Aryl-capped lysine-dehydroamino acid dipeptide supergelators as potential drug release systems

• Published in: International journal of molecular sciences Vol. 23; no. 19; p. 11811
• Main Authors: Oliveira, Carlos B. P., Pereira, Renato B., Pereira, David M., Hilliou, L., Castro, Tarsila Gabriel, Martins, J. A. R., Jervis, Peter John, Ferreira, Paula M. T.
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI 05-10-2022; MDPI AG
• Subjects: Amino Acids - chemistry; Biocompatibility; Biodegradability; Biological activity; Cell viability; Ciprofloxacin; Circular dichroism; Controlled release; critical gelation concentration; Cytotoxicity; dehydrodipeptides; Delayed-Action Preparations; Dichroism; Dipeptides; drug delivery systems; Drug Liberation; Dyes; Emission microscopy; Fluorescence spectroscopy; Gelation; Humans; Hydrogels; Hydrogels - chemistry; Keratinocytes; Low molecular weights; Lysine; Methylene Blue; Molecular modelling; Molecular weight; Peptides; Peptides - chemistry; Proteolysis; Rheological properties; Rheology; Scanning transmission electron microscopy; Science & Technology; Self-assembly; Solvents; Spectroscopy; Spectrum analysis; supramolecular hydrogels; Sustained release; Transmission electron microscopy; lysine; drug delivery systems; self-assembly; dehydrodipeptides; supramolecular hydrogels; critical gelation concentration
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms231911811

Employing amino acids and peptides as molecular building blocks provides unique opportunities for generating supramolecular hydrogels, owing to their inherent biological origin, bioactivity, biocompatibility, and biodegradability. However, they can suffer from proteolytic degradation. Short peptides (<8 amino acids) attached to an aromatic capping group are particularly attractive alternatives for minimalistic low molecular weight hydrogelators. Peptides with low critical gelation concentrations (CGCs) are especially desirable, as the low weight percentage required for gelation makes them more cost-effective and reduces toxicity. In this work, three dehydrodipeptides were studied for their self-assembly properties. The results showed that all three dehydrodipeptides can form self-standing hydrogels with very low critical gelation concentrations (0.050.20 wt%) using a pH trigger. Hydrogels of all three dehydrodipeptides were characterised by scanning tunnelling emission microscopy (STEM), rheology, fluorescence spectroscopy, and circular dichroism (CD) spectroscopy. Molecular modelling was performed to probe the structural patterns and interactions. The cytotoxicity of the new compounds was tested using human keratinocytes (HaCaT cell line). In general, the results suggest that all three compounds are non-cytotoxic, although one of the peptides shows a small impact on cell viability. In sustained release assays, the effect of the charge of the model drug compounds on the rate of cargo release from the hydrogel network was evaluated. The hydrogels provide a sustained release of methyl orange (anionic) and ciprofloxacin (neutral), while methylene blue (cationic) was retained by the network.
This work was supported by the Portuguese Foundation for Science and Technology (FCT) in the framework of the Strategic Funding of CQUM (UID/QUI/00686/2019), IPC (UIDP/CTM/05256/2020 and UIDB/05256/2020) and REQUIMTE/LAQV (UIDB/50006/2020). L.H. acknowledges grant CEECINST/00156/2018. FCT, FEDER, PORTUGAL2020 and COMPETE2020 are also acknowl edged for funding under research project PTDC/QUI-QOR/29015/2017 (POCI-01-0145-FEDER 029015). TGC thanks FCT under the scope of the strategic funding of UIDB/04469/2020 unit, and LABBELS—Associate Laboratory in Biotechnology, Bioengineering and Microelectromechanical Systems, LA/P/0029/2020.