of their energy. Zn2+ further initiates the adenosine 5'-monophosphate activated protein kinase (AMPK) pathway, which leads to PD-L1 protein degradation and sensitizes CRC cells to immunotherapy. Moreover, the damaged double-stranded DNA during MTX treatment activates the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, which works together with TP5 induced the proliferation and differentiation of T lymphocytes and dendritic cells to further enhance the anti-CRC immune response. Therefore, CS/NPs efficiently sensitize cells to chemotherapy and stimulate systemic antitumor immune responses both in vitro and in vivo, representing a promising strategy to increase the feasibility of CRC immunotherapy.
Assuntos
Neoplasias Colorretais , Inibidores de Checkpoint Imunológico , Imunoterapia , Proteínas de Membrana , Estruturas Metalorgânicas , Mitoxantrona , Nucleotidiltransferases , Neoplasias Colorretais/tratamento farmacológico , Imunoterapia/métodos , Animais , Estruturas Metalorgânicas/química , Estruturas Metalorgânicas/farmacologia , Humanos , Camundongos , Nucleotidiltransferases/metabolismo , Proteínas de Membrana/metabolismo , Mitoxantrona/farmacologia , Mitoxantrona/química , Inibidores de Checkpoint Imunológico/farmacologia , Linhagem Celular Tumoral , Transdução de Sinais/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Antígeno B7-H1/metabolismo , Feminino , ImidazóisRESUMO
Photothermal therapy (PTT) and photodynamic therapy (PDT) provide targeted approaches to cancer treatment, but each therapy has inherent limitations such as insufficient tissue penetration, uneven heat distribution, extreme hypoxia, and overexpressed HSP90 in tumor cells. To address these issues, herein, by encapsulating the IR780 dye and glucose oxidase (GOx) enzyme within ZIF-8 nanoparticles, we created a versatile system capable of combining photodynamic and enhanced photothermal therapy. The integration of the IR780 dye facilitated the generation of reactive oxygen species and hyperthermia upon light activation, enabling dual-mode cancer cell ablation. Moreover, GOx catalyzes the decomposition of glucose into gluconic acid and hydrogen peroxide, leading to the inhibition of ATP production and downregulation of heat shock protein 90 (HSP90) expression, sensitizing cancer cells to heat-induced cytotoxicity. This synergistic combination resulted in significantly improved therapeutic outcomes. Both in vitro and in vivo results validated that the nanoplatform demonstrated superior specificity and favorable therapeutic responses. Our innovative approach represents a promising strategy for overcoming current limitations in cancer treatments and offers the potential for clinical translation in the future.
Assuntos
Glucose Oxidase , Estruturas Metalorgânicas , Fotoquimioterapia , Terapia Fototérmica , Glucose Oxidase/química , Glucose Oxidase/metabolismo , Humanos , Animais , Camundongos , Estruturas Metalorgânicas/química , Estruturas Metalorgânicas/farmacologia , Estruturas Metalorgânicas/síntese química , Concentração de Íons de Hidrogênio , Indóis/química , Indóis/farmacologia , Linhagem Celular Tumoral , Nanopartículas/química , Camundongos Endogâmicos BALB C , Espécies Reativas de Oxigênio/metabolismo , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/terapia , Neoplasias/patologia , Camundongos Nus , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , ImidazóisRESUMO
Damaged skin is susceptible to invasion by harmful microorganisms, especially Staphylococcus aureus and Escherichia coli, which can delay healing. Epigallocatechin-3-gallate (EGCG) is a natural compound known for effectively promoting wound healing and its potent anti-inflammatory effects. However, its application is limited due to its susceptibility to oxidation and isomerization, which alter its structure. The use of zeolitic imidazolate framework-8 (ZIF-8) can effectively tackle these issues. This study introduces an oxygen (O2) and hydrogen peroxide (H2O2) self-supplying ZIF-8 nanoplatform designed to enhance the bioavailability of