Fundemental Delivery Science: Enabling Microgels to Walk and Talk

PI’s: Thomas Barker

Synthetic particles are made in a plethora of flavors. The chemistry, crosslinking, particle size, and bioconjugated ligands are tuned over and over again in an attempt to refine particle design to evade the immune system and target specific tissues or cells. We ourselves have engaged in this formula.1 This is somewhat of a losing battle: the inherent noise within biological systems presents a significant roadblock to highly specific targeting of drug or gene carrying particles. Additionally, the inanimate particles used exclusively in delivery science are “static” and can only passively target tissues.  This limits their reach to the vasculature (the most routine mode of delivery) or the regions immediately adjacent to vessels depending on their pathological leakiness. One need only look to inflammatory cells for guidance in concept. Neutrophils and macrophages extravasate vessels squeezing between endothelial cells and actively invade/migrate within the interstitial spaces of tissues following chemotactic, haptotactic and durotactic gradients as directional guides for their required location.2 How does one port these critical and complex functions onto particle systems? Is it possible to create particles that perform physical work and/or are capable of motility along directional cues. Such a conceptual leap would revolutionalize delivery science and enable a level of particle targeting and tissue penetration not yet observed.

Traditional, inherently “stiff” particles are simply incapable of performing the complex behaviors mentioned above in part because they cannot deform their edge as a cell does. Haptotactic cell spreading and invasion is a consequence of non-regular, cycling of cell body protrusions that each have small numbers of receptors with specificity to various microenvironmental cues, like the extracellular matrix scaffold. Simple biochemistry leads to binding events along the protrusions and in response to a physical gradient the probability of binding increases in the direction of the gradient, thus cells are stimulated to move up a physical gradient. While cells certainly enhance the rate of these reactions by imputing energy, the physics of cell membrane deformability and the biochemistry and biophysics of kinetic receptor-ligand binding are the underlying fundamentals of cell motility.3

In this project, using a unique class of particles known as ultra-low crosslinked (ULC) microgels we aim to enable synthetic particle motility up haptotactic gradients based on these fundamental underpinnings of cell motility. ULC microgels are synthesized in a completely novel way; there is no exogenous crosslinker used to form the polymeric microparticle. As a consequence these particles are very loosely held together due to rare parasitic interchain transfer reactions during the polymerization process. The uniqueness of their deformability can be demonstrated by their complete collapse under their own weight; 1 mm sized particles in suspension collapse into 4 nm thin films on surfaces. We have previously demonstrated the potential of such highly deformable particles to perform physical work. By enabling ULC microgels with a fibrin-specific antibody we observed that the particles spread along fibrin fibers and subsequently collapsed fibrin clots to a exact same degree as native platelets, but on a slower time scale.4 Here will employ a similar approach to enabling ULC microgels with the power of motility for advanced delivery of therapeutics. This inherently high-risk/high-reward project has the potential to significantly transform gene and drug delivery.