(67f) Designing better drug delivery particles: Protein corona formation and multicomponent aggregation of particles in blood plasma

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, adding 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. Additionally, due to the unique visualization of the nanoparticles, the aggregation behavior of the particles in blood plasma can be observed and quantified. In this work, polystyrene particles were modified with multi-arm and linear polyethylene glycol (PEG) to determine their aggregation profiles and protein corona formation. Multi-arm PEGs were found to aggregate more than linear PEGs, due to the change in zeta potential from unreacted end groups, which may lead to shorter circulation half-lives. Furthermore, the protein corona formation and composition were studied after different washing procedures, highlighting the importance of studying protein corona formation with undiluted blood plasma.