{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T17:48:13Z","timestamp":1779126493784,"version":"3.51.4"},"reference-count":44,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2020,1,21]],"date-time":"2020-01-21T00:00:00Z","timestamp":1579564800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003407","name":"MIUR","doi-asserted-by":"publisher","award":["PRIN-2017A2KEPL"],"award-info":[{"award-number":["PRIN-2017A2KEPL"]}],"id":[{"id":"10.13039\/501100003407","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Regione Campania-POR Campania FESR 2014\/2020","award":["B61G18000470007"],"award-info":[{"award-number":["B61G18000470007"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Poly-aromatic peptide sequences are able to self-assemble into a variety of supramolecular aggregates such as fibers, hydrogels, and tree-like multi-branched nanostructures. Due to their biocompatible nature, these peptide nanostructures have been proposed for several applications in biology and nanomedicine (tissue engineering, drug delivery, bioimaging, and fabrication of biosensors). Here we report the synthesis, the structural characterization and the relaxometric behavior of two novel supramolecular diagnostic agents for magnetic resonance imaging (MRI) technique. These diagnostic agents are obtained for self-assembly of DTPA(Gd)-PEG8-(FY)3 or DOTA(Gd)-PEG8-(FY)3 peptide conjugates, in which the Gd-complexes are linked at the N-terminus of the PEG8-(FY)3 polymer peptide. This latter was previously found able to form self-supporting and stable soft hydrogels at a concentration of 1.0% wt. Analogously, also DTPA(Gd)-PEG8-(FY)3 and DOTA(Gd)-PEG8-(FY)3 exhibit the trend to gelificate at the same range of concentration. Moreover, the structural characterization points out that peptide (FY)3 moiety keeps its capability to arrange into \u03b2-sheet structures with an antiparallel orientation of the \u03b2-strands. The high relaxivity value of these nanostructures (~12 mM\u22121\u00b7s\u22121 at 20 MHz) and the very low in vitro cytotoxicity suggest their potential application as supramolecular diagnostic agents for MRI.<\/jats:p>","DOI":"10.3390\/ph13020019","type":"journal-article","created":{"date-parts":[[2020,1,21]],"date-time":"2020-01-21T11:25:59Z","timestamp":1579605959000},"page":"19","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":42,"title":["Peptide-Based Soft Hydrogels Modified with Gadolinium Complexes as MRI Contrast Agents"],"prefix":"10.3390","volume":"13","author":[{"given":"Enrico","family":"Gallo","sequence":"first","affiliation":[{"name":"IRCCS SDN, Via E. Gianturco 113, 80143 Napoli, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9273-0136","authenticated-orcid":false,"given":"Carlo","family":"Diaferia","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Interuniversity Research Centre on Bioactive Peptides (CIRPeB), University of Naples \u201cFederico II\u201d, via Mezzocannone 16, 80134 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Enza","family":"Di Gregorio","sequence":"additional","affiliation":[{"name":"Department of Molecular Biotechnology and Health Science, University of Turin, Via Nizza 52, 10125 Turin, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giancarlo","family":"Morelli","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Interuniversity Research Centre on Bioactive Peptides (CIRPeB), University of Naples \u201cFederico II\u201d, via Mezzocannone 16, 80134 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eliana","family":"Gianolio","sequence":"additional","affiliation":[{"name":"Department of Molecular Biotechnology and Health Science, University of Turin, Via Nizza 52, 10125 Turin, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonella","family":"Accardo","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Interuniversity Research Centre on Bioactive Peptides (CIRPeB), University of Naples \u201cFederico II\u201d, via Mezzocannone 16, 80134 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,1,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"290","DOI":"10.3389\/fphar.2015.00290","article-title":"MRI contrast agents for pharmacological research","volume":"6","author":"Terreno","year":"2015","journal-title":"Front. Pharmacol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e4016","DOI":"10.1002\/nbm.4016","article-title":"Integration of MRI and MRS approaches to monitor molecular imaging and metabolomic effects of trabectedin on a preclinical ovarian cancer model","volume":"32","author":"Canese","year":"2019","journal-title":"NMR Biomed."},{"key":"ref_3","first-page":"9","article-title":"MRI and CT in the diagnosis of coronary artery disease: Indications and applications","volume":"2","author":"Nikolaou","year":"2011","journal-title":"Ins. Imag."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1319","DOI":"10.3892\/ijmm.2016.2744","article-title":"MRI contrast agents: Classification and application","volume":"38","author":"Xiao","year":"2016","journal-title":"Int. J. Mol. Med."