RESUMO
Intra-articular drugs used to treat osteoarthritis (OA) often suffer from poor pharmacokinetics and stability. Nano-platforms as drug delivery systems for drug delivery are promising for OA therapy. In this study, we reported an M1 macrophage-targeted delivery system Bai@FA-UIO-66-NH2 based on folic acid (FA) -modified metal-organic framework (MOF) loaded with baicalin (Bai) as antioxidant agent for OA therapy. With outstanding biocompatibility and high drug loading efficiency, Bai@FA-UIO-66-NH2 could be specifically uptaken by LPS-induced macrophages to serve as a potent ROS scavenger, gradually releasing Bai at the subcellular level to reduce ROS production, modulate macrophage polarization to M2, leading to alleviation of synovial inflammation in OA joints. The synergistic effect of Bai@FA-UIO-66-NH2 on macrophage polarization and ROS scavenging significantly improved the therapeutic efficacy of OA, which may provide a new insight into the design of OA precision therapy.
Assuntos
Flavonoides , Macrófagos , Estruturas Metalorgânicas , Osteoartrite , Espécies Reativas de Oxigênio , Estruturas Metalorgânicas/química , Osteoartrite/tratamento farmacológico , Animais , Flavonoides/farmacologia , Flavonoides/química , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Células RAW 264.7 , Antioxidantes/farmacologia , Antioxidantes/química , Sistemas de Liberação de Medicamentos/métodos , Ácido Fólico/química , Masculino , Ratos , Lipopolissacarídeos/farmacologia , Ratos Sprague-DawleyRESUMO
Excessive reactive oxygen species (ROS)-induced mitochondrial damage has impact on osteoarthritis (OA). Nanozyme mimics as natural enzyme alternatives to scavenge excessive ROS has offered a promising strategy for OA therapy. Herein, we reported a novel mitochondrial-targeting Mn3O4/UIO-TPP nanozyme using metal-organic frameworks with loaded Mn3O4 as the enzyme-like active core combining mitochondria-targeting triphenylphosphine (TPP) groups to serve as ROS scavengers for therapy of OA. With sequential catalysis of superoxide dismutase-like, catalase (CAT)-like, and hydroxyl radical (·OH) scavenging potentials, the nanozyme can target mitochondria by crossing subcellular barriers to effectively eliminate ROS to restore mitochondrial function and inhibit inflammation and chondrocyte apoptosis. It also has favorable biocompatibility and biosafety. Based on anterior cruciate ligament transection-induced OA joint models, this mitochondrial-targeting nanozyme effectively mitigated the inflammatory response with the Pelletier score reduction of 49.9% after 8-week therapy. This study offers a prospective approach to the design of nanomedicines for ROS-related diseases.
RESUMO
Electrospun nanofiber membranes have been widely used for guided bone regeneration (GBR). For assistance in bone healing, photothermal therapy which renders moderate heat stimulation to defect regions by near-infrared (NIR) light irradiation has attracted much attention in recent years. Combined with photothermal therapy, novel electrospun poly(ε-caprolactone)/molybdenum disulfide (PCL/MoS2 ) nanofiber membranes are innovatively synthesized as GBR for bone therapy, wherein the exfoliated MoS2 nanosheets served as osteogenic enhancers and NIR photothermal agents. With the doping of MoS2 , the mechanical properties of nanofiber membranes got improved with the degradation unaffected. The composite PCL/MoS2 membranes show enhanced cell growth and osteogenic performance compared with PCL alone. Under NIR-triggered mild photothermal therapy, osteogenesis and bone healing are accelerated by using PCL/MoS2 nanofiber membranes for growth of bone mesenchymal stem cells in vitro and repair of rat tibia bone defect in vivo. The novel nanofiber membranes may be developed as intelligent GBR in the therapy of bone defects.
Assuntos
Nanofibras , Animais , Regeneração Óssea , Molibdênio , Osteogênese , Terapia Fototérmica , Poliésteres , RatosRESUMO
BACKGROUND: During the past few decades, drug delivery system (DDS) has attracted many interests because it could enhance the therapeutic effects of drugs and reduce their side effects. The advent of nanotechnology has promoted the development of nanosized DDSs, which could promote drug cellular uptake as well as prolong the half-life in blood circulation. Novel polymer micelles formed by self-assembly of amphiphilic polymers in aqueous solution have emerged as meaningful nanosystems for controlled drug release due to the reversible destabilization of hydrophobic domains under different conditions. RESULTS: The amphiphilic polymers presented here were composed of cholesterol groups end capped and poly (poly (ethylene glycol) methyl ether methacrylate) (poly (OEGMA)) as tailed segments by the synthesis of cholesterol-based initiator, followed by atom transfer radical polymerization (ATRP) with OEGMA monomer. FT-IR and NMR confirmed the successfully synthesis of products including initiator and polymers as well as the Mw of the polymers were from 33,233 to 89,088 g/mol and their corresponding PDI were from 1.25 to 1.55 by GPC. The average diameter of assembled polymer micelles was in hundreds nanometers demonstrated by DLS, AFM and SEM. The behavior of the amphiphilic polymers as micelles was investigated using pyrene probing to explore their critical micelle concentration (CMC) ranging from 2.53 × 10-4 to 4.33 × 10-4 mg/ml, decided by the balance between cholesterol and poly (OEGMA). Besides, the CMC of amphiphilic polymers, the quercetin (QC) feeding ratio and polarity of solvents determined the QC loading ratio maximized reaching 29.2% certified by UV spectrum, together with the corresponding size and stability changes by DLS and Zeta potential, and thermodynamic changes by TGA and DSC. More significantly, cholesterol end-capped polymer micelles were used as nanosized systems for controlled drug release, not only alleviated the cytotoxicity of QC from 8.6 to 49.9% live cells and also achieved the QC release in control under different conditions, such as the presence of cyclodextrin (CD) and change of pH in aqueous solution. CONCLUSIONS: The results observed in this study offered a strong foundation for the design of favorable polymer micelles as nanosized systems for controlled drug release, and the molecular weight adjustable amphiphilic polymer micelles held potential for use as controlled drug release system in practical application.
Assuntos
Colesterol/química , Portadores de Fármacos/química , Nanopartículas/química , Polietilenoglicóis/química , Animais , Linhagem Celular , Sobrevivência Celular , Ciclodextrinas/química , Liberação Controlada de Fármacos , Interações Hidrofóbicas e Hidrofílicas , Camundongos , Micelas , Mioblastos/citologia , Mioblastos/efeitos dos fármacos , Pirenos/química , Quercetina/administração & dosagem , Quercetina/químicaRESUMO
A series of biocompatible and non- toxic polysaccharide molecules have been successfully fabricated and explored their potential application for scavenging the carbonyl species in vitro. These macromolecules were dextrans with different hydrazide substitution ratios determined by TNBS assay, NMR and FTIR characterization. The colorimetric assay had demonstrated that these macromolecules could effectively scavenge acrolein, oxidized bovine serum albumin (BSA) in buffer solutions as well as carbonyl proteins from serum. The scavengers could achieve twice more scavenging effects for modified dextrans with high molecular weight (Mwâ¯=â¯100,000) than those of low ones (Mwâ¯=â¯40,000) with the same substitution ratio. Protein gel electrophoresis confirmed that the formation of the complex between carbonyls and modified dextrans resulted in appearance of slower bands. It also revealed that such macromolecules could protect cultured cells against the toxicity of acrolein or its derivatives. The proposed macromolecules indicated a very promising capability as scavengers for oxidative stress plus its derivatives without side effects.