RESUMEN
Despite extensive research on corticosteroids for treating asthma, their short residence time in the lungs has limited their therapeutic effects in vivo. Nanoparticles have been widely investigated for inhaled drug delivery due to their potential benefits in prolonging drugs' residence time in the lungs. However, the retention of nanoparticles may be limited by mucus and ciliated epithelium clearance mechanisms in the airway. Herein, we anchored a neonatal-Fc-receptor-targeted peptide (FcBP) onto "mucus-penetrating" polyethylene glycol (PEG) nanoparticles (PEG-NP). Interestingly, the mucus-permeability of PEG-NP was not impaired by FcBP-functionalization. Moreover, FcBP modification enhanced cellular internalization and exocytosis via specific receptor-mediated processes, which subsequently ameliorated transepithelial transport and prolonged pulmonary retention. Importantly, after loading dexamethasone, FcBP-functionalization could effectively help nanoparticles cross the airway epithelial layer and be endocytosed by inflammatory cells, resulting in a marked decrease in inflammatory cytokines. Finally, FcBP modification significantly enhanced the therapeutic effect of dexamethasone-loaded nanoparticles in asthma mice. This study demonstrates that FcBP-functionalized PEG-NP can overcome multiple obstacles in the airway to prolong the pulmonary retention of drugs, providing a promising strategy for inhalation therapy.
Asunto(s)
Asma , Nanopartículas , Ratones , Animales , Sistemas de Liberación de Medicamentos/métodos , Asma/tratamiento farmacológico , Moco , Terapia Respiratoria , Dexametasona/uso terapéutico , Dexametasona/farmacologíaRESUMEN
Ligand-modified nanocarriers can promote oral or inhalative administration of macromolecular drugs across the intestinal or pulmonary mucosa. However, enhancing the unidirectional transport of the nanocarriers through "apical uptakeâintracellular transportâbasolateral exocytosis" route remains a hot topic and challenge in current research. Forskolin is a naturally occurring diterpenoid compound extracted from the roots of C. forskohlii. In our studies, we found that forskolin could increase the transcellular transport of butyrate-modified nanoparticles by 1.67-fold and 1.20-fold in Caco-2 intestinal epithelial cell models and Calu-3 lung epithelial cell models, respectively. Further mechanistic studies revealed that forskolin, on the one hand, promoted the cellular uptake of butyrate-modified nanoparticles by upregulating the expression of monocarboxylic acid transporter-1 (MCT-1) on the apical membrane. On the other hand, forskolin facilitated the binding of MCT-1 to caveolae, thereby mediating butyrate-modified nanoparticles hijacking caveolae to promote the basolateral exocytosis of butyrate-modified nanoparticles. Studies in normal mice model showed that forskolin could promote the transmucosal absorption of butyrate-modified nanoparticles by >2-fold, regardless of oral or inhalative administration. Using semaglutide as the model drug, both oral and inhalation delivery approaches demonstrated significant hypoglycemic effects in type 2 diabetes mice model, in which inhalative administration was more effective than oral administration. This study optimized the strategies aimed at enhancing the transmucosal absorption of ligand-modified nanocarriers in the intestinal or pulmonary mucosa.
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Colforsina , Nanopartículas , Animales , Humanos , Colforsina/administración & dosificación , Administración Oral , Nanopartículas/administración & dosificación , Pulmón/metabolismo , Butiratos/administración & dosificación , Butiratos/farmacocinética , Transportadores de Ácidos Monocarboxílicos/metabolismo , Células CACO-2 , Masculino , Simportadores/metabolismo , Ratones , Administración por Inhalación , Sistemas de Liberación de MedicamentosRESUMEN
Background: Most preschool children are distressed during anesthesia induction. While current pharmacological methods are useful, there is a need for further optimization to an "ideal" standard. Remimazolam is an ultra-short-acting benzodiazepine, and intranasal remimazolam for pre-induction sedation may be promising. Methods: This study included 32 preschool children who underwent short and minor surgery between October 2022 and January 2023. After pretreatment with lidocaine, remimazolam was administered to both nostrils using a mucosal atomizer device. The University of Michigan Sedation Score (UMSS) was assessed for sedation 6, 9, 12, 15, and 20 min after intranasal atomization. We used Dixon's up-and-down method, and probit and isotonic regressions to determine the 50% effective dose (ED50) and 95% effective dose (ED95) of intranasal remimazolam for pre-induction sedation. Results: Twenty-nine pediatric patients were included in the final analysis. The ED50 and ED95 of intranasal remimazolam for successful pre-induction sedation, when processed via probit analysis, were 0.65 (95% confidence interval [CI], 0.59-0.71) and 0.78 mg/kg (95% CI, 0.72-1.07), respectively. In contrast, when processed by isotonic regression, they were 0.65 (95% CI: 0.58-0.72 mg/kg) and 0.78 mg/kg (95% CI: 0.69-1.08 mg/kg), respectively. At 6 min after intranasal remimazolam treatment, 81.2% (13/16) of "positive" participants were successfully sedated with a UMSS ⧠1. All the "positive" participants were successfully sedated within 9 min. Conclusion: Intranasal remimazolam is feasible for preschool children with a short onset time. For successful pre-induction sedation, the ED50 and ED95 of intranasal remimazolam were 0.65 and 0.78 mg/kg, respectively.
