Design Strategy of T 1-Weighted MRI Contrast Agents for High Relaxivity Based on a Self-Folding Macromolecular Architecture

Conjugation of gadolinium chelates to macromolecular nanoplatforms has emerged as a promising strategy for developing high-performance contrast agents for T1-weighted MRI. However, conventional macromolecular gadolinium-based contrast agents (GBCAs) typically achieve limited enhancement of longitudinal relaxivity merely by tethering Gd chelates to macromolecular platforms to slow their global rotational motion. Here, we present a rational design strategy based on a self-folded macromolecular contrast agent (SMCA), formed through intramolecular self-folding of a single amphiphilic polymer chain incorporating a minimized amount of Gd chelate. The SMCA forms a nanosized micellar structure with a hydrophobic core and a hydration shell, while positioning the Gd chelates at the core-shell interface. Experimental results suggest that the rigid architecture of SMCA may contribute to relatively slow global motion, while the PEG shell may restrict segmental dynamics, potentially contributing to the enhanced longitudinal relaxivity. Systematic structural modulation, including control of the degree of polymerization and hydrophilic chain length, enables enhanced relaxivity while ensuring renal clearance. The optimized Gd-DOTA-conjugated SMCA exhibits a longitudinal relaxivity of 31.5 mM-1 s-1 at 0.47 T, representing an 8.5-fold increase over clinically used Gd-DOTA. In a proof-of-concept MRI study, SMCA enhances strong and long-lasting vascular contrast even at one-eighth of the Gd-DOTA dose, yielding a 2.7-fold higher peak signal intensity while maintaining favorable clearance. This work would contribute to establishing mechanistic guidance for designing next-generation macromolecular GBCAs with high relaxivity and ensured safety.