Hydrophilicity engineering of amphiphilic macrocyclic MRI contrast agents for enhanced hepatic targeting efficiency.

Effective hepatic enhancement and high kinetic inertness are pivotal driving forces for developing gadolinium-based hepatobiliary MRI contrast agents (CAs). Although lipophilic modifications have dominated efforts to promote hepatic uptake, the vital role of hydrophilicity has been overlooked. Herein, we investigated the structure-activity relationship by fine-tuning of an amphiphilic macrocyclic complex through hydrophilicity engineering. The water-soluble Gd-HE(BnOPh)-DO3A exhibited exceptional kinetic inertness with a dissociation half-life of 8.3 h at pH 1.2, nearly 5-fold longer than the 1.7 h observed for the non-hydroxyl Gd-BnOBn-DO3A. More importantly, Gd-HE(BnOPh)-DO3A achieved rapid and pronounced hepatic enhancement, with a 3.1-fold increase in signal intensity observed as early as 2 min post-injection, while the amphiphilic Gd-BnOBn-DO3A displayed delayed hepatic enhancement, peaking at 30 min. These markedly different pharmacokinetic profiles might arise from altered molecular assembly behavior. Hydroxyl incorporation in Gd-HE(BnOPh)-DO3A disrupted amphiphilic equilibrium and prevented nanoparticle self-assembly, enabling rapid hepatic enhancement in the form of small molecules. Conversely, Gd-BnOBn-DO3A dynamically formed nanoparticles with hydrodynamic size over 200 nm, leading to slower hepatic uptake. In summary, this work established strategic hydrophilicity engineering as an effective, previously underappreciated approach to optimizing hepatic targeting of CAs, offering unique insights into MRI agent design.