RESUMEN
Lipoic acid (LA), which has good safety and oral absorption, is obtained from various plant-based food sources and needs to be supplemented through human diet. Moreover, substances with a disulfide structure can enter cells through dynamic covalent disulfide exchange with thiol groups on the cell membrane surface. Based on these factors, we constructed LA-modified nanoparticles (LA NPs). Our results showed that LA NPs can be internalized into intestinal epithelial cells through surface thiols, followed by intracellular transcytosis via the endoplasmic reticulum-Golgi pathway. Further mechanistic studies indicated that disulfide bonds within the structure of LA play a critical role in this transport process. In a type I diabetes rat model, the oral administration of insulin-loaded LA NPs exhibited a more potent hypoglycemic effect, with a pharmacokinetic bioavailability of 5.42 ± 0.53%, representing a 1.6 fold enhancement compared to unmodified PEG NPs. Furthermore, a significant upregulation of surface thiols in inflammatory macrophages was reported. Thus, we turned our direction to investigate the uptake behavior of inflammatory macrophages with increased surface thiols towards LA NPs. Inflammatory macrophages showed a 2.6 fold increased uptake of LA NPs compared to non-inflammatory macrophages. Surprisingly, we also discovered that the antioxidant resveratrol facilitates the uptake of LA NPs in a concentration-dependent manner. This is mainly attributed to an increase in glutathione, which is involved in thiol uptake. Consequently, we employed LA NPs loaded with resveratrol for the treatment of colitis and observed a significant alleviation of colitis symptoms. These results suggest that leveraging the variations of thiol expression levels on cell surfaces under both healthy and diseased states through an oral drug delivery system mediated by the small-molecule nutrient LA can be employed for the treatment of diabetes and certain inflammatory diseases.
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Compuestos de Sulfhidrilo , Ácido Tióctico , Ácido Tióctico/química , Animales , Compuestos de Sulfhidrilo/química , Administración Oral , Ratas , Humanos , Nanopartículas/química , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Hipoglucemiantes/administración & dosificación , Sistemas de Liberación de Medicamentos , Masculino , Inflamación/tratamiento farmacológico , Ratones , Propiedades de Superficie , Portadores de Fármacos/química , Insulina/metabolismo , Ratas Sprague-Dawley , Tamaño de la Partícula , Macrófagos/metabolismo , Macrófagos/efectos de los fármacos , Células RAW 264.7RESUMEN
Exosomes, as promising vehicles, have been widely used in the research of oral drug delivery, but the generally low drug loading efficiency of exosomes seriously limits its application and transformation. In this study, we systematically investigated the effects of drug loading methods and physicochemical properties (lipophilicity and molecular weight) on drug loading efficiency of milk-derived exosomes to explore the most appropriate loading conditions. Our finding revealed that the drug loading efficiency of exosomes was closely related to the drug loading method, drug lipophilicity, drug molecular weight and exosome/drug proportions. Of note, we demonstrated the universality that hydrophilic biomacromolecule drugs were the most appropriate loading drugs for milk-derived exosomes, which was attributed to the efficient loading capacity and sustained release behavior. Furthermore, milk-derived exosomes could significantly improve the transepithelial transport and oral bioavailability of model hydrophilic biomacromolecule drugs (octreotide, exendin-4 and salmon calcitonin). Collectively, our results suggested that the encapsulation of hydrophilic biomacromolecule drugs might be the most promising direction for milk exosomes as oral drug delivery vehicles.