| Polymeric nano- and microparticles have long been sought after as intravascular circulation vehicles due to their potential use in many clinical applications, including drug delivery and blood pool imaging. By controlling the polymer characteristics and formulation parameters, it is possible to encapsulate and protect sensitive therapeutic agents within the particles whilst providing a steady and controlled release of these agents. This allows for sustained drug concentrations thus reducing dose frequency, toxicity, and patient non-compliance. This is of particular interest in treatments requiring repeated injections, including growth hormone replacement and chemotherapy.;Unfortunately, the successful application of polymeric particles has been prevented by their short in vivo circulation lifetimes. When polymeric particles are introduced into vascular circulation they are opsononized (tagged as foreign) and subsequently removed from circulation by macrophages. Previous attempts to improve vascular circulation have focused on coating the particles with hydrophilic polymer brushes which interferes with opsononization. However, surface modifying agents provide limited improvement and trigger particle recognition upon repeated exposure.;To overcome rapid recognition and removal, we have "hidden" polymeric particles on the surface of red blood cells (RBCs). Particles attached to RBCs can evade recognition and clearance by macrophages and thus remain in circulation for extended periods of time. This method is motivated by the naturally evolved strategy of various pathogens, such as hemobartonella, that adhere to RBCs and remain in circulation for several weeks. RBCs are advantageous carriers due to their abundance and naturally long circulation lifetimes.;Although RBC-bound particles exhibit dramatically improved circulation, they are still cleared before the natural lifespan of the RBC. In order to improve particle circulation, a variety of particle characteristics were explored (size and surface chemistry) and the role of macrophages and the strength of particle-RBC binding was determined. It was determined that the mechanism of particle removal is passive (non-immune) separation of the particle from the RBC surface. Based on this mechanistic understanding, a particle-RBC strategy was engineered that further improves circulation to orders of magnitude longer compared to unbound particles and over six times longer compared to the best surface modified particles. |
