Supramolecular Phenylalanine-Derived Hydrogels for the Sustained Release of Functional Proteins

Abstract

Protein-based therapeutics have emerged as nextgeneration pharmaceutical agents for oncology, bone regeneration, autoimmune disorders, viral infections, and other diseases. The clinical application of protein therapeutics has been impeded by pharmacokinetic and pharmacodynamic challenges including offtarget toxicity, rapid clearance, and drug stability. Strategies for the localized and sustained delivery of protein therapeutics have shown promise in addressing these challenges. Hydrogels are critical materials that enable these delivery strategies. Supramolecular hydrogels composed of self-assembled materials have demonstrated biocompatibility advantages over polymer hydrogels, with peptide and protein-based gels showing strong potential. However, cost is a significant drawback of peptide-based supramolecular hydrogels. Supramolecular hydrogels composed of inexpensive low-molecular-weight (LMW) gelators, including modified amino acid derivatives, have been reported as viable alternatives to peptide-based materials. Herein, we report the encapsulation and release of proteins from supramolecular hydrogels composed of perfluorinated fluorenylmethyloxcarbonyl-modified phenylalanine (Fmoc-F 5 -Phe-DAP). Specifically, we demonstrate release of four model proteins (ribonuclease A (RNase A), trypsin inhibitor (TI), bovine serum albumin (BSA), and human immunoglobulin G (IgG)) from these hydrogels. The emergent viscoelastic properties of these materials are characterized, and the functional and time-dependent release of proteins from the hydrogels is demonstrated. In addition, it is shown that the properties of the aqueous solution used for hydrogel formulation have a significant influence on the in vitro release profiles, as a function of the isoelectric point and molecular weight of the protein payloads. These studies collectively validate that this class of supramolecular LMW hydrogel possesses the requisite properties for the sustained and localized release of protein therapeutics.

Cationic and amphiphilic peptide-based hydrogels with dual activities as anticancer and antibacterial agents

“…19 These peptide gelators form hydrogels with micro-and nanofibril network structures under appropriate conditions through the selfassembly of individual molecules by using various noncovalent interactions including hydrogen bonding, p-p interactions, van der Waals interactions, hydrophobic interactions and others. [20][21][22][23][24] These hydrogels have a wide range of applications in the biomedical field, such as sustained release of drugs and important biomolecules, [25][26][27][28] drug delivery, 25,29 cell culture, 27 tissue engineering, 1,29 wound healing, 19,32 and antimicrobial, [30][31][32][33][34][35][36][37][38][39][40] antiparasitic 37,42 and anticancer agents. [41][42][43][44][45][46][47][48] The self-assembled nanostructures show a remarkably increased bioactivity compared to the unassociated peptide molecules.…”

FF Activates Nucleation for Aggregation in Aqueous Medium: A Key Insight of Amyloid Plaque Formation

“…[7] Hydrogels are created by securely encasing water molecules in interstitial hydrophilic pockets with hydrogen bond donor and acceptors. [8,9] Hydrogels must overcome various obstacles before they can be considered successful in terms of modifying their chemical characteristics, which are necessary for the generation of useful materials. [10] Out of 20 naturally occurring amino acids Phenylalanine (F) is considered as a good low molecular weight gelator (LMWG).…”

“…Under certain conditions, nano‐structured hydrogels can be created by leveraging the spontaneous or induced molecular organization of peptides and their derivatives in aqueous solutions [7] . Hydrogels are created by securely encasing water molecules in interstitial hydrophilic pockets with hydrogen bond donor and acceptors [8,9] . Hydrogels must overcome various obstacles before they can be considered successful in terms of modifying their chemical characteristics, which are necessary for the generation of useful materials [10] …”

Effect of molar ratio and concentration on the rheological properties of two-component supramolecular hydrogels: tuning of the morphological and drug releasing behaviour

“…20,21 Adams and co-workers have recently shown a new short peptide-based hydrogel with the variation of pH triggered by glucono-d-lactone. 22 Hydrogels have been studied widely as soft materials due to their fascinating applications in different fields, including delivery and sustained release of encapsulated important biomolecules 23,24 and drugs, 25,26 tissue engineering, 27 regenerative medicine, 28 antibacterial activity, 29 3D cell culture, 30 sensors, 31,32 formation of nanocomposites, 33 catalysis in organic reactions, 16,34 toxic dyes, 4,35 metal ion removal from wastewater, 4,35 and wound healing. 36 Smith and co-workers have developed the formation of a gel tube by a heating-cooling effect accompanied by the presence of salt.…”