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1.
Int J Pharm ; 639: 122946, 2023 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-37044230

RESUMO

Dexamethasone is a well-known anti-inflammatory drug readily used to treat many lung diseases. However, its side effects and poor lower airway deposition and retention are significant limitations to its usage. In this work, we developed lipid nanoparticulate platforms loaded with dexamethasone and evaluated their behavior in inflammatory lung models in vitro and in vivo. Dexamethasone-loaded liposomes with an average diameter below 150 nm were obtained using a solvent injection method. Three different formulations were produced with a distinct surface coating (polyethylene glycol, hyaluronic acid, or a mixture of both) as innovative strategies to cross the pulmonary mucus layer and/or target CD44 expressed on alveolar proinflammatory macrophages. Interestingly, while electron paramagnetic spectroscopy showed that surface modifications did not induce any molecular changes in the liposomal membrane, drug loading analysis revealed that adding the hyaluronic acid in the bilayer led to a decrease of dexamethasone loading (from 3.0 to 1.7 w/w%). In vitro experiments on LPS-activated macrophages demonstrated that the encapsulation of dexamethasone in liposomes, particularly in HA-bearing ones, improved its anti-inflammatory efficacy compared to the free drug. Subsequently, in vivo data revealed that while intratracheal administration of free dexamethasone led to an important inter-animals variation of efficacy, dexamethasone-loaded liposomes showed an improved consistency within the results. Our data indicate that encapsulating dexamethasone into lipid nanoparticles is a potent strategy to improve its efficacy after lung delivery.


Assuntos
Ácido Hialurônico , Lipossomos , Animais , Lipossomos/química , Ácido Hialurônico/química , Anti-Inflamatórios , Macrófagos , Dexametasona
2.
Br J Pharmacol ; 179(18): 4534-4548, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35726496

RESUMO

BACKGROUND AND PURPOSE: Interstitial lung disease (ILD) is the main cause of mortality in systemic sclerosis (SSc), and current therapies available are of low efficacy or high toxicity. Thus, the identification of innovative less toxic and high efficacy therapeutic approaches to ILD treatment is an urgent need. The interaction of P-selectin glycoprotein ligand-1 (PSGL-1) with P-selectin initiates leukocyte extravasation and deletion of the corresponding gene (Selplg) induces a SSc-like syndrome with high incidence of ILD in aged mice. EXPERIMENTAL APPROACH: Aged PSGL-1 KO (Selplg-/- ) mice were used to assess the therapeutic effects of nanotherapy with everolimus, included in liposomes decorated with high MW hyaluronic acid (LipHA+Ev) and administered intratracheally to specifically target CD44-expressing lung cells. KEY RESULTS: PSGL-1 KO mice had increased numbers of CD45+ and CD45- cells, including alveolar and interstitial macrophages, eosinophils, granulocytes and NK cells, and myofibroblasts in bronchoalveolar lavage (BAL). CD45+ and CD45- cells expressing pro-inflammatory and pro-fibrotic cytokines were also increased. Lungs from PSGL-1 KO mice showed increased immune cell infiltration and apoptosis and exacerbated interstitial and peribronchial fibrosis. Targeted nanotherapy with LipHA+Ev decreased the myofibroblasts in BAL, cells producing proinflammatory and profibrotic cytokines, and the degree of lung inflammation at histology. LipHA+Ev treatment also decreased the severity of peribronchial and interstitial lung fibrosis, from moderate to mild levels. CONCLUSIONS AND IMPLICATIONS: In PSGL-1 KO mice, targeted nanotherapy with LipHA+Ev was an effective treatment for SSc-ILD, reducing the number of inflammatory and fibrotic cells in BAL and reducing inflammation and fibrosis in lungs.


Assuntos
Doenças Pulmonares Intersticiais , Fibrose Pulmonar , Escleroderma Sistêmico , Animais , Citocinas , Everolimo/farmacologia , Everolimo/uso terapêutico , Fibrose , Inflamação/patologia , Pulmão/patologia , Doenças Pulmonares Intersticiais/tratamento farmacológico , Doenças Pulmonares Intersticiais/etiologia , Glicoproteínas de Membrana , Camundongos , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/genética , Escleroderma Sistêmico/patologia
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