Suchergebnisse

Tuberculosis (TB) is still a devastating disease and more people have died of TB than any other infectious diseases throughout the history. The current therapy consists of a multidrug combination in a long-term treatment, being associated with the appearance of several adverse effects. Thus, solid lipid nanoparticles (SLNs) were developed using mannose as a lectin receptor ligand conjugate for macrophage targeting and to increase the therapeutic index of rifampicin (RIF). The developed SLNs were studied in terms of diameter, polydispersity index, zeta potential, encapsulation efficiency (EE) and loading capacity (LC). Morphology, in vitro drug release and differential scanning calorimetry studies, macrophage uptake studies, cell viability and storage stability studies were also performed. The diameter of the SLNs obtained was within the range of 160–250 nm and drug EE was above 75%. The biocompatibility of M-SLNs was verified and the internalization in macrophages was improved with the mannosylation. The overall results suggested that the developed mannosylated formulations are safe and a promising tool for TB therapy targeted for macrophages. ; The authors also thank the CNPq Foundation, Ministry of Education of Brazil for the Doctoral fellowship 246514/2012–4 and FCT for the PostDoctoral fellowship SFRH/BPD/99124/2013. SCL thanks Operac¸ão NORTE-01–0145-FEDER-000011 for her investigator contract. This work received financial support from the European Union (FEDER funds) and National Funds [FCT/MEC, Fundac¸ão para a Ciência e Tecnologia and Ministério da Educac¸ão e Ciência] under the Partnership Agreement PT2020 UID/MULTI/04378/2013 – POCI/01/0145/FEDER/ 007728. This work was financed by FEDER – Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020 – Operational Programme for Competitiveness and Internationalisation (POCI), Portugal 2020 [NORTE-01–0145-FEDER-000012], and by Portuguese funds through FCT – Fundac¸ão para a Ciência e a Tecnologia/Ministério da Ciência, Tecnologia e Inovac¸ão in the framework of the project "Institute for Research and Innovation in Health Sciences" [POCI-01–0145-FEDER-007274].

Orally administrable drug delivery vehicles are developed to manage incurable inflammatory bowel disease (IBD), however, their therapeutic outcomes are compromised by the side effects of systemic drug exposure. Herein, we use hyaluronic acid functionalized porous silicon nanoparticle to bridge enzyme-responsive hydrogel and pH-responsive polymer, generating a hierarchical structured (nano-in-nano-in-micro) vehicle with programmed properties to fully and sequentially overcome the multiple obstacles for efficiently delivering drugs locally to inflamed sites of intestine. After oral administration, the pH-responsive matrix protects the embedded hybrid nanoparticles containing drug loaded hydrogels against the spatially variable physiological environments of the gastrointestinal tract until they reach the inflamed sites of intestine, preventing premature drug release. The negatively charged hybrid nanoparticles selectively target the inflamed sites of intestine, and gradually release drug in response to the microenvironment of inflamed intestine. Overall, the developed hierarchical structured and programmed vehicles load, protect, transport and release drugs locally to inflamed sites of intestine, contributing to superior therapeutic outcomes. Such strategy could also inspire the development of numerous hierarchical structured vehicles by other porous nanoparticles and stimuli-responsive materials for the local delivery of various drugs to treat plenty of inflammatory gastrointestinal diseases, including IBD, gastrointestinal cancers and viral infections. ; W.L. acknowledges the Orion Research Foundation for financial support. Z.L. acknowledges the Chinese Scholarship Council for financial support. T.B.-R. acknowledges financial support from the Fundação para a Ciência e a Tecnologia (grant no. SFRH/BD/110859/2015 ). H.Z. acknowledges Jane and Aatos Erkko Foundation (grant no. 4704010 ), Academic of Finland (grant no. 297580 ) and Sigrid Jusélius Foundation (grant no. 28001830K1 ) for financial support. D.L. acknowledges the Jane and Aatos Erkko Foundation for financial support. X.D. acknowledges financial support from the National Key R&D Program (Grant Nos. 2017YFA0504504 and 2016YFA0502001 ), the National Natural Science Foundation of China (Grant Nos. U1405223 and 81661138005 ), the Fundamental Research Funds for the Central Universities of China (Grant No. 20720160064 ), and the Program of Introducing Talents of Discipline to Universities (111 Project, B12001 ). H.A.S. acknowledges financial support from the Sigrid Jusélius Foundation (Decision No. 4704580 ), the European Research Council under the European Union's Seventh Framework Programme ( FP/2007-2013 , Grant No. 310892 ) and the HiLIFE Research Funds.