Depletion Flocculation in a Dual Delivery System for the Treatment of Lung Cancer

Abstract

Nanoparticle- and gel microparticle-based drug delivery systems have the potential to vastly improve temporal and distributional control of drug delivery. However, prior to clinical use a number of aspects of these systems must be controlled and optimized. In this study we consider the phase behavior of nanoparticles and various homopolymers in order to tune the behavior of a novel gel microparticle-nanoparticle dual delivery system in which nanoparticles are embedded into gel matrices formed from these homopolymers. The process of constructing this system involves synthesizing nanoparticles and then mixing them with the hydrogel homopolymer prior to polymerization. At this stage, interactions between the nanoparticles and homopolymer may lead to the flocculation of the nanoparticles. Therefore, we investigate the general phenomenon of depletion flocculation of soft spheres in this context. We use the Flash Nano-Precipitation process to construct nanoparticles with polystyrene cores and polyethylene glycol surface layers, and we vary the block copolymer during synthesis to alter the hardness of the spheres. These nanoparticles are functionalized with the dye ETTP-5 during synthesis, and emulsions of these nanoparticles and various homopolymers are visualized using confocal microscopy. The homogeneity of fluorescence may then be used as an indicator of nanoparticle aggregation, which implies phase separation between the nanoparticles and the homopolymer. The resulting phase diagrams are consistent with expectations, showing that in general nanoparticle solubility is inversely related to the size of the adsorbed polyethylene glycol layer and directly proportional to the chain length of the homopolymer in solution. The 4000 MW polyethylene glycol is demonstrated to be a relative lower limit: for this homopolymer, none of the nanoparticles tested in this study exhibited phase separation over the tested range of concentrations. The 1.6k-2.1k PS-b-PEG nanoparticles phase separated in 10000 MW polyethylene glycol, while the 1.6k-5k PS-b-PEG nanoparticles remained homogenous over the concentrations observed when mixed with 10000 MW polyethylene glycol but were observed to phase separate in 20000 MW polyethylene glycol. These data elucidate the phase behavior of polyethylene glycol-based soft spheres, and they are also valuable in the selection of nanoparticles for the purposes of the drug delivery system based on the expected release characteristics resulting from this variation in phase behavior.