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

Paramagnetic gadolinium (Gd3+)-based nanocrystals (NCs) with a large number of confined gadolinium ions can be expected to heavily enhance the longitudinal T-1 relaxation of water protons compared to clinical gadolinium complexes with only a single paramagnetic center. However, paramagnetic Gd3+-NCs reported to date show only a modest T-1 relaxivity of similar to 10 mM(-1) s(-1) per Gd3+ at 1.5 T, only about 3-times higher than clinical Gd3+ complexes. Here we demonstrate a strategy that achieves ultrahigh T-1 relaxivity that is about 25-times higher than clinical Gd3+ complexes by controlling the proximity of water protons to a paramagnetic NC surface. Using NaGdF4 NCs (similar to 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 similar to 5 nm) with ultrahigh T-1 relaxivity of similar to 80 mM(-1) s(-1) per Gd3+ at 1.41 T. The findings reported here demonstrate a nanostructured Gd3+-contrast agent (CA) that simultaneously achieves an ultrahigh T-1 relaxivity approaching theoretical predictions, extremely compact size (HD < 5 nm), and a biocompatible surface. Our results show the hitherto unknown ultrahigh T-1 relaxation enhancement of water protons in close proximity to a colloidal gadolinium-NC surface that is achievable by precise control of their surface structure.