(3dh) Towards the Rational Design of Materials; Effect of Ionizable Head Group Architecture On the Delivery Efficiency of Lipid-Based siRNA Nanoparticles

As a Postdoctoral fellow, my current research involves the design of non-invasive probes for tracking the assembly and stability of siRNA nanoparticles in both extracellular and intracellular environments. So far, I have designed two different siRNA-based fluorescent probes whose fluorescence emission changes in response to the assembly state of the nanoparticle. The first probe involves a redox-sensitive fluorescence-quenched probe that fluoresces only when the nanoparticle is disassembled in a reductive environment. The second is based on a FRET-labeled siRNA pair that fluoresces due to the proximity of the siRNA pair when the nanoparticle is intact. In both approaches, the delivery vehicle need not be labeled, thus making both techniques applicable to all types of delivery vehicles. This work was initiated based on my interest in understanding how the function of nanoparticles is related to their biophysical properties. In an effort to comprehend this relationship, I have synthesized a focused library of lipid-based nanoparticles and evaluated the effect of lipid structure and biophysical properties such as particle size, siRNA entrapment, pKa, lytic ability and extracellular stability on the in vitro and in vivo gene silencing performance.

The underlying theme of my research career so far is centered on the use synthetic design as a probe to investigate and answer fundamental mechanistic questions in an effort to improve the function of materials employed in both energy and biological research. As a graduate student, I explored both biological and energy-related research directions. My research in the latter involved the design and synthesis of novel cleavable polymerizable surfactants for the preparation of acid-modified mesoporous silicates towards their use as proton conductive membranes in hydrated fuel cells. Along this line of research, I also investigated the mechanism of proton transport in bitriazole-PEG composites towards their use in anhydrous membranes. With regards to biological research, I worked on the synthesis and evaluation of transferrin-targeted gold nanoparticles as imaging agents to elucidate the uptake mechanism and transport of targeted nanoparticles both in vitro and in vivo. The afore-mentioned research directions, both biological and energy-related, involved a careful combination of synthesis and mechanistic evaluation in order to understand and build a framework for future rational design.