Biomimetic Dual-Multivalent Strategy Enabled In Vivo Tumor-Targeted Molecular MRI.

Magnetic resonance (MR) imaging is a noninvasive, nonionizing clinical modality widely used to detect and visualize anatomical and pathological conditions, including cancer. However, its effectiveness is often limited by low intrinsic sensitivity, insufficient targeting specificity, and poor contrast between normal and tumor tissues. Inspired by the natural use of multivalent interactions in biological adhesion, recognition, and signaling, we report a dual-multivalent enhancement strategy for designing a tetra-armed macrocyclic gadolinium(III)-based molecular MR contrast agent (GdCAG). This agent incorporates four carboxylic alkyl arms and four glucosyl targeting ligands, enabling simultaneous relaxivity enhancement and tumor-selective recognition. GdCAG exhibits significantly improved MR relaxivity as well as markedly enhanced tumor affinity, resulting in effective in vivo tumor-targeted MR imaging following intravenous administration. Compared with the monomultivalent analogue GdG (bearing only four glucosyl units) and the clinically approved control Gd-DOTA, GdCAG produces stronger whole-body MR signal enhancement and prolonged signal retention in healthy mice. In 4T1 breast cancer xenograft models, GdCAG further demonstrates a progressive MR signal increase at tumor sites, underscoring its superior tumor-targeting efficacy in vivo. Collectively, this work establishes a molecular dual-multivalent enhancement paradigm for advancing tumor-specific MR contrast design with broad potential for improving early cancer diagnosis, precision bioimaging, and image-guided therapies.