(153a) Shedding Light on “the Dark Side”: Particle Tracking as A Catalyst for Drug Delivery Nanotechnology Innovation

Drug and gene delivery to target tissues, including within the lungs, is often limited by inefficient nanoparticle transport within complex extra- and intracellular biological environments. For example, although the gene capable of correcting the defect in the transmembrane protein that causes Cystic Fibrosis (CF) has been known since 1989, no patient has yet been cured of this devastating disease. In the lungs, gene delivery through highly viscous and elastic (solid-like) environments present in both airway mucus and the cell cytoplasm is the Achilles heel to effective gene therapy. An improved understanding of the transport of nanoparticulate drug and gene carriers is needed to guide the rational development of improved delivery systems.

Our laboratory synthesizes new polymeric materials that, when formulated into micro- or nanoparticles, possess controlled physicochemical properties that dictate their behavior in biological fluids. We use several methods to guide the design of such materials for specific diseases, including high-resolution video confocal microscopy (or ?confocal particle tracking?, CPT). CPT allows us to quantitatively study the real time movements of drug and gene carriers in complex biological fluids, including mucus and live cells. CPT provides information on the trafficking patterns of hundreds of individual particles/vesicles, and in some cases individual macromolecules, allowing excellent insight into transport phenomena that has largely been studied using bulk-average techniques in the past. CPT also allows the quantitative correlation of particle location with various cellular structures and/or pathways and, thus, provides critical insights into bottleneck(s) to efficient drug/gene delivery in live cells. We also seek to understand how effective systems, such as viruses, are trafficked as compared to currently-available synthetic systems in an attempt to learn potentially desirable properties that can/should be mimicked. Promising drug carrier systems, as identified by in vitro and ex vivo characterization methods, are then loaded with appropriate bioactive agents, characterized, and tested for efficacy in relevant animal models.

This talk will discuss recent results from our laboratory that demonstrate the utility of our more fundamental work using real time video microscopy, including CPT, in providing insight that guides our rational improvement of new synthetic drug and gene delivery systems for use in the lungs. New polymers for drug and gene delivery following inhalation have been synthesized based on our findings, and these systems have shown promise for use against lung cancer and lung inflammation in animals. Surprising findings with important implications for drug carrier design will be discussed, including recent results related to particle design parameters that allow for: (i) rapid transport of particles in mucus and (ii) particle trafficking via a novel non-degradative pathway in live cells.