{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T04:27:09Z","timestamp":1772252829154,"version":"3.50.1"},"reference-count":46,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2021,4,29]],"date-time":"2021-04-29T00:00:00Z","timestamp":1619654400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","award":["UID\/QUI\/00686\/2019"],"award-info":[{"award-number":["UID\/QUI\/00686\/2019"]}]},{"name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","award":["UID\/CTM\/50025\/2019"],"award-info":[{"award-number":["UID\/CTM\/50025\/2019"]}]},{"name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","award":["UIDB\/50006\/2020"],"award-info":[{"award-number":["UIDB\/50006\/2020"]}]},{"name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","award":["IF\/00606\/2014"],"award-info":[{"award-number":["IF\/00606\/2014"]}]},{"name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","award":["PTDC\/QUI-QOR\/29015\/2017"],"award-info":[{"award-number":["PTDC\/QUI-QOR\/29015\/2017"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Gels"],"abstract":"<jats:p>The self-assembly of nanometric structures from molecular building blocks is an effective way to make new functional materials for biological and technological applications. In this work, four symmetrical bolaamphiphiles based on dehydrodipeptides (phenylalanyldehydrophenylalanine and tyrosyldehydrophenylalanine) linked through phenyl or naphthyl linkers (terephthalic acid and 2,6-naphthalenedicarboxylic acid) were prepared, and their self-assembly properties were studied. The results showed that all compounds, with the exception of the bolaamphiphile of tyrosyldehydrophenylalanine and 2,6-naphthalene dicarboxylic acid, gave self-standing hydrogels with critical gelation concentrations of 0.3 wt % and 0.4 wt %, using a pH trigger. The self-assembly of these hydrogelators was investigated using STEM microscopy, which revealed a network of entangled fibers. According to rheology, the dehydrodipeptide bolaamphiphilic hydrogelators are viscoelastic materials with an elastic modulus G\u2032 that falls in the range of native tissue (0.37 kPa brain\u20134.5 kPa cartilage). In viability and proliferation studies, it was found that these compounds were non-toxic toward the human keratinocyte cell line, HaCaT. In sustained release assays, we studied the effects of the charge present on model drug compounds on the rate of cargo release from the hydrogel networks. Methylene blue (MB), methyl orange (MO), and ciprofloxacin were chosen as cationic, anionic, and overall neutral cargo, respectively. These studies have shown that the hydrogels provide a sustained release of methyl orange and ciprofloxacin, while methylene blue is retained by the hydrogel network.<\/jats:p>","DOI":"10.3390\/gels7020052","type":"journal-article","created":{"date-parts":[[2021,4,30]],"date-time":"2021-04-30T05:10:55Z","timestamp":1619759455000},"page":"52","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Bolaamphiphilic Bis-Dehydropeptide Hydrogels as Potential Drug Release Systems"],"prefix":"10.3390","volume":"7","author":[{"given":"Carolina","family":"Amorim","sequence":"first","affiliation":[{"name":"Center of Chemistry, University of Minho, 4710-057 Braga, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2724-5772","authenticated-orcid":false,"given":"S\u00e9rgio R. S.","family":"Veloso","sequence":"additional","affiliation":[{"name":"Center of Physics, University of Minho, 4710-057 Braga, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5829-6081","authenticated-orcid":false,"given":"Elisabete M. S.","family":"Castanheira","sequence":"additional","affiliation":[{"name":"Center of Physics, University of Minho, 4710-057 Braga, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9936-8088","authenticated-orcid":false,"given":"Loic","family":"Hilliou","sequence":"additional","affiliation":[{"name":"Institute for Polymers and Composites, University of Minho, 4800-058 Guimar\u00e3es, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8500-7364","authenticated-orcid":false,"given":"Renato B.","family":"Pereira","sequence":"additional","affiliation":[{"name":"REQUIMTE\/LAQV, Laborat\u00f3rio de Farmacognosia, Departamento de Qu\u00edmica, Faculdade de Farm\u00e1cia, Universidade do Porto, R. Jorge Viterbo Ferreira, n 228, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0384-7592","authenticated-orcid":false,"given":"David M.","family":"Pereira","sequence":"additional","affiliation":[{"name":"REQUIMTE\/LAQV, Laborat\u00f3rio de Farmacognosia, Departamento de Qu\u00edmica, Faculdade de Farm\u00e1cia, Universidade