EGCG, combining photodynamic therapy (PDT) and chemodynamic therapy (CDT) to improve antibacterial properties and ultimately accelerate wound healing. For this purpose, EGCG and indocyanine green (ICG), a photosensitizer, were successively integrated into a ZIF-8, and coated with bovine serum albumin (BSA) to enhance biocompatibility. The outer layer of this construct was further modified with manganese dioxide (MnO2) to promote CDT and calcium peroxide (CaO2) to supply H2O2 and O2, resulting in the final nanoplatform EGCG-ICG@ZIF-8/BSA-MnO2/CaO2 (EIZBMC). In in vitro experiments under 808 nm laser, EIZBMC exhibited synergistic antibacterial effects through PDT and CDT. This combination effectively released reactive oxygen species (ROS), which mediated oxidative stress to inhibit the bacteria. Subsequently, in a murine model of wound infection, EIZBMC not only exerted antibacterial effects through PDT and CDT but also alleviated the inflammatory condition and promoted the regeneration of collagen fibers, which led to accelerated wound healing. Overall, this research presents a promising approach to enhancing the therapeutic efficacy of EGCG by leveraging the synergistic antibacterial effects of PDT and CDT. This multifunctional nanoplatform maximizes EGCG's anti-inflammatory properties, offering a potent solution for promoting infected wound healing.
Assuntos
Antibacterianos , Catequina , Escherichia coli , Verde de Indocianina , Fotoquimioterapia , Fármacos Fotossensibilizantes , Staphylococcus aureus , Cicatrização , Animais , Catequina/química , Catequina/análogos & derivados , Catequina/farmacologia , Cicatrização/efeitos dos fármacos , Antibacterianos/farmacologia , Antibacterianos/química , Camundongos , Verde de Indocianina/química , Verde de Indocianina/farmacologia , Escherichia coli/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Peróxido de Hidrogênio/farmacologia , Estruturas Metalorgânicas/química , Estruturas Metalorgânicas/farmacologia , Óxidos/química , Óxidos/farmacologia , Compostos de Manganês/química , Compostos de Manganês/farmacologia , Zeolitas/química , Zeolitas/farmacologia , Nanopartículas/química , Testes de Sensibilidade Microbiana , Imidazóis/química , Imidazóis/farmacologia , PeróxidosRESUMO
Zinc metal-organic frameworks have emerged as promising candidates, demonstrating excellent biological properties stemming from the unique characteristics of MOFs and zinc. In this study, we employed a facile method to synthesize a zinc metal-organic framework [Zn(IP)(H2O)] using ultrasound irradiation, with the linker being isophthalic acid (IPA) (1,3-benzene dicarboxylic acid). The parent Zn-MOF and two Ag/Zn-MOF samples prepared via loading and encapsulation methods were comprehensively characterized using various techniques, including FT-IR, XRD, SEM, TEM, N2 adsorption-desorption isotherm, UV-vis spectroscopy and TGA. The parent Zn-MOF and two Ag/Zn-MOF samples exhibited a broad spectrum of antibacterial effects. Remarkably, genomic DNA of P. aeruginosa was effectively degraded by Zn-MOF, further supporting its potent antibacterial results. The free radical inhibition assay demonstrated a 71.0% inhibition under the influence of Zn-MOF. In vitro cytotoxicity activity of Zn-MOF against HepG-2 and Caco-2 cell lines revealed differential cytotoxic effects, with higher cytotoxicity against Caco-2 as explored from the IC50 values. This cytotoxicity was supported by the high binding affinity of Zn-MOF to CT-DNA. Importantly, the non-toxic property of Zn-MOF was confirmed through its lack of cytotoxic effects against normal lung cell (Wi-38). The anti-inflammatory treatment of Zn-MOF achieved 75.0% efficiency relative to the standard Ibuprofen drug. DFT and docking provided insights into the geometric stability of Zn-MOF and its interaction with active amino acids within selected proteins associated with the investigated diseases. Finally, the synthesized Zn-MOF shows promise for applications in cancer treatment, chemoprevention, and particularly antibacterial purposes.
