Silicate Clay-Hydrogel Nanoscale Composites for Sustained Delivery of Small Molecules

Abstract

Hydrogels have been widely used for therapeutic delivery applications due to their tunability and biocompatibility, although delivery of small molecules is difficult due to high burst release and rapid diffusion from the device. Nanosilicate clays (nanoclays) have shown the adsorption potential of small molecules, offering a lever to prolong the release kinetics of hydrogel delivery devices. However, further characterization of small molecule–nanoclay interactions and their effect on molecule release is needed to allow for the custom design of tunable nanocomposite hydrogel delivery devices. Here, we have characterized the adsorption of small molecules onto three nanoclays, Laponite, montmorillonite, and halloysite, and monitored their release in various conditions. The layered structures of Laponite and montmorillonite led to cationic exchange of the small molecules into the interlayer space, whereas the small molecules were adsorbed onto the surface of the tubular halloysite. The addition of nanoclays to polyethylene glycol (PEG) hydrogels significantly slowed the release of small molecules, especially from Laponite (500-fold decrease) and montmorillonite (∼3000-fold decrease) composite gels. Cationic small molecules were shown to be released significantly slower from nanocomposite hydrogels than anionic ones. The incubation time of small molecules with nanoclays prior to hydrogel encapsulation also played a key role in determining their release rate, with montmorillonite showing near-immediate adsorption while halloysite exhibited a higher dependence on incubation time due to slower adsorption kinetics. Release buffer salt concentration and pH were shown to affect release kinetics due to modulation of nanoclay–small molecule interactions. These results show the potential for formation of a highly tunable nanocomposite hydrogel delivery device for a greatly prolonged release of small molecules compared to traditional hydrogels.

Nanosilicate-hydrogel microspheres formed by aqueous two-phase separation for sustained release of small molecules

“…Higher release buffer salt concentrations were shown to increase release kinetics, as more cations were present to desorb AO, further implicating AO desorption as one of release mechanisms at play in this delivery device (Supplementary Figure S11). Similar studies have shown changing release buffer pH also affects release kinetics due to a similar desorption of small molecules from NS (Gonçalves et al, 2014a;Khachani et al, 2022). Additionally, NS particles naturally degrade into non-cytotoxic components within 30-50 days (Gaharwar et al, 2019).…”

“…Our lab and others have demonstrated the usefulness of incorporating two-dimensional nanosilicate clays such as Laponite (NS) into hydrophilic hydrogels to prolong release of both small molecules and proteins, including cationic, neutral, and anionic species (Howell et al, 2018;Cross et al, 2019;Stealey et al, 2021;Khachani et al, 2022;Stealey et al, 2022). Acridine Orange (AO) was used here as a model cationic small molecule.…”

“…Here, release was only followed to 20 days, so degradation of NS particles was likely not the main mechanism of AO release but could be expected to play a larger role for release times nearing the typical degradation time of NS (30-50 days). Crucially, release of AO could be tuned based on NS concentration, allowing for a "plug-and-play" type delivery device, in which release kinetics can be easily modulated by rational design (Khachani et al, 2022).…”

“…Instead of PBS, 100 mg/ mL NaCl solution was used as the release buffer for both samples. AO concentration was again measured via fluorescence, where the decrease in AO fluorescence due to higher solution salinity was accounted for, as previously described (Khachani et al, 2022).…”

“…The addition of two-dimensional layered nanosilicate Laponite XLG (NS) particles to hydrogels has been shown to achieve sustained release of small molecules (Khachani et al, 2022). The high surface area, biocompatibility and biodegradability of NS particles makes them a suitable addition to PEG hydrogels (Tomás et al, 2018).…”