do Porto, R. Jorge Viterbo Ferreira, n 228, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9323-3978","authenticated-orcid":false,"given":"Jos\u00e9 A.","family":"Martins","sequence":"additional","affiliation":[{"name":"Center of Chemistry, University of Minho, 4710-057 Braga, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5550-4535","authenticated-orcid":false,"given":"Peter J.","family":"Jervis","sequence":"additional","affiliation":[{"name":"Center of Chemistry, University of Minho, 4710-057 Braga, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3279-6731","authenticated-orcid":false,"given":"Paula M. T.","family":"Ferreira","sequence":"additional","affiliation":[{"name":"Center of Chemistry, University of Minho, 4710-057 Braga, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"6366","DOI":"10.1039\/D0TB01157F","article-title":"Electrostatic interactions regulate the release of small molecules from supramolecular hydrogels","volume":"8","author":"Abraham","year":"2020","journal-title":"J. Mater. Chem. B"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1016\/j.msec.2017.02.118","article-title":"Fabrication of thermal sensitive folic acid based supramolecular hybrid gels for injectable drug release gels","volume":"75","author":"Song","year":"2017","journal-title":"Mater. Sci. Eng. C"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1016\/j.actbio.2009.01.006","article-title":"Introducing chemical functionality in Fmoc-peptide gels for cell culture","volume":"5","author":"Jayawarna","year":"2009","journal-title":"Acta Biomater."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"14976","DOI":"10.1039\/D0NR03785K","article-title":"Nanocomposite hydrogels for tissue engineering applications","volume":"12","author":"Zhao","year":"2020","journal-title":"Nanoscale"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1039\/C9BM01304K","article-title":"Short to ultrashort peptide-based hydrogels as a platform for biomedical applications","volume":"8","author":"Yadav","year":"2020","journal-title":"Biomater. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1002\/mabi.201000316","article-title":"Dipeptide and Tripeptide Conjugates as Low-Molecular-Weight Hydrogelators","volume":"11","author":"Adams","year":"2011","journal-title":"Macromol. Biosci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"10001","DOI":"10.1039\/D0SM01198C","article-title":"Exploring the properties and potential biomedical applications of NSAID-capped peptide hydrogels","volume":"16","author":"Jervis","year":"2020","journal-title":"Soft Matter"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"110581","DOI":"10.1016\/j.colsurfb.2019.110581","article-title":"Non-proteinogenic amino acid based supramolecular hydrogel material for enhanced cell proliferation","volume":"185","author":"Arokianathan","year":"2020","journal-title":"Colloids Surf. B Biointerfaces"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1960","DOI":"10.1021\/cr9003067","article-title":"Metal- and Anion-Binding Supramolecular Gels","volume":"110","author":"Piepenbrock","year":"2010","journal-title":"Chem. Rev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"6506","DOI":"10.1021\/acs.langmuir.9b00716","article-title":"Controlling the Assembly and Properties of Low-Molecular-Weight Hydrogelators","volume":"35","author":"Draper","year":"2019","journal-title":"Langmuir"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"850","DOI":"10.1039\/B611255B","article-title":"Conjugates of naphthalene and dipeptides produce molecular hydrogelators with high efficiency of hydrogelation and superhelical nanofibers","volume":"17","author":"Yang","year":"2007","journal-title":"J. Mater. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3562","DOI":"10.1021\/acs.biomac.5b01006","article-title":"Dehydrodipeptide Hydrogelators Containing Naproxen N-Capped Tryptophan: Self-Assembly, Hydrogel Characterization, and Evaluation as Potential Drug Nanocarriers","volume":"16","author":"Castanheira","year":"2015","journal-title":"Biomacromolecules"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"6355","DOI":"10.1039\/C5TB00501A","article-title":"New self-assembled supramolecular hydrogels based on dehydropeptides","volume":"3","author":"Pereira","year":"2015","journal-title":"J. Mater. Chem. B"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Carvalho, A., Gallo, J., Pereira, D.M., Valent\u00e3o, P., Andrade, P.B., Hilliou, L., Ferreira, P.M.T., Ba\u00f1obre-L\u00f3pez, M., and Martins, J.A. (2019). Magnetic Dehydrodipeptide-Based Self-Assembled Hydrogels for Theragnostic Applications. Nanomaterials, 9.","DOI":"10.3390\/nano9040541"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"10377","DOI":"10.1039\/C9CP00352E","article-title":"Novel dehydropeptide-based magnetogels containing manganese ferrite nanoparticles as antitumor drug nanocarriers","volume":"21","author":"Veloso","year":"2019","journal-title":"Phys. Chem. Chem. Phys."