Assuntos
Anti-Inflamatórios , Antineoplásicos , Estruturas Metalorgânicas , Simulação de Acoplamento Molecular , Zinco , Humanos , Zinco/química , Zinco/farmacologia , Estruturas Metalorgânicas/química , Estruturas Metalorgânicas/farmacologia , Estruturas Metalorgânicas/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/síntese química , Células CACO-2 , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/síntese química , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Materiais Biocompatíveis/síntese química , Células Hep G2 , Anti-Infecciosos/farmacologia , Anti-Infecciosos/química , Anti-Infecciosos/síntese química , Teoria da Densidade Funcional , Pseudomonas aeruginosa/efeitos dos fármacosRESUMO
A novel Gd-MOF based on tetrafluoro-terephthalic acid has been synthesized and its structure has been solved using X-ray single crystal diffraction data. The compound, with the formula [Gd2(F4BDC)3·H2O]·DMF, is isostructural with other Ln-MOFs based on the same ligand and has been recently reported. Its crystals were also reduced to nanometer size by employing acetic acid or cetyltrimethylammonium bromide (CTAB) as a modulator. The relaxometric properties of the nanoparticles were evaluated in solution by measuring 1H T1 and T2 as a function of the applied magnetic field and temperature. The biocompatibility of Gd-MOFs was evaluated on murine microglial BV-2 and human glioblastoma U251 cell lines. In both cell lines, Gd-MOFs do not modify the cell cycle profile or the activation levels of ERK1/2 and Akt, which are protein-serine/threonine kinases that participate in many signal transduction pathways. These pathways are fundamental in the regulation of a large variety of processes such as cell migration, cell cycle progression, differentiation, cell survival, metabolism, transcription, tumour progression and others. These data indicate that Gd-MOF nanoparticles exhibit high biocompatibility, making them potentially valuable for diagnostic and biomedical applications.
Assuntos
Gadolínio , Estruturas Metalorgânicas , Gadolínio/química , Gadolínio/farmacologia , Humanos , Estruturas Metalorgânicas/química , Estruturas Metalorgânicas/farmacologia , Estruturas Metalorgânicas/síntese química , Camundongos , Animais , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Materiais Biocompatíveis/síntese química , Linhagem Celular Tumoral , Nanoestruturas/química , Halogenação , Sobrevivência Celular/efeitos dos fármacos , Linhagem CelularRESUMO
Chemodynamic therapy (CDT) can induce cancer cell death through hydroxyl radicals (·OH) generated from Fenton or Fenton-like reactions. Compared with traditional therapies, CDT effectively overcomes inevitable drug resistance and exhibits low side effects. However, clinical application still faces challenges, primarily due to insufficient ·OH generation and the short-lifetime of ·OH in vivo. To address these challenges, we developed a peroxynitrite (ONOO-)-based CDT nanodrug (DOX@PMOF) composed of MOF-199, NO donor (PArg), and nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) activator (doxorubicin, DOX). In DOX@PMOF, MOF-199 serves as both a carrier for loading DOX and a source of Cu+ for triggering CDT. Upon uptake by cancer cells, the high concentration of glutathione (GSH) reduces MOF-199 to Cu+, which then reacts with H2O2 to generate ·OH. Moreover, the released DOX upregulates NOX4 expression, leading to the elevated H2O2 level and thereby promoting a high-efficiency Fenton-like reaction for sufficient ·OH generation. Subsequently, PArg generates abundant NO in response to the tumor microenvironment, leading to a cascade of NO and ·OH for the in situ synthesis of ONOO-. ONOO- is more toxic and has a longer lifetime and diffusion distance than ·OH, resulting in a more effective CDT treatment. To further enhance the in vivo therapeutic effect, we coated DOX@PMOF with a homologous cell membrane to form an active tumor-targeting nanodrug (DOX@MPMOF), which has demonstrated the ability to effectively inhibit tumor growth and metastasis while exhibiting good biosafety.
