Phenylalanine-Derived Supramolecular Hydrogels for Sustained Release

Supramolecular hydrogels have shown promise as biomaterials for sustained drug delivery. Peptide-based hydrogels have garnered special interest because they can form rapidly under physiological conditions and are inherently biocompatible.¹ Synthetic peptides can be easily customized to impart desired functionality, but a major impediment to the widespread adoption of these materials is the high cost of bulk manufacturing.² Modified phenylalanine (Phe) derivatives are a privileged class of low molecular weight (LMW) supramolecular gelator that can be produced inexpensively on a large-scale, making them promising potential replacements for peptide gelators. Recently, we demonstrated that Phe derivatives modified at both termini (Fmoc-Phe-DAP) form hydrogels suitable for <i>in vivo</i> sustained drug release.³ The hydrogel, loaded with a nonsteroidal anti-inflammatory drug, acted as a reservoir for localized and sustained release in a mouse model to mitigate pain for nearly two weeks. To further understand the interactions between small molecules and the hydrogel network, we characterized the release of cationic, neutral, and anionic cargo from both cationic and anionic supramolecular hydrogels.⁴ Cargo that was neutral or of the same charge as the gelator were released at similar rates, but cargo in hydrogels with complementary charge was highly retained. These results highlight the importance of considering electrostatic interactions between the cargo and LMW gelator when designing supramolecular hydrogel systems for drug delivery.<br/>References:<br/>1. Caliari, S. R. and Burdick, J. A. <i>Nat. Methods</i> <b>2016</b>, <i>13</i>, 405–414.<br/>2. Sis, M. J. and Webber M. J. <i>Trends Pharmacol. Sci.</i> <b>2019</b>, <i>40</i>, 747–762.<br/>3. Raymond, D. L.; Abraham, B. L.; Fujita, T.; Watrous, M. J.; Toriki, E. S.; Takano, T.; Nilsson, B. L. <i>ACS Appl. Bio Mater. </i><b>2019</b>, <i>2</i>, 2116–2124.<br/>4. Abraham, B. L.; Toriki, E. S.; Tucker, N. J.; Nilsson, B. L. <i>J. Mater. Chem. B</i> <b>2020</b>, <i>8</i>, 6366–6377.