Dual-Radical Gardenia Blue Conjugated Polymers with High Relaxivity and Bioreductive Stability as Metal-Free MRI Contrast Agents

Abstract

T 1-weighted MRI contrast agents are essential for accurate diagnosis. However, clinical gadolinium-based contrast agents (Gd-CAs) are increasingly questioned because of risks of nephrogenic systemic fibrosis (NSF) and long-term tissue accumulation. Metal-free organic nitroxides like TEMPO emerge as safer alternatives but are limited by rapid in vivo bioreduction and suboptimal r1 relaxivity. Here, we report TEMPO-PROXY@pGen, a dual-radical, bio-based, π-conjugated polymer synthesized through mechanochemical copolymerization of 4-amino-TEMPO with 4-amino-PROXYL (3,3,5,5-tetramethyl-1-pyrroline N-oxide) on genipin-crosslinked scaffolds. TEMPO-PROXY@pGen integrates rigid π-conjugated backbone anchoring with possible intramolecular biradical interactions, causing the apparent rotational correlation time (τR,app) to approach the regime where Solomon–Bloembergen–Morgan (SBM) theory predicts enhanced relaxivity for simple monoradical systems while preserving high effective spin density (>80 radicals per chain). This yields a longitudinal relaxivity (r1) of 4.35 mM–1s–1 at 1.4 T and 3.69 mM–1s–1 at 3.0 T, 33.5-fold higher than TEMPO and comparable per-molecule r1 to clinically approved gadobutrol at the same field strength. The polymeric architecture confers high resistance to bioreduction and lower cell toxicity. Preliminary biosafety evaluation, including histopathology, serum biomarkers, and functional imaging, in both healthy and cisplatin-induced renal impairment models, suggests an improved safety profile relative to Gd-CAs under the tested conditions. This work establishes a rational molecular engineering framework for fully organic, metal-free MRI contrast agents that separates high relaxivity from heavy metal dependence for safe imaging in patients with compromised renal function.