Organic Radical Dendrimers as Metal-Free T₁ MRI Contrast Agents
Moderator: Boris Epel, O2M Technologies LLC; Department of Radiation and Cellular Oncology, The University of Chicago
About the Speaker: Vega Lloveras is a researcher at the Institut de Ciència de Materials de Barcelona (ICMAB-CSIC) and CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Cerdanyola del Vallès, Spain.
About the Webinar: Gadolinium-based contrast agents (GBCAs) are the most widely used contrast agents in clinical magnetic resonance imaging (MRI). As paramagnetic T₁ contrast agents, their high relaxivity arises from the Gd(III) ion, which possesses seven unpaired electrons (S = 7/2). However, concerns regarding nephrogenic systemic fibrosis in patients with severe renal impairment and the retention of toxic Gd(III) ions in various tissues have driven the development of safer, metal-free alternatives.
Persistent organic radicals represent attractive metal-free T₁ MRI contrast agents because of their low in vivo toxicity. However, their widespread application is hindered by intrinsically low relaxivity, resulting from a single unpaired electron (S = ½), and rapid bioreduction under physiological conditions. Conjugating multiple nitroxide radicals to dendritic scaffolds overcomes these limitations by enhancing relaxivity and radical stability through multivalency and steric shielding. The well-defined architecture of dendrimers further enables precise control over radical loading and spatial organization, offering clear advantages over conventional polymers.
Several generations of water-soluble radical dendrimers fully functionalized with peripheral nitroxide radicals have been synthesized. Water solubility was achieved using either amino acid or PEG linkers, with amino acid-based dendrimers exhibiting superior performance. These radical dendrimers exhibited no detectable toxicity, enhanced stability, and remarkably high r₁ relaxivity, surpassing that of commercial GBCAs. EPR spectroscopy combined with molecular dynamics simulations revealed that radical location, water accessibility, and hydrogen-bonding interactions with nitroxide groups are key determinants of relaxivity.
In vivo MRI studies demonstrated that higher-generation radical dendrimers provide contrast enhancement comparable to commercial GBCAs. In a murine GL261 glioblastoma model, they selectively accumulated in tumor tissue, enabling prolonged imaging (>2.5 h), while exhibiting high biological stability and renal clearance. These findings highlight the potential of radical dendrimers as safe, metal-free T₁ MRI contrast agents.
References:
- L. Pinto et al., ACS Appl. Bio Mater., 2020, 3, 369.
- S. Zhang et al., Biomacromolecules, 2022, 23, 2767.
- Y. Wu et al., ACS Appl. Mater. Interfaces, 2024, 16, 47, 65295.
- Y. Wu et al., Acta Biomater., 2025, 192, 461.
- Y. Wu et al., ACS Polym. Au, 2026, 6, 3, 806.