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Pierre, V.C., and Allen, M.J. (2018). Contrast Agents for MRI: Experimental Methods, The Royal Society of Chemistry, CPI group (UK) Ltd.","DOI":"10.1039\/9781788010146"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Luchinat, C., Parigi, G., and Ravera, E. (2018). Paramagnetism in Experimental Biomolecular NMR, Royal Society of Chemistry.","DOI":"10.1039\/9781788013291"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1148\/radiol.2018181151","article-title":"Gadolinium Retention: A Research Roadmap from the 2018 NIH\/ACR\/RSNA Workshop on Gadolinium Chelates","volume":"289","author":"McDonald","year":"2018","journal-title":"Radiology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1097\/RLI.0000000000000605","article-title":"Gadolinium Retention as a Safety Signal Experience of a Manufacturer","volume":"55","author":"Lancelot","year":"2020","journal-title":"Invest. Radiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1021\/bc980086+","article-title":"Polymeric gadolinium chelate Magnetic Resonance Imaging contrast agents:\u2009 design, synthesis, and properties","volume":"10","author":"Ladd","year":"1999","journal-title":"Biocon. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"118577","DOI":"10.1016\/j.ijpharm.2019.118577","article-title":"Gadolinium-based contrast agents: From gadolinium complexes to colloidal systems","volume":"569","author":"Yon","year":"2019","journal-title":"Int. J. Pharm."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"26906","DOI":"10.1021\/acsami.8b08021","article-title":"Biodegradable nanoglobular Magnetic Resonance Imaging contrast agent constructed with host-guest self-assembly for tumor-targeted imaging","volume":"10","author":"Cao","year":"2018","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"10944","DOI":"10.1002\/chem.201402418","article-title":"Dendrimeric \u03b2-Cyclodextrin\/GdIII chelate supramolecular host-guest adducts as high-relaxivity MRI probes","volume":"20","author":"Martinelli","year":"2014","journal-title":"Chem. Eur. J."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"10907","DOI":"10.1021\/cr500314d","article-title":"Noninvasive imaging of nanomedicines and nanotheranostics: Principles, progress, and prospects","volume":"115","author":"Kunjachan","year":"2015","journal-title":"Chem. Rev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2193","DOI":"10.1016\/j.ccr.2009.01.015","article-title":"Supramolecular aggregates containing lipophilic Gd(III) complexes as contrast agents in MRI","volume":"253","author":"Accardo","year":"2009","journal-title":"Coord. Chem. Rev."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"945","DOI":"10.1039\/C8CC08875F","article-title":"MRI micelles self-assembled from synthetic gadolinium-based nano building blocks","volume":"55","author":"Babic","year":"2019","journal-title":"Chem. Commun."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"21","DOI":"10.4155\/tde.13.128","article-title":"Multifunctional liposomes for MRI and image-guided drug delivery","volume":"5","author":"Langereis","year":"2014","journal-title":"Ther. Deliv."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"501","DOI":"10.2147\/IJN.S113607","article-title":"Liposomes derivatized with multimeric copies of KCCYSL peptide as targeting agents for HER-2-overexpressing tumor cells","volume":"12","author":"Ringhieri","year":"2017","journal-title":"Intern. J. Nanomed."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3411","DOI":"10.1021\/acsami.6b14219","article-title":"Gadolinium-loaded poly(n-vinylcaprolactam) nanogels: Synthesis, characterization, and application for enhanced tumor MR Imaging","volume":"9","author":"Sun","year":"2017","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Gheran, C.V., Rigaux, G., Callewaert, M., Berquand, A., Molinari, M., Chuburu, F., Voicu, S.N., and Dinischiotu, A. (2018). Biocompatibility of Gd-loaded chitosan-hyaluronic acid nanogels as contrast agents for magnetic resonance cancer imaging. Nanomaterials, 8.","DOI":"10.3390\/nano8040201"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1166\/jbn.2007.043","article-title":"Gadofullerenes and gadonanotubes: A new paradigm for high-performance magnetic resonance imaging contrast agent probes","volume":"3","author":"Sitharaman","year":"2007","journal-title":"J. Biomed. Nanotechnol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.ica.2012.07.004","article-title":"The gadonanotubes revisited: A new frontier in MRI contrast agent design","volume":"393","author":"Sethi","year":"2012","journal-title":"Inorg. Chimica Acta"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"7003","DOI":"10.1002\/adfm.201502458","article-title":"Peptide materials obtained by aggregation of polyphenylalanine conjugates as gadolinium-based Magnetic Resonance Imaging contrast agents","volume":"25","author":"Diaferia","year":"2015","journal-title":"Adv. Funct. Mater."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e3157","DOI":"10.1002\/psc.3157","article-title":"Peptide-based building blocks as structural elements for supramolecular Gd-containing MRI contrast agents","volume":"25","author":"Diaferia","year":"2019","journal-title":"J. Pept. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1038\/s41598-017-00332-3","article-title":"Cross-beta nanostructures based on dinaphthylalanine Gd-conjugates loaded with doxorubicin","volume":"7","author":"Diaferia","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3234","DOI":"10.1021\/acs.biomac.6b00966","article-title":"One-dimensional supramolecular nanoplatforms for theranostics based on co-assembly of peptide amphiphiles","volume":"17","author":"Kim","year":"2016","journal-title":"Biomacromolecules"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"6804","DOI":"10.1002\/chem.201800351","article-title":"Amyloid-like fibrillary morphology originated by tyrosine-containing aromatic hexapeptides","volume":"24","author":"Diaferia","year":"2018","journal-title":"Chem. Eur. J."