Resumen:
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[EN] Acute lung injury (ALI) is a critical inflammatory syndrome, characterized by increased diffuse inflammation and severe lung damage, which represents a clinical concern due to the high morbidity and mortality in ...[+]
[EN] Acute lung injury (ALI) is a critical inflammatory syndrome, characterized by increased diffuse inflammation and severe lung damage, which represents a clinical concern due to the high morbidity and mortality in critical patients. In last years, there has been a need to develop more effective treatments for ALI, and targeted drug delivery to inflamed lungs has become an attractive research field. Here, we present a nanodevice based on mesoporous silica nanoparticles loaded with dexamethasone (a glucocorticoid extensively used for ALI treatment) and capped with a peptide that targets the TNFR1 receptor expressed in pro-inflammatory macrophages (TNFR-Dex-MSNs) and avoids cargo leakage. TNFR-Dex-MSNs nanoparticles are preferentially internalized by pro-inflammatory macrophages, which overexpressed the TNFR1 receptor, with the subsequent cargo release upon the enzymatic hydrolysis of the capping peptide in lysosomes. Moreover, TNFR-Dex-MSNs are able to reduce the levels of TNF-alpha and IL-1I3 cytokines in activated pro-inflammatory M1 macrophages. The antiinflammatory effect of TNFR-Dex-MSNs is also tested in an in vivo ALI mice model. The administered nanodevice (intravenously by tail vein injection) accumulated in the injured lungs and the controlled dexamethasone release reduces markedly the inflammatory response (TNF-alpha IL-6 and IL-1I3 levels). The attenuation in lung damage, after treatment with TNFR-Dex-MSNs, is also confirmed by histopathological studies. Besides, the targeted-lung dexamethasone delivery results in a decrease of dexamethasone derived side-effects, suggesting that targeted nanoparticles can be used for therapy in ALI and could help to overcome the clinical limitations of current treatments.
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Agradecimientos:
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A. Garcia-Fernandez thanks the Spanish government for her FPU fellowship. The R. Martinez-Manez group is grateful to the Spanish Government (projects RTI2018-100910-B-C41 and RTI2018-101599-BC22-AR (MCUI/AEI/FEDER, UE) and ...[+]
A. Garcia-Fernandez thanks the Spanish government for her FPU fellowship. The R. Martinez-Manez group is grateful to the Spanish Government (projects RTI2018-100910-B-C41 and RTI2018-101599-BC22-AR (MCUI/AEI/FEDER, UE) and the Generalitat Valencia (Project PROMETEO/2018/024) for support. M.Orz ' aez group thanks to the financial support from the Spanish Government (SAF2017-84689-R project MINECO/AEI/FEDER, UE) and the Generalitat Valenciana (project PROMETEO/2019/065). The authors would thank the Server Medical Art platform for using their templates to design some schemes. Would like to thank I. Borreda and J. Forteza from Instituto Valenciano de Patologia for its technical support in the histopathology analysis and Animal Facilities from Centro de Investigación Principe Felipe for its support in the animal research and procedures.
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