Controlling Doxorubicin Release from a Peptide Hydrogel through Fine-Tuning of Drug–Peptide Fiber Interactions

Abstract

Hydrogels are versatile materials that have emerged in the last few decades as promising candidates for a range of applications in the biomedical field, from tissue engineering and regenerative medicine to controlled drug delivery. In the drug delivery field, in particular, they have been the subject of significant interest for the spatially and temporally controlled delivery of anticancer drugs and therapeutics. Self-assembling peptide-based hydrogels, in particular, have recently come to the fore as potential candidate vehicles for the delivery of a range of drugs. In order to explore how drug–peptide interactions influence doxorubicin (Dox) release, five β-sheet-forming self-assembling peptides with different physicochemical properties were used for the purpose of this study, namely: FEFKFEFK (F8), FKFEFKFK (FK), FEFEFKFE (FE), FEFKFEFKK (F8K), and KFEFKFEFKK (KF8K) (F: phenylalanine; E: glutamic acid; K: lysine). First, Dox-loaded hydrogels were characterized to ensure that the incorporation of the drug did not significantly affect the hydrogel properties. Subsequently, Dox diffusion out of the hydrogels was investigated using UV absorbance. The amount of drug retained in F8/FE composite hydrogels was found to be directly proportional to the amount of charge carried by the peptide fibers. When cation−π interactions were used, the position and number of end-lysine were found to play a key role in the retention of Dox. In this case, the amount of Dox retained in F8/KF8K composite hydrogels was linked to the amount of end-lysine introduced, and an end-lysine/Dox interaction stoichiometry of 3/1 was obtained. For pure FE and KF8K hydrogels, the maximum amount of Dox retained was also found to be related to the overall concentration of the hydrogels and, therefore, to the overall fiber surface area available for interaction with the drug. For 14 mM hydrogel, ∼170–200 μM Dox could be retained after 24 h. This set of peptides also showed a broad range of susceptibilities to enzymatic degradation opening the prospect of being able to control also the rate of degradation of these hydrogels. Finally, the Dox released from the hydrogel was shown to be active and affect 3T3 mouse fibroblasts viability in vitro. Our study clearly shows the potential of this peptide design as a platform for the formulation of injectable or sprayable hydrogels for controlled drug delivery.

Plasmonic lipogels: driving co-assembly of composites with peptide-based gels for controlled drug release

“…Supramolecular peptide-based hydrogels afford several advantages over the polymeric counterparts, including the biocompatibility and tunability of the gel properties. However, implementing a stimulus often requires changes of the gelator's chemical structure, 53,54 which can lead to undesired effects in the gel properties and require the screening of a large library of compounds. Alternatively, the combination of liposomes and/ or hydrogels with nanoparticles has been a recent strategy to endow materials with a triggered release.…”

An Amino Acid‐Based Thixotropic Hydrogel: Tuning of Gel Recovery Time by Mechanical Shaking

“…These stimuli are the key ingredients for controlling the self‐assembly behavior of the hydrogelator [15–17] . The stimuli responsive property of hydrogel structure [18–21] is frequently installed into artificial hydrogel system to carry out sol‐gel transition for various potential applications including targeted drug release, self‐healing, shape memory, and supramolecular adhesion purposes [22–27] . Among these supramolecular hydrogels, amino acid and peptide‐based [1–10] hydrogels attract special attention due to their ease of synthesis, amino acids mutation, purifications and characterizations, structure‐function relationship, building blocks for supramolecular architectonics, biocompatible and biodegradable properties.…”

Switching the Mode of Drug Release from a Reaction-Coupled Low-Molecular-Weight Gelator System by Altering Its Reaction Pathway

“…Self-assembled biomaterials based on low-molecular-weight gelators (LMWG) possess features such as easy handling and tunability of their properties because of the well-defined nature of the chemical building blocks. − Peptides, sugars, nucleosides, or small aromatic molecules self-assemble through noncovalent interactions such as hydrogen bonding, electrostatic, or π–π interactions encoded into the gelator chemical structure to yield gel phase materials. − The hydrophobic and hydrophilic regions of the resultant hierarchical assemblies can interact noncovalently with drugs of a matched polarity, dictating the drug release rate through their binding affinity. − To further tailor the release profile for drug delivery applications, (reversible) covalent bonding of the drug molecule to the low-molecular-weight gelator can be also pursued, relying on bond hydrolysis under physiological or enzymatic means to trigger drug release. − While both approaches share advantages and disadvantages in their preparation and application, the flexibility to alter the drug release profile for a particular gelator is limited, as a commitment to a release strategy is taken early on the molecular design of the gelator.…”

“… 6 − 11 The hydrophobic and hydrophilic regions of the resultant hierarchical assemblies can interact noncovalently with drugs of a matched polarity, dictating the drug release rate through their binding affinity. 12 − 17 To further tailor the release profile for drug delivery applications, (reversible) covalent bonding of the drug molecule to the low-molecular-weight gelator can be also pursued, relying on bond hydrolysis under physiological or enzymatic means to trigger drug release. 18 − 24 While both approaches share advantages and disadvantages in their preparation and application, the flexibility to alter the drug release profile for a particular gelator is limited, as a commitment to a release strategy is taken early on the molecular design of the gelator.…”