Synthesis and Relaxivity study of amino acid-branched radical dendrimers as MRI contrast agents for potential brain tumor imaging
Wu, Yufei (Institut de Ciència de Materials de Barcelona)
Lloveras Monserrat, Vega (Institut de Ciència de Materials de Barcelona)
Lope-Piedrafita, Silvia (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Mulero-Acevedo, Marta (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Candiota Silveira, Ana Paula (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Vidal-Gancedo, José (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)

Data:	2025
Descripció:	12 pàg.
Resum:	This study introduces a series of water-soluble radical dendrimers (G0 to G5) as promising magnetic resonance imaging (MRI) contrast agents that could potentially address clinical safety concerns associated with current gadolinium-based contrast agents. By using a simplified synthetic approach based on a cyclotriphosphazene core and lysine-derived branching units, we successfully developed a G5 dendrimer containing up to 192 units of 2,2,6,6-Tetramethylpiperidinyloxy (TEMPO) radical. This synthesis offers advantages including ease of preparation, purification, and tunable water solubility through the incorporation of glutamic acid anion residues. Comprehensive characterization using 1H NMR, FT-IR, and SEC-HPLC confirmed the dendrimers' structures and purity. Electron paramagnetic resonance (EPR) spectroscopy revealed that TEMPO groups in higher generation dendrimers exhibited decreased mobility and stronger spin exchange in their local environments. In vitro MRI showed that relaxivity (r1) increased with higher dendrimer generations, with G5 exhibiting an exceptionally high r1 of over 24 mM-1s-1. Molecular dynamics simulations provided crucial insights into structure-property relationships, revealing the importance of water accessibility to TEMPO groups for enhancing relaxivity. Vero cell viability assay demonstrated G3 and G3. 5 have good biocompatibility. In vivo MRI experiments in mice demonstrated that G3. 5 was excreted through the kidneys and selectively accumulated in glioblastoma tumors. Statement of significance: This study explores a class of MRI contrast agents based on organic radical dendrimers as a potential alternative to gadolinium-based agents. We present a simplified synthesis method for water-soluble dendrimers containing up to 192 TEMPO radical units-the highest number achieved to date for this class of compounds-resulting in record-high relaxivity values. Our approach offers easier preparation, purification, and tunable water solubility, representing an improvement over existing methods. Through combined experimental and computational studies, we provide insights into the structure-property relationships governing relaxivity. In vivo experiments demonstrate the dendrimers' potential for glioblastoma imaging, with predominantly renal excretion. This work represents a step towards developing metal-free MRI contrast agents with promising relaxivity and biocompatibility, potentially opening new avenues for diagnostic imaging research.
Ajuts:	Agencia Estatal de Investigación PID2022-137332OB-I00 Agència de Gestió d'Ajuts Universitaris i de Recerca 2021/SGR-00438 Agencia Estatal de Investigación PID2020-113058GB-I00 Agencia Estatal de Investigación PID2023-147750NB-I00
Nota:	Altres ajuts: CIBER-BBN (BBN23PIV01); Intramural CSIC project (202360E61); Severo Ochoa Centres of Excellence Programme (CEX2019-000917-S, CEX2023-001263-S)
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	EPR ; MRI ; Radical Dendrimers ; Relaxivity ; TEMPO radical
Publicat a:	Acta Biomaterialia, Vol. 192 (January 2025) , p. 461-472, ISSN 1878-7568

DOI: 10.1016/j.actbio.2024.12.006
PMID: 39647652

12 p, 7.9 MB

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