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"8607","DOI":"10.1039\/C7TB01883E","article-title":"Self-assembled RGD dehydropeptide hydrogels for drug delivery applications","volume":"5","author":"Castro","year":"2017","journal-title":"J. Mater. Chem. B"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"111869","DOI":"10.1016\/j.msec.2021.111869","article-title":"Supramolecular ultra-short carboxybenzyl-protected dehydropeptide-based hydrogels for drug delivery","volume":"122","author":"Veloso","year":"2021","journal-title":"Mater. Sci. Eng. C"},{"key":"ref_18","first-page":"1269","article-title":"Biomedically Relevant Applications of Bolaamphiphiles and Bolaamphiphile-Containing Materials","volume":"8","author":"Hughes","year":"2021","journal-title":"Med. Pharm. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1002\/mabi.200800180","article-title":"De Novo Design of a Bolaamphiphilic Peptide with only natural amino acids","volume":"8","author":"Qiu","year":"2008","journal-title":"Macromol. Biosci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.1021\/cr0302049","article-title":"Water Gelation by Small Organic Molecules","volume":"104","author":"Estroff","year":"2004","journal-title":"Chem. Rev."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3231","DOI":"10.1039\/c2sm06927j","article-title":"C2-symmetric benzene-based hydrogels with unique layered structures for controllable organic dye adsorption","volume":"8","author":"Dou","year":"2012","journal-title":"Soft Matter"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"13165","DOI":"10.1021\/acs.chemrev.5b00299","article-title":"Supramolecular Hydrogelators and Hydrogels: From Soft Matter to Molecular Biomaterials","volume":"115","author":"Du","year":"2015","journal-title":"Chem. Rev."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1906043","DOI":"10.1002\/adma.201906043","article-title":"Unusual two-step assembly of a minimalistic dipeptide-based functional hypergelator","volume":"32","author":"Chakraborty","year":"2020","journal-title":"Adv. Mater."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1038\/nchem.2122","article-title":"Exploring the sequence space for (tri-)peptide self-assembly to design and discover new hydrogels","volume":"7","author":"Frederix","year":"2015","journal-title":"Nat. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1080\/00268976.2018.1523482","article-title":"Computational prediction of tripeptide-dipeptide co-assembly","volume":"117","author":"Moreira","year":"2019","journal-title":"Mol. Phys."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2800","DOI":"10.1039\/c3nr02505e","article-title":"Triphenylalanine peptides self-assemble into nanospheres and nanorods that are different from the nanovesicles and nanotubes formed by diphenylalanine peptides","volume":"6","author":"Guo","year":"2014","journal-title":"Nanoscale"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2380","DOI":"10.1021\/jz2010573","article-title":"Virtual screening for dipeptide aggregation: Toward predictive tools for peptide self-assembly","volume":"2","author":"Frederix","year":"2011","journal-title":"J. Phys. Chem. Lett."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"15997","DOI":"10.3390\/ijms160715997","article-title":"Hydrogels for Engineering of Perfusable Vascular Networks","volume":"16","author":"Liu","year":"2015","journal-title":"Int. J. Mol. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1971","DOI":"10.1039\/b921863g","article-title":"Relationship between molecular structure, gelation behaviour and gel properties of Fmoc-dipeptides","volume":"6","author":"Adams","year":"2010","journal-title":"Soft Matter"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1110\/ps.9.5.867","article-title":"Conformational transitions and fibrillation mechanism of human calcitonin as studied by high-resolution solid-state 13C NMR","volume":"9","author":"Kamihira","year":"2000","journal-title":"Protein Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1166\/jbn.2015.1998","article-title":"Mechanism of Anti-Cancer Activity of Benomyl Loaded Nanoparticles in Multidrug Resistant Cancer Cells","volume":"11","author":"Kini","year":"2015","journal-title":"J. Biomed. Nanotechnol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"858","DOI":"10.1002\/adma.200601774","article-title":"Self-Assembly of a Dipeptide- Containing Conformationally Restricted Dehydrophenylalanine Residue to Form Ordered Nanotubes","volume":"19","author":"Gupta","year":"2007","journal-title":"Adv. Mater."