Assuntos
Doxorrubicina , Ácido Peroxinitroso , Microambiente Tumoral , Ácido Peroxinitroso/metabolismo , Ácido Peroxinitroso/química , Microambiente Tumoral/efeitos dos fármacos , Doxorrubicina/farmacologia , Doxorrubicina/química , Humanos , Animais , Camundongos , Camundongos Endogâmicos BALB C , Linhagem Celular Tumoral , Antibióticos Antineoplásicos/farmacologia , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/síntese química , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Estruturas Metalorgânicas/química , Estruturas Metalorgânicas/farmacologia , Estruturas Metalorgânicas/síntese química , Feminino , Nanopartículas/químicaRESUMO
The anti-PD-L1 and its bispecific antibodies have exhibited durable antitumor immunity but still elicit immunosuppression mainly caused by tumor-derived exosomes (TDEs), leading to difficulty in clinical transformation. Herein, engineered Escherichia coli Nissle 1917 (EcN) coexpressing anti-PD-L1 and anti-CD9 nanobodies (EcN-Nb) are developed and decorated with zinc-based metal-organic frameworks (MOFs) loaded with indocyanine green (ICG), to generate EcN-Nb-ZIF-8CHO-ICG (ENZC) for spatiotemporal lysis of bacteria for immunotherapy. The tumor-homing hybrid system can specifically release nanobodies in response to near-infrared (NIR) radiation, thereby targeting TDEs and changing their biological distribution, remodeling tumor-associated macrophages to M1 states, activating more effective and cytotoxic T lymphocytes, and finally, leading to the inhibition of tumor proliferation and metastasis. Altogether, the microfluidic-enabled MOF-modified engineered probiotics target TDEs and activate the antitumor immune response in a spatiotemporally manipulated manner, offering promising TDE-targeted immune therapy.
Assuntos
Exossomos , Estruturas Metalorgânicas , Probióticos , Anticorpos de Domínio Único , Exossomos/metabolismo , Exossomos/imunologia , Exossomos/química , Animais , Anticorpos de Domínio Único/química , Anticorpos de Domínio Único/imunologia , Camundongos , Estruturas Metalorgânicas/química , Estruturas Metalorgânicas/farmacologia , Humanos , Verde de Indocianina/química , Escherichia coli/genética , Imunoterapia , Proliferação de Células/efeitos dos fármacos , Neoplasias/terapia , Neoplasias/imunologia , Neoplasias/patologia , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Antineoplásicos/química , Antígeno B7-H1/imunologia , Antígeno B7-H1/metabolismo , Antígeno B7-H1/antagonistas & inibidoresRESUMO
The synthesis of bioinspired metal-organic frameworks (MOFs) performed in mild conditions with a high quality is greatly demanded. Moreover, the influence of the morphology and structure of bio-MOFs on the cell interaction and toxicity is important to determine. In this work, we developed an ultrasound (US)-assisted synthesis of HKUST-1 MOFs under mild conditions and investigated the influence of the parameters of synthesis on the morphology, structure, and biological properties of the developed MOFs. It was found that the US power, reaction time, temperature, and type of solvent composition would affect the morphology, size, and yield of the obtained crystals. Employing the optimal synthetic conditions, five types of HKUST-1 MOFs were prepared, achieving highest yields (67.8-96.2%) and different morphologies (octahedral, dodecahedral, icosahedral). The relationship between the morphological features and biological properties of developed bio-MOFs was evaluated and discussed. The cellular association and cytotoxicity of MOF@US and MOF@US-PARG were studied on various cell cultures, i.e. normal mouse embryonic fibroblasts (MEF NF2), chronic myeloid leukemia (K562), and mouse melanoma (B16-F10). The experimental results showed that MOF@US-PARG has a higher percentage of association compared to MOF@US. It has also been shown that the cytotoxicity depends on the concentration and surface modification of the developed MOFs.
