Research Focus: Engineering Nanoparticle-in-Microgel Controlled Release Delivery Systems for Pulmonary Diseases.

Drug delivery to the human lung is made difficult by macrophage clearance, and size constraints. Various cells (epithelium, macrophages, inflammatory neutrophils) are present in the lung lumen and differentially involved in pathogenesis, which makes cell-specific drug delivery desirable. To address these issues, we used a two-step delivery strategy consisting in drug-filled poly (D,L-lactide-co-glycolide) (PLGA) nanoparticles embedded in a micro hydrogel (Nano-in-Micro). The micro hydrogel (microgel) is crosslinked with a protease-sensitive peptide enabling cell targeting and controlled release. In a recent study (Mejias JCI Insight 2019), we delivered the “effector” drug and neutrophil degranulation inhibitor, NexInhib20, within matrix metallopreteinase-9-sensitive Nano-in-Micro vehicles to inflamed mouse lungs and normalized disease with a single dose. In ongoing studies, we are investigating “modulator” drugs that alter the fate of transcriptionally reprogrammed lung leukocytes, which are key contributors to pathogenesis (Margaroli Cell Rep Med 2021). We are exploring synergies among “effector” and “modulator” drugs and their compatibility with Nano-in-Micro vehicles to better target lung disease. Furthermore, we are interested in broadening the effects and use of the Nano-in-Micro system by using it in cancer models.

Relevant Publications:

• C. Margaroli, D. Moncada-Giraldo, D.A. Gulick, B. Dobosh, V.D. Giacalone, O.A. Forrest, F. SUn, C. Gu, A. Gaggar, H. Kissick, R. Wu, G. Gibson, R. Tirouvanziam. Cell Reports Medicine 2021. Transcriptional firing represses bactericidal activity in cystic fibrosis airway neutrophils
• J.C. Mejias, O.A. Forrest, C. Margaroli, D.A. Frey Rubio, L. Viera, J. Li, X. Xu, A. Gaggar, R. Tirouvanziam, and K. Roy. JCI Insight 2019. Neutrophil-targeted, protease-activated pulmonary drug delivery blocks airway and systemic inflammation.