Gated nanomaterials as delivery platform for the treatment of inflammatory disorders

Resumen

This PhD thesis entitled "Gated nanomaterials as delivery platform to manage inflammatory disorders" is focused on the design, synthesis and evaluation of hybrid organic-inorganic nanomaterials using mesoporous silica nanoparticles, for controlled drug release in biomedical applications, specifically in the field of inflammation. In a fist step, we present a new nanodevice for the controlled delivery of VX-765, a caspase 1 inhibitor, which takes advantage of the intrinsic passive targeting effect of the nanoparticles to inflamed tissues. In particular, mesoporous silica nanoparticles loaded with the drug VX-765 and functionalized with ¿-poly-L-lysine (acting as gatekeeper) have been prepared. The anti-inflammatory activity of the prepared nanodevice has been evaluated both in vitro, in the cellular model of monocytes THP-1, and in vivo using air pouch mouse as model of inflammation. The results showed the preferential accumulation of the nanoparticles in the inflamed tissue, as well as an increase in the therapeutic effect of the entrapped drug. As conclusion, gated mesoporous silica nanoparticles constitute an important tool for the development of new therapeutic strategies in the inflammatory field. Based on the previous results presented, a drug delivery system for the treatment of acute lung injury is described in chapter four as alternative therapy that allow the direct delivery of drugs into the lungs. Mesoporous silica nanoparticles has been prepared, loaded with the glucocorticoid dexamethasone and capped with a peptide gatekeeper that recognizes the receptor of tumour necrosis factor 1 (TNFR1), which also targets the pro-inflammatory macrophages. The therapeutic activity of the designed nanoparticles has been studied in vitro in pro-inflammatory macrophages, and in vivo in an acute lung injury mouse model. The preferential accumulation of the nanoparticles in the inflamed lungs has been corroborated through biodistribution assays, as well as the ability to enhance the dexamethasone therapeutic effect by the reduction of lung injury and minimizing the undesired side effects associated of the free drug administration. As conclusion, gated mesoporous silica nanoparticles can be used for the treatment of acute lung injury and represent a potential tool to overcome the limitations of current treatments. Finally, a drug delivery system for acute lung injury is also presented. In this case, we use the novel inflammasome inhibitor QM-378 as pharmacological alternative therapy to the treatment of uncontrolled inflammation in acute lung injury. With the aim of enhancing the direct drug delivery in lungs, QM-378 is encapsulated in mesoporous silica nanoparticles capped with a peptidic gate that recognizes TNFR1. The preferential accumulation of nanoparticles to inflamed lungs has been also corroborated through biodistribution assays. An enhancement of the therapeutic effect of QM-378 by reducing lung inflammation is demonstrated, due to the advantages of drug encapsulation in a targeted-lung nanosystem. As conclusion, the QM-378 is a suitable candidate for acute lung injury treatment, and its encapsulation in mesoporous silica nanoparticles offers a direct lung drug delivery thus improving the therapeutic profile of the drug. The principal conclusion from this PhD thesis is that the preparation of mesoporous silica nanoaprticles for drug delivery is presented as potential strategy in the field of inflammatory disorders.