Utilizing Oxygen-Inhibited Photopolymerization to Control Size of Multimodal PEGDA Hydrogel Nanoparticles for Cancer Therapeutics

Cancer is a class of diseases characterized by hyperproliferative cell growth. Although there are many treatment options for cancer, it has been shown that the use of various modalities at the same time is a more effective treatment than sequentially applying the same modalities. Combining chemotherapy and immunotherapy agents in a nanoparticle equipped with targeting abilities has been shown to facilitate the elimination of cancerous tumors without the need of invasive surgery. Poly(ethylene glycol) diacrylate (PEGDA) hydrogel nanoparticles are of particular interest because of their biocompatibility, non-immunogenity, resistance to protein adsorption, and adjustable mechanical and chemical properties. One of the advantages of PEGDA includes its ability to be photopolymerized, which, consequently, provides increased spatial and temporal control over the hydrogel formation process.

Among the existing methods to produce hydrogels, droplet microfluidics has gained popularity because it offers a higher degree of control over size and composition than traditional methods such as dispersion and emulsion polymerization. Although there are microfluidic techniques to produce monodisperse nanodroplets, they are sensitive to pressure variations and require high energy inputs, as well as having strict solution and oil viscosity requirements. Moreover, photopolymerization of PEGDA droplets in microfluidic devices is susceptible to oxygen inhibition, a phenomenon in which radical species are quenched by oxygen present in the system, resulting in an incomplete gelation. Here we address these challenges by taking advantage of the usually undesirable oxygen inhibited photopolymerization to create a facile route to miniaturize hydrogels from larger, more easily produced droplets. In addition, we demonstrate that size and shape of PEGDA hydrogel particles can be controlled, in addition to generating surfaces that can be easily functionalized. Specifically, simply by changing macromer solution composition, exposure intensity, and initiator concentration, particles with sizes and shapes independent of the parent spherical droplets can be fabricated using conventional microfluidic devices.

Hydrogel permeability and network structure can be finely tuned by varying the PEGDA precursor solution composition and controlling the exposure time. In addition, functional surfaces can be obtained by adding acrylated functional molecules, such as acryl-PEG-biotin, to the macromer solution, which are incorporated into the particle matrix and exhibit surface activity. Using this method, we can produce monodisperse hydrogel nanoparticles with functional surfaces and enhanced control over drug loading, retention, and release of chemotherapy and immunotherapy agents.