Low-Molecular-Weight Supramolecular Hydrogels for Sustained and Localized in Vivo Drug Delivery

Abstract

Supramolecular hydrogels are emerging as next-generation alternatives to synthetic polymers for drug delivery applications. Self-assembling peptides are a promising class of supramolecular gelators for in vivo drug delivery that have been slow to be adopted despite advantages in biocompatibility due to the relatively high cost of producing synthetic peptide hydrogels compared to synthetic polymer gels. Herein, we describe the development and use of inexpensive low-molecular-weight cationic derivatives of phenylalanine (Phe) as injectable hydrogels for in vivo delivery of an anti-inflammatory drug, diclofenac, for pain mitigation in a mouse model. N-Fluorenylmethoxycarbonyl phenylalanine (Fmoc-Phe) derivatives were modified at the carboxylic acid with diaminopropane (DAP) to provide Fmoc-Phe-DAP molecules that spontaneously and rapidly self-assemble in aqueous solutions upon addition of physiologically relevant sodium chloride concentrations to give hydrogels. When self-assembly occurs in the presence of diclofenac, the drug molecule is efficiently encapsulated within the hydrogel network. These hydrogels exhibit robust shear-thinning behavior, mechanical stability, and drug release profiles to enable application as injectable hydrogels for in vivo drug delivery. Delivery of diclofenac in vivo was demonstrated by a localized injection of an Fmoc-F 5 -Phe-DAP/diclofenac hydrogel into the ankle joint of mice with induced ankle injury and associated inflammation-induced pain. Remediation of pain in the ankle joint was observed immediately after the initial injection and was sustained for a period of nearly 2 weeks, while diclofenac controls remediated pain for less than 1 day. These data demonstrate the promise of these supramolecular hydrogels as inexpensive next-generation materials for sustained and localized drug delivery in vivo.

Ultrashort Peptide Self-Assembly: Front-Runners to Transport Drug and Gene Cargos

“…The hydrogels exhibited encapsulation of non-steroidal antiinflammatory drug, diclofenac, during the self-assembly process and in vivo drug release profile showed their usefulness as injectable materials. The release study of diclofenac, which decreased from Fmoc-F 5 -Phe-DAP to monofluorinated to the non-fluorinated gelator, demonstrated the role of the molecular structure of the gelators advocating the importance of aromatic benzyl side chain for π-π interactions between the gelator and cargo (Figure 4) (Raymond et al, 2019).…”

Fluorinated peptide biomaterials

“…[ 103 ] Exploiting these properties, the Nilsson group have encapsulated the anti‐inflammatory drug diclofenac in the cationic gel via charge complementation and validated its activity in vivo using a pain mitigation mouse model. [ 104 ] Beyond C‐terminal modifications, the same group investigated the assembly of dipeptides prepared from Fmoc‐Phe‐ and either ‐Asp or ‐Arg residues that form supramolecular fibronectin mimetics. [ 105 ] Co‐assembly of these hydrogelators creates a fibril stack that imitates the presentation of the cell‐adhesion motif RGD.…”

Recent Progress in the Design and Application of Supramolecular Peptide Hydrogels in Cancer Therapy

“…Nilsson and coworkers created an SPH self-assembled from Fmoc-F 5 -Phe-DAP (DAP, diaminopropane) for localized delivery of diclofenac. [138] Due to the -interaction between the altered quadrupole in the aromatic benzyl side chain of the gelator and aromatic rings of the diclofenac, sustained release of the drug from SPH over two weeks in vivo after a single injection was achieved. Li and colleagues explored the influence of hydrogelators' structure on drug encapsulation efficiency.…”