Controlling doxorubicin release from peptide hydrogel through fine-tuning drug-peptide fibre interactions

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 spatial and temporal controlled delivery of anti-cancer 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), FKFKFEFK (FK), FEFKFEFE (FE), FEFKFEFKK (F8K) and KFEFKFEFKK (KF8K) (F: phenylalanine; E: glutamic acid; K: lysine). First, Dox loaded hydrogels were characterised to ensure that the incorporation of the drug did not significantly affect the hydrogels 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 fibres. When cation-π interactions were used, the position and number of endlysine was 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 endlysine / 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 fibre surface area available for interaction with the drug. For 14 mM hydrogel ~ 170-200 μM of 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 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 work clearly shows the potential of this peptide design as a platform for the formulation of injectable or sprayable hydrogels for controlled drug delivery.