Engineering nanoparticle adhesive properties for selective targeting of cardiovascular disease
Receptor-mediated targeting of nano-metric drug or contrast agent carriers holds great potential for treating cardiovascular and vascular-associated diseases. However, predicting the adhesive behavior of these vectors under dynamic conditions is complex due to the interplay of transport, hydrodynamic force and multivalent bond formation dynamics. To address this problem we first developing techniques to analyze multivalent particle adhesion using data that was generated using a model nanocarrier comprised of a 200 nm diameter polystyrene particle coated with monoclonal antibody (Chapter 3). These analytical techniques included a transport-reaction model to track particle species, account for transport phenomena and define kinetic parameters for attachment and detachment. In addition, since particles displayed history-dependent detachment behavior, we employed a Monte Carlo simulation to recreate binding data by stochastically sampling for detachment events based on a time-dependent detachment rate. Next we extended the model system to include 40 nm and 1 µm particles, and demonstrated that size can dramatically affect both carrier recruitment efficiency and bound-state stability (Chapter 4). This included influences from both fluid flow dependent factors as well as the size of the contact area. Furthermore, we demonstrated how particle size can be exploited to engineer delivery carriers with optimal binding characteristics for given therapeutic applications. Next we examined the dependence of receptor/ligand bond properties on nanoparticle adhesion using numerous molecular adhesion systems, including recombinant antibody fragment proteins engineered with specific kinetic and structural characteristics (Chapter 5). Using these systems we demonstrated a significant role for receptor size but observed limited influences from kinetics and mechanics. Finally, we developed a novel single-chain antibody that was specific for VCAM-1 and demonstrated that it can effectively mediate nanoparticle binding under flow, and thus could serve as a viable option to target nanocarriers to VCAM-1 related pathologies such as atherosclerosis and inflammation (Chapter 6). Taken together, these findings demonstrate that targeted nanocarrier adhesion can be engineered through appropriate selection of carrier size, molecular binding efficiency and valency tuning, which could hold important implications for optimizing the efficacy of targeted therapies.