Nano-in-micro multi-stage particles for pulmonary drug delivery

Abstract

Pulmonary drug delivery is a non-invasive method for targeted delivery of therapeutics for the treatment of respiratory diseases such as asthma, idiopathic pulmonary fibrosis, or cystic fibrosis. Although the lung appears to be an “easy” target for site-specific delivery, there are several physiologic barriers hindering its effectiveness. For particle deposition in respiratory airways, the aerodynamic diameter of particles should fall between 0.5-5 µm, however, alveolar macrophages rapidly clear particles within this geometric range. Additionally, nano-scale particles are required for efficient transport through the pulmonary mucosa and to facilitate efficient endocytosis for intracellularly targeting therapeutics. These design parameters suggest a two-stage system is necessary for efficient therapeutic delivery; a microparticle for aerodynamic properties and a nanoparticle for drug delivery. A nanoparticle-inside-microgel multi-stage formulation could provide efficient, intracellular delivery of nanoparticles to target cells of interest. The microgel carriers are designed for (a) protease-triggered release of drug loaded nanoparticles, (b) avoiding rapid clearance by alveolar macrophages, and (c) appropriate aerodynamic properties, while the nanoparticles are designed to (a) carry small hydrophobic molecules. The overall objective is to test this delivery system by investigating (i) how the microgels and nanoparticles interact with the phagocytic immune cells in vitro (Aim 1) and in vivo (Aim 2) and (ii) how we can recapitulate the vascular pulmonary environment to study these interactions in an in vitro setting (Aim 3).