The Effect of Multivalent Interactions on the Electrostatic Stability of Poly(N-isopropylacrylamide) Nanogels

Poly(<i>N</i>-isopropylacrylamide) (PNIPAM) nanogels are promising responsive colloidal particles that can be used in pharmaceutical applications as drug carriers. With an attempt to understand the stability of the PNIPAM-based drug carriers in complex chemical environments, in this work, we investigated the temperature-dependent morphological changes and agglomeration dynamics of PNIPAM nanogels in the presence of mono- and multi-valent cationic electrolytes. Our work provides new insights on the deswelling, flocculation and aggregated morphology of PNIPAM nanogels over a range of electrolyte concentrations and temperatures revealing the threshold of stability and spontaneous agglomeration states. To complement our results on flocculation of these colloidal particles, we also implemented a Debye screening model that accounts for the shielding effect of multivalent cationic electrolytes on these nanogel systems. We demonstrated that, while the order of deswelling ability of the electrolytes follows the trend AlCl₃ &gt; MgCl₂ ≥ CaCl₂ &gt; KCl ≥ NaCl, the nanogels reach a minimum hydrodynamic diameter at 10 mM in all electrolyte solutions. The flocculating ability trend and the response time to form aggregates follow a similar order to the deswelling behavior. Interestingly, our statistical analysis on the SEM and TEM images of the PNIPAM nanogels supported our hypothesis on the presence of a shell-like layer around the nanogels with varying density in the electrolyte solutions as compared to those in aqueous medium, and the shell softness of nanogels became harder in multi-valent electrolyte solution than in monovalent system. Furthermore, the retention of the thermo-induced size reversibility for the Na⁺and K⁺below 10 mM and for the Mg²⁺ and Ca²⁺ below 1 mM indicates the effective destabilization of the electrolyte system with multivalence following the Schulze–Hardy rule, except for Al³⁺. In terms of surface charge screening effect, cations with a higher valence shortened Debye length to a greater extent and this ability was found to be in the order of Al³⁺&gt; Mg²⁺&gt; Ca²⁺&gt; K⁺&gt; Na⁺.