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"4571","DOI":"10.1021\/la7034533","article-title":"Nanovesicles Based on Self-Assembly of Conformationally Constrained Aromatic Residue Containing Amphiphilic Dipeptides","volume":"24","author":"Mishra","year":"2008","journal-title":"Langmuir"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3096","DOI":"10.1039\/c3tb21856b","article-title":"Self-assembled dipeptide nanotubes constituted by flexible \u03b2-phenylalanine and conformationally constrained \u03b1,\u03b2-dehydrophenylalanine residues as drug delivery system","volume":"2","author":"Parween","year":"2014","journal-title":"J. Mater. Chem. B"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1039\/C9TB01900F","article-title":"Dehydropeptide-based plasmonic magnetogels: A supramolecular composite nanosystem for multimodal cancer therapy","volume":"8","author":"Veloso","year":"2020","journal-title":"J. Mater. Chem. B"},{"key":"ref_36","unstructured":"Frisch, G.W., Trucks, H.B., Schlegel, G.E., Scuseria, M.A., Robb, J.R., Cheeseman, G., Scalmani, V., Barone, B., Mennucci, G.A., and Petersson, H. (2009). Gaussian 09, Revision, A.02, Fox, Gaussian, Inc."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1237","DOI":"10.1021\/ct100747y","article-title":"Rapid sampling of folding equilibria of \u03b2-Peptides in methanol using a supramolecular solvent model","volume":"5","author":"Huang","year":"2011","journal-title":"J. Chem. Theory Comput."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1007\/s00249-011-0700-9","article-title":"Definition and testing of the GROMOS force-field versions 54A7 and 54B7","volume":"40","author":"Schmid","year":"2011","journal-title":"Eur. Biophys. J. Biophys. Lett."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"6269","DOI":"10.1021\/j100308a038","article-title":"The missing term in effective pair potentials","volume":"91","author":"Berendsen","year":"1987","journal-title":"J. Phys. Chem."},{"key":"ref_40","unstructured":"Abraham, M.J., van der Spoel, D., Lindahl, E., and Hess, B. (2021, March 15). The GROMACS Development Team. GROMACS User Manual Version 5.1.4. Available online: www.gromacs.org."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"7812","DOI":"10.1021\/jp071097f","article-title":"The MARTINI force field: Coarse grained model for biomolecular simulations","volume":"111","author":"Marrink","year":"2007","journal-title":"J. Phys. Chem. B"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1021\/ct700324x","article-title":"The MARTINI coarse-grained force field: Extension to proteins","volume":"4","author":"Monticelli","year":"2008","journal-title":"J. Chem. Theory Comput."},{"key":"ref_43","first-page":"3684","article-title":"Molecular dynamics with coupling to an external bath","volume":"81","author":"Berendsen","year":"1984","journal-title":"Chem. Phys."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1463","DOI":"10.1002\/(SICI)1096-987X(199709)18:12<1463::AID-JCC4>3.0.CO;2-H","article-title":"LINCS: A linear constraint solver for molecular simulations","volume":"18","author":"Hess","year":"1997","journal-title":"J. Comput. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1021\/jp036508g","article-title":"Coarse Grained Model for Semiquantitative Lipid Simulations","volume":"108","author":"Marrink","year":"2004","journal-title":"J. Phys. Chem. B"},{"key":"ref_46","first-page":"106219","article-title":"Aggregation kinetics of short peptides: All-atom and coarse-grained molecular dynamics study","volume":"53","author":"Molski","year":"2019","journal-title":"Biophys. Chem."}],"container-title":["Gels"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2310-2861\/7\/2\/52\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:55:27Z","timestamp":1760162127000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2310-2861\/7\/2\/52"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,29]]},"references-count":46,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2021,6]]}},"alternative-id":["gels7020052"],"URL":"https:\/\/doi.org\/10.3390\/gels7020052","relation":{"has-preprint":[{"id-type":"doi","id":"10.26434\/chemrxiv.14261903.v1","asserted-by":"object"}]},"ISSN":["2310-2861"],"issn-type":[{"value":"2310-2861","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,29]]}}}