A highly tuneable inverse emulsion polymerization for the synthesis of stimuli-responsive nanoparticles for biomedical applications

Polymeric nanomaterials have seen widespread use in biomedical applications as they are highly tuneable to achieve the desired stimuli-responsiveness, targeting, biocompatibility, and degradation needed for fields such as drug delivery and biosensing. However, adjustments to composition and the introduction of new monomers often necessitate reoptimization of the polymer synthesis to achieve the target parameters. In this study, we explored the use of inverse emulsion polymerization to prepare a library of polymeric nanoparticles with variations in pH and temperature response and examined the impact of overall batch volume and the volume of the aqueous phase on nanoparticle size and composition. We were able to prepare copolymeric nanoparticles using three different nonionic and three different anionic comonomers. Varying the non-ionizable comonomers, acrylamide (AAm), 2-hydroxyethyl methacrylate, and N-isopropylacrylamide (NIPAM), was found to alter the mass percentage of methacrylic acid (MAA) incorporated (from 26.7 ± 3.5 to 45.8 ± 1.8 mass%), the critical swelling pH (from 5.687 ± 0.194 to 6.637 ± 0.318), and the volume swelling ratio (from 1.389 ± 0.064 to 2.148 ± 0.037). Additionally, the use of NIPAM was found to allow for temperature-responsive behavior. Varying the ionizable comonomers, MAA, itaconic acid, and 2-acrylamido-2-methylpropane sulfonic acid (AMPSA), was found to significantly alter the critical swelling pH and, in the case of AMPSA, remove the pH-responsive behavior entirely. Finally, we found that for the base P(AAm-co-MAA) formulation, the pH-responsive swelling behavior was independent of the scale of the reaction; however, variations in the aqueous volume relative to the volume of the continuous phase significantly affected both the nanoparticle size and the critical swelling pH.