Assuntos
Materiais Biocompatíveis , Teste de Materiais , Estruturas Metalorgânicas , Tamanho da Partícula , Camundongos , Animais , Estruturas Metalorgânicas/química , Estruturas Metalorgânicas/farmacologia , Estruturas Metalorgânicas/síntese química , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Materiais Biocompatíveis/síntese química , Humanos , Sobrevivência Celular/efeitos dos fármacos , Ondas Ultrassônicas , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Propriedades de Superfície , Proliferação de Células/efeitos dos fármacos , Linhagem Celular TumoralRESUMO
Matrine (MT) is a kind of alkaloid extracted from Sophora and is a promising substitute for chemical nematicides and botanical pesticides. The present study utilized sodium alginate (SA), zeolite imidazole salt skeleton (ZIF), and MT as raw materials to prepare a pH-response-release nematicide through the electrostatic spray technique. Zinc metal-organic framework (ZIF-8) was initially synthesized, followed by the successful loading of MT. Subsequently, the electrostatic spray process was employed to encapsulate it in SA, resulting in the formation of MT/ZIF-8@SA microcapsules. The efficiency of encapsulation and drug loadings can reach 79.93 and 26.83%, respectively. Soybean cyst nematode (SCN) is one of the important pests that harm crops; acetic acid produced by plant roots and CO2 produced by root respiration causing a decrease in the pH of the surrounding environment, which is most attractive to the SCN when the pH is between 4.5 and 5.4. MT/ZIF-8@SA releases the loaded MT in response to acetic acid produced by roots and acidic oxides produced by root respiration. The rate of release was 37.67% higher at pH 5.25 compared with pH 8.60. The control efficiency can reach 89.08% under greenhouse conditions. The above results demonstrate that the prepared MT/ZIF-8@SA not only exhibited excellent efficacy but also demonstrated a pH-responsive release of the nematicide.
Assuntos
Alginatos , Alcaloides , Cápsulas , Glycine max , Matrinas , Quinolizinas , Eletricidade Estática , Alginatos/química , Alcaloides/química , Alcaloides/farmacologia , Animais , Concentração de Íons de Hidrogênio , Quinolizinas/química , Glycine max/química , Glycine max/parasitologia , Cápsulas/química , Estruturas Metalorgânicas/química , Estruturas Metalorgânicas/farmacologia , Antinematódeos/química , Antinematódeos/farmacologia , Nematoides/efeitos dos fármacos , Liberação Controlada de Fármacos , Ácido Glucurônico/química , Ácidos Hexurônicos/químicaRESUMO
5-fluorouracil (5-FU), a chemotherapeutic agent against oral squamous cell carcinoma (OSCC), is limited by poor pharmacokinetics and toxicity. The pH-sensitive zeolite imidazolate framework-8 (ZIF-8) may increase the selectivity and length of 5-FU released into the acidic tumor microenvironment. This study examined the in vitro 5-FU absorption and release profiles of ZIF-8, and then progressed to cytotoxicity assays using the OSCC primary cell line SCC7. The 5-FU loading capacity of ZIF-8 was calculated with UV-vis spectroscopy (λ = 260 nm). 5-FU release was quantified by submerging 5-FU@ZIF-8 in pH 7.4 and 5.5 acetate buffer over 48 h. For the cytotoxicity assays, 5-FU, ZIF-8, and 5-FU@ZIF-8 were added to SCC7 cultures at 25, 50, and 100 µg/mL. Cell viability was assessed through toluidine blue staining and further quantified through transcriptomic RNA sequencing. ZIF-8 stabilized at a maximum absorption of 2.71 ± 0.22 mg 5-FU, and released 0.66 mg more 5-FU at pH 5.5 than 7.4 for at least 72 h. The cytotoxicity assays showed that 5-FU@ZIF-8 had a synergistic inhibitory effect at 50 µg/mL. The RNA sequencing analysis further revealed the molecular targets of 5-FU@ZIF-8 in SCC7. 5-FU@ZIF-8 may release 5-FU based on the pH of the surrounding microenvironments and synergistically inhibit OSCC.
