(636e) Surface Modification of Polymer Nanoparticles for Drug Delivery and Their Behavior in Blood Plasma Using Nanoparticle Tracking Analysis

Drug delivery particles must overcome many biological barriers to successfully reach their target. One of those challenges is to evade the immune system and circulate through the body until they find their intended target. Many different engineered particles have been used to improve the circulation time of particles such as by adding poly(ethylene glycol) (PEG) ligands, zwitterionic polymers, adjusting particle size and shape, and attaching peptides to the surface. Though some of these tactics have resulted in longer circulation times, there is still significant off-site accumulation of the particles. It is difficult to determine why off-site accumulation occurs and how changes to the particle surface affect it as there are very few tools available to directly study particles in blood.

Characterizing the size of the particles directly in blood plasma is important to determine the extent of protein corona formation on the particles. With DLS, this is typically done by exposing particles to blood plasma followed by washing or dilution with water, then the increase in particle size can be measured. By washing the particles, however, the loosely bound proteins of the soft corona are removed and the measurements do not reflect what the particle would experience in vivo. As an alternative, we have developed a method of analyzing particles in blood plasma using nanoparticle tracking analysis (NTA) using fluorescently labeled particles. The size of the particle, and thus the size of the protein corona, can be measured in pure blood plasma using this method.

In this work, polymer particles incubated in blood plasma are measured using NTA in pure blood plasma. As a preliminary proof of concept experiment, polystyrene particles are surface modified to attach PEG ligands of different molecular weights to the particles and the size of the particle is measured in blood plasma using both DLS and NTA. The size of the PEGylated particles as measured by NTA shows surprisingly large protein coronas. A dilution study was done comparing the size of the particles measured at different plasma concentrations. At low plasma concentration, size results are consistent with DLS measurements, however a particle size trends with plasma concentration suggesting that the soft corona disappears when plasma is diluted. This method is then used to analyze a potential targeting system, PLGA particles functionalized with poly(zwitterion)-mannose brushes for macrophage targeting. The PLGA particles are examined in blood plasma and the protein corona at shorter time frames is smaller for the brush particles than PEGylated particles. The aggregation behavior between brush modified and PEG modified are similar, suggesting that this particle system is a likely candidate for successful drug delivery. The use of this characterization method will allow for testing of engineered particles for drug delivery directly in blood plasma to determine the features that improve behavior in the blood and can improve outcomes in drug delivery.