Tuning the pH-Responsive Properties of (2-Diisopropylamino) Ethyl Methacrylate-Based Cationic Nanoparticles: Toward...

Cationic nanoparticles have been widely investigated for their potent ability to transport therapeutic agents intracellularly. Previous studies in our lab have demonstrated that increasing network hydrophobicity in these polymers induces favorable pH-responsive phase transition and membrane-disruptive behavior for intracellular drug delivery. Building upon this idea, the work presented herein analyzes the physiochemical attributes and cargo delivery efficiency of a cationic nanoparticle system with the introduction with 2-(diisopropylamino)ethyl methacrylate (henceforth designated as DPAEMA), a comonomer heightening the hydrophobic content of the inner particle core. DPAEMA is a cationic, amine-containing monomer often introduced as an ionizable hydrophobic block to nanoparticles due to its high biocompatibility and ability to impart pH-sensitivity with a pK_a of around 6.2. DPAEMA bears a hydrophobic nature under pH conditions greater than its pK_a from protonation and rapidly transitions into a hydrophobic state under pH conditions lower than 6.2 (acidic) from deprotonation which makes it an ideal candidate for use as a comonomer or as the main functional monomer when synthesizing pH-responsive nanoparticles for use in biological applications. In addition, the use of monomers with tertiary amines as a functional group offers other desired properties to hydrogels and nanostructures, such as antimicrobial behavior and good biocompatibility characteristics. Most studies with DPAEMA have only explored the delivery of hydrophobic, non-charged anticancer agents wherein the release of the payload is aided by diffusion out of the nanocarriers to the target location. Generally, nanoparticles synthesized with DPAEMA in the literature for drug delivery applications have been small (less than 150 nm) with hydrodynamic diameters varying between studies due to the nature of comonomers or differences in the nominal feed ratios of DPAEMA used. Due to the limited number of studies investigating the function of DPAEMA in cationic nanoparticles, it is imperative to attain a deeper comprehension of its solution behavior to optimize the properties of these vectors. In our work presented here we concentrated upon the synthesis of stable cationic DPAEMA nanoparticles with controlled particle nanometric size and stability for drug-release applications. We investigate the following key factors impacting the responsive characteristics of the particle: hydrodynamic size, pK_a, volume swelling ratio, and the pH range of particle swelling. Furthermore, a cell proliferation assay was determined to evaluate particle cytocompatibility, membrane disruption, and transfection capabilities. The insights obtained from these studies will facilitate the design of novel drug delivery platforms for intracellular transport by explicating the role of charge and hydrophobicity in the operation of cationic nanoparticle systems.