Assuntos
Carcinoma de Células Escamosas , Fluoruracila , Neoplasias Bucais , Fluoruracila/farmacologia , Humanos , Concentração de Íons de Hidrogênio , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/patologia , Neoplasias Bucais/metabolismo , Linhagem Celular Tumoral , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Sobrevivência Celular/efeitos dos fármacos , Estruturas Metalorgânicas/química , Estruturas Metalorgânicas/farmacologia , Zeolitas/química , Microambiente Tumoral/efeitos dos fármacos , Liberação Controlada de Fármacos , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Nanopartículas/química , ImidazóisRESUMO
Nanoporous aluminum metal-organic framework (Al-MOF) was synthesized via solvothermal methods and employed as a carrier matrix for in vitro drug delivery of Umbelliferon (Um). The encapsulated Um was gradually released over seven days at 37 °C, using simulated body fluid phosphate-buffered saline (PBS) at pH 7.4 as the release medium. The drug release profile suggests the potential of Al-MOF nanoparticles as effective drug delivery carriers. Structural and chemical analyses of Um-loaded Al-MOF nanoparticles (Um-Al MOF) were conducted using Fourier-transform infrared (FTIR) spectroscopy, X-ray diffractometry (XRD), and ultraviolet-visible (UV-Vis) spectroscopy. Thermal gravimetric analysis (TGA) was employed to investigate the thermal stability of the Al-MOF nanoparticles, while Transmission Electron Microscopy (TEM) was utilized to assess their morphological features. Um-Al MOF nanoparticles demonstrated notable antioxidant and anti-inflammatory properties compared to Um and Al-MOF nanoparticles individually. Moreover, they exhibited significant enhancement in wound healing in an earthworm model. These findings underscore the potential of Al-MOF nanoparticles as a promising drug delivery system, necessitating further investigations to explore their clinical applicability.
Assuntos
Alumínio , Anti-Inflamatórios , Antioxidantes , Estruturas Metalorgânicas , Oligoquetos , Umbeliferonas , Cicatrização , Animais , Antioxidantes/química , Antioxidantes/farmacologia , Estruturas Metalorgânicas/química , Estruturas Metalorgânicas/farmacologia , Umbeliferonas/química , Umbeliferonas/farmacologia , Oligoquetos/efeitos dos fármacos , Cicatrização/efeitos dos fármacos , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Alumínio/química , Nanopartículas/química , Liberação Controlada de Fármacos , Portadores de Fármacos/químicaRESUMO
Chemotherapy as a common anticancer therapeutic modality is often challenged by various obstacles such as poor stability, low solubility, and severe side effects of chemotherapeutic agents as well as multidrug resistance of cancerous cells. Nanoparticles in the role of carriers for chemotherapeutic drugs and platforms for combining different therapeutic approaches have effectively participated in overcoming such drawbacks. In particular, nanoparticles able to induce their therapeutic effect in response to specific stimuli like tumor microenvironment characteristics (e.g., hypoxia, acidic pH, high levels of glutathione, and overexpressed hydrogen peroxide) or extrinsic stimulus of laser light bring about more precise and selective treatments. Among them, nanostructures of covalent organic frameworks (COFs) have drawn great interest in biomedical fields during recent years. Possessing large surface area, high porosity, structural stability, and customizable architecture, these biocompatible porous crystalline polymers properly translate to promising platforms for drug delivery and induction of combination therapies. With the focus on stimuli-responsive characteristics of nanoscale COFs, this study aims to propose an overview of their potentiality in cancer treatment on the basis of chemotherapy alone or in combination with sonodynamic, chemodynamic, photodynamic, and photothermal therapies.
