Compact Micellization: A Strategy for Ultrahigh T₁ Magnetic Resonance Contrast with Gadolinium-Based Nanocrystals

Paramagnetic gadolinium (Gd(3+))-based nanocrystals (NCs) with a large number of confined gadolinium ions can be expected to heavily enhance the longitudinal (T1) relaxation of water protons compared to clinical gadolinium complexes with only a single paramagnetic center. However, paramagnetic Gd(3+)-NCs reported to date show only a modest T1 relaxivity of ∼10 mM(-1) s(-1) per Gd(3+) at 1.5 T, only about 3-times higher than clinical Gd(3+) complexes. Here we demonstrate a strategy that achieves ultrahigh T1 relaxivity that is about 25-times higher than clinical Gd(3+) complexes by controlling the proximity of water protons to a paramagnetic NC surface. Using NaGdF4 NCs (∼3 nm) coated with PEG-ylated phospholipid (DSPE-PEG) micelles, we show that the distance of water protons to the NCs surface can be tuned by controlling the NC-micelle sizes. Increasing the ratio of DSPE-PEG to NCs during micellization decreases the size of NC-micelles, enhancing the proximity of water to the NC surface. Using this strategy, we have achieved compact NC-micelles (hydrodynamic diameter, HD ∼ 5 nm) with ultrahigh T1 relaxivity of ∼80 mM(-1) s(-1) per Gd(3+) at 1.41 T. The findings reported here demonstrate a nanostructured Gd(3+)-contrast agent (CA) that simultaneously achieves an ultrahigh T1 relaxivity approaching theoretical predictions, extremely compact size (HD < 5 nm), and a biocompatible surface. Our results show the hitherto unknown ultrahigh T1 relaxation enhancement of water protons in close proximity to a colloidal gadolinium-NC surface that is achievable by precise control of their surface structure.