Biodistribution and circulatory persistence of hyper-compliant microcarriers

Project abstract The goal of this pilot project is to investigate the vascular persistence of a novel hydrogel microcarrier that mimics the size of white blood cells but is extremely deformable, which is hypothesized to help avoid entrapment in small blood vessels and limit engulfment by phagocytic cells. The carriers we developed for this purpose are called hyper-compliant microparticles (HCMPs). The HCMPs, which can encapsulate other nano/microparticles that elute drugs or chelate toxins, are expected to circulate throughout the body for days, weeks, or even months just like native blood cells. The proposed project will compare the circulatory persistence of “hyper-compliant” versus “stiff” microparticles (MPs) following tail vein injection in an immunocompetent mouse model. Periodic blood draws will be taken to perform MP counts via spectrophotometry and microscopy. We will also investigate biodistribution and potential clearance of the near-infrared fluorescence-labeled MPs following the same administration procedures but with inclusion of live animal imaging over the course of a week. Animals will then be sacrificed, blood collected, and organs explanted before completing a secondary analysis of MP distribution via fluorescence imaging and histology. It is expected that “hyper-compliant” MPs will remain in circulation and be able to pass through even the smallest capillaries, whereas stiffer MPs will become entrapped in organs like the lung. Vascular persistence is also expected to be influenced by HCMP evasion of immune cell uptake due to its hydrophilic surface, relatively large size, and high deformability. We will explore this further through a small in vitro experiment comparing macrophage uptake of “hyper-compliant” versus “stiff” MPs when left uncoated or opsonized with IgG. If HCMPs can continue to circulate for even a week, this would have a significant impact for multiple therapeutic directions. Perhaps foremost would be the sustained release of intravascular drugs, which would greatly benefit from having a microcarrier technology that prevents drug-eluting nano/microparticles from being filtered out of the blood or cleared by the mononuclear phagocytic system. Likewise, strategies for toxin removal from blood, e.g, heavy metals or harmful drug metabolites, would have many new avenues of discovery with a vascular vehicle that functions as a long-acting sorbent. The current project is necessary before pursuing these exciting new directions, and while preliminary work is very encouraging, a more rigorous study is needed for completion.