Assuntos
Antineoplásicos , Estruturas Metalorgânicas , Neoplasias , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/terapia , Estruturas Metalorgânicas/química , Estruturas Metalorgânicas/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Portadores de Fármacos/química , Nanopartículas/química , Nanopartículas/uso terapêutico , Animais , Microambiente Tumoral/efeitos dos fármacosRESUMO
The widespread use and contamination of natural sources by new-generation drugs and pesticides have enhanced concern about environmental pollution. Understanding the above importance, we developed a superhydrophobic metal-organic framework (MOF) (SHMOF': [Zr6O4(OH)4(BDC-NH-CO-R)2.4(BDC-NH2)0.6(CF3COO)6]·2.5H2O·4DMF) for ecological remediation via adsorption-based separation of hydrophobic drugs (flurbiprofen) and pesticides (fluazinam). The newly developed SHMOF' has a high adsorption capacity toward flurbiprofen and fluazinam, i.e., 435 and 575 mg/g, respectively. The adsorption equilibrium time of the MOF is very short (15 and 10 min for flurbiprofen and fluazinam, respectively). The outstanding superhydrophobic nature of the MOF was employed to separate flurbiprofen and fluazinam from highly alkaline and acidic media and environmental water samples. The SHMOF' has excellent selectivity toward the adsorption-based separation of flurbiprofen and fluazinam in the coexistence of common analytes. Again, we developed a polypropylene (PP) fabric-based composite of SHMOF' (SHMOF'@PP) to separate the hydrophobic targeted analytes by using a zero-energy-consuming filtration-based separation method, which made this separation process cost-efficient and user-friendly. Moreover, Ag nanoparticles were doped to the superhydrophobic composite. The Ag-doped reusable SHMOF'@PP@Ag composite exhibited excellent bacterial antiadhesion and antibacterial properties toward Staphylococcus aureus bacteria.
Assuntos
Antibacterianos , Interações Hidrofóbicas e Hidrofílicas , Estruturas Metalorgânicas , Praguicidas , Estruturas Metalorgânicas/química , Estruturas Metalorgânicas/farmacologia , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/isolamento & purificação , Praguicidas/isolamento & purificação , Praguicidas/química , Praguicidas/farmacologia , Adsorção , Staphylococcus aureus/efeitos dos fármacos , Poluentes Químicos da Água/isolamento & purificação , Poluentes Químicos da Água/química , Testes de Sensibilidade Microbiana , Propriedades de Superfície , Flurbiprofeno/química , Flurbiprofeno/farmacologia , Flurbiprofeno/isolamento & purificação , Estrutura MolecularRESUMO
Metal-organic framework nanoparticles (MOF NPs) have received much attention for their potential use in nanopesticides. However, little is known about the potential health and environmental risks associated with these materials. In this study, the toxicological responses of zebrafish exposed to five MOF NPs for short and long periods of time were evaluated. The acute toxicity results showed that the toxicity of the five MOF NPs to zebrafish embryos and adult zebrafish was in the order of Cu-MOF > ZIF-90 > ZIF-8 > Fe-MOF > Zr-MOF. Histopathological analysis revealed that ZIF-8, ZIF-90, and Cu-MOF NPs caused liver swelling and vacuolization in zebrafish. The cellular ultrastructure showed that ZIF-8, ZIF-90, and Cu-MOF NPs severely damaged the mitochondrial structure in intestinal epithelial cells and liver cells. The 16S rDNA sequencing data showed that all five MOF NPs significantly altered the dominant microorganisms in the zebrafish intestine. The microbial markers of intestinal inflammation, Proteobacteria (Aeromonas, Plesiomonas, and Legionella), were significantly increased in the Fe-MOF, ZIF-8, Zr-MOF, and Cu-MOF treatment groups. Metabolomics results indicated that the levels of inflammatory promoting factors (Leukotriene E4, 20-hydroxyeicosatetraenoic acid) in arachidonic acid metabolism were decreased, and the levels of inflammatory suppressing factors (8,9-epoxyeicosatrienoic acid) were increased. Metabolites related to oxidative stress, such as glutamine, pyridoxamine, and l-glutamic acid in vitamin B6 metabolism and other signaling pathways, were significantly reduced. Overall, these results suggest that the different MOF NPs had widely varying toxicity to zebrafish, and further attention should be paid to the toxicity of MOF NPs in the real environment.