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2876","DOI":"10.1038\/nprot.2006.202","article-title":"Using circular dichroism spectra to estimate protein secondary structure","volume":"1","author":"Greenfield","year":"2006","journal-title":"Nat. Protoc."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1111\/j.1745-7270.2007.00320.x","article-title":"Fourier transform infrared spectroscopic analysis of protein secondary structures","volume":"39","author":"Kong","year":"2007","journal-title":"Acta Biochim. Biophys. Sin."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/j.micron.2008.10.002","article-title":"Optical properties of amyloid stained by Congo Red: History and mechanisms","volume":"40","author":"Howie","year":"2009","journal-title":"Micron"},{"key":"ref_30","unstructured":"Chap., 5, Merbach, A.E., and Toth, E. (2001). Protein-Bound Metal Chelates. The Chemistry of Contrast Agents in Medical Magnetic Resonance Imaging, John Wiley & Sons, LTD."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1063\/1.1743771","article-title":"Proton relaxation times in paramagnetic solutions","volume":"27","author":"Blombergen","year":"1957","journal-title":"J. Chem. Phys."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1103\/PhysRev.99.559","article-title":"Relaxation processes in a system of two spins","volume":"99","author":"Solomon","year":"1955","journal-title":"Phys. Rev."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"4551","DOI":"10.1002\/chem.200701587","article-title":"High-relaxivity magnetic resonance imaging (MRI) contrast agent based on supramolecular assembly between a gadolinium chelate, a modified dextran, and poly-beta-cyclodextrin","volume":"14","author":"Battistini","year":"2008","journal-title":"Chem. Eur. J."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Tei, L., Gugliotta, G., Baranyai, Z., and Botta, M. (2009). A new bifunctional Gd-III complex of enhanced efficacy for MR-molecular imaging applications. Dalton Trans., 9712\u20139714.","DOI":"10.1039\/b917566k"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"8080","DOI":"10.1002\/chem.201000508","article-title":"Target visualization by MRI using the avidin\/biotin amplification route: Synthesis and testing of a biotin-Gd-DOTA monoamide trimer","volume":"16","author":"Tei","year":"2010","journal-title":"Chem. Eur. J."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"4546","DOI":"10.1021\/ja00381a009","article-title":"Model-free approach to the interpretation of nuclear magnetic resonance relaxation in macromolecules. 1. Theory and range of validity","volume":"104","author":"Lipari","year":"1982","journal-title":"J. Am. Chem. Soc."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"4559","DOI":"10.1021\/ja00381a010","article-title":"Model-free Approach to the interpretation of nuclear magnetic resonance relaxation in macromolecules. 2. Analysis of experimental results","volume":"104","author":"Lipari","year":"1982","journal-title":"J. Am. Chem. Soc."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1007\/s10534-018-0109-3","article-title":"Gadopentatic acid affects in vitro proliferation and doxorubicin response in human breast adenocarcinoma cells","volume":"31","author":"Fattah","year":"2018","journal-title":"Biometals"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1148\/radiol.2422060245","article-title":"Cytotoxicity of iodinated and gadolinium-based contrast agents in renal tubular cells at angiographic concentrations: In vitro study","volume":"242","author":"Heinrich","year":"2007","journal-title":"Radiology"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1097\/RLI.0000000000000567","article-title":"Gadolinium-Based MRI Contrast Agents Induce Mitochondrial Toxicity and Cell Death in Human Neurons, and Toxicity Increases With Reduced Kinetic Stability of the Agent","volume":"54","author":"Bower","year":"2019","journal-title":"Invest. Radiol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1039\/C8SM02366B","article-title":"Fmoc-FF and hexapeptide-based multicomponent hydrogels as scaffold materials","volume":"15","author":"Diaferia","year":"2019","journal-title":"Soft Matter"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1002\/psc.2942","article-title":"Gadolinium containing telechelic PEG-polymers end-capped by di-phenylalanine motives as potential supramolecular MRI contrast agents","volume":"23","author":"Diaferia","year":"2017","journal-title":"J. Pept. Sci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2625","DOI":"10.1021\/bc200486j","article-title":"Beta-Gal gene expression MRI reporter in melanoma tumor cells. design, synthesis, and in vitro and in vivo testing of a Gd (III) Containing Probe Forming a High Relaxivity, Melanin-Like Structure upon Beta-Gal enzymatic activation","volume":"22","author":"Arena","year":"2011","journal-title":"Bioconj. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1007\/BF00121199","article-title":"TS\/A: A new metastasizing cell line from a BALB\/c spontaneous mammary adenocarcinoma","volume":"1","author":"Nanni","year":"1983","journal-title":"Clin. Exp. Metastasis"}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/13\/2\/19\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T13:20:31Z","timestamp":1760361631000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/13\/2\/19"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,1,21]]},"references-count":44,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2020,2]]}},"alternative-id":["ph13020019"],"URL":"https:\/\/doi.org\/10.3390\/ph13020019","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,1,21]]}}}