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

Abstract

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.

Simultaneous Enhancement of Photoluminescence, MRI Relaxivity, and CT Contrast by Tuning the Interfacial Layer of Lanthanide Heteroepitaxial Nanoparticles

“…32 Comparing the high relaxivity reported here for the CSS NP, we emphasize that only an ultrasmall Gd 3+ NP with controlled surface coating has reported higher relaxivity. 59 For Yb/Er@Lu CS-NPs, an r 1 value of 0.1 mM −1 s −1 is well within the detection limit, confirming that the Yb/Er@Lu CS with strong PL is silent in MRI. This is because Lu 3+ does not have any unpaired electrons in the 4f orbitals but has extremely short electron spin relaxation time (10 −13 s).…”

Engineering of inorganic nanoparticles as magnetic resonance imaging contrast agents

“…Several other research groups also reported similar size effects of NaGdF 4 NPs on relaxivity. 36,39 However, τ R became much lower for larger NaGdF 4 NPs (>15 nm) and played a dominant role in affecting r 1 value, as demonstrated by Gao and co-workers, who found r 1 values of 5.7 mM −1 s −1 for 15 nm NaGdF 4 NPs, which increased to 8.78 mM −1 s −1 for 20 nm ones (Fig. 3c).…”

“…8a–c). 39 The compactly packed PEGylated lipids would bring the water protons closer to the surface of NaGdF 4 NPs and thus lead to enhanced relaxivity. They also found that the relaxivity was independent of outer PEG chain length (Fig.…”

Surface Engineering to Boost the Performance of Nanoparticle‐Based T1 Contrast Agents

“…3 nm in diameter) with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-poly(ethylene glycol) (DSPE-PEG) at a w/w ratio of 1:40 as a novel type of T 1 CA. [30] Remarkably, these NaGdF 4 NC micelles could achieve a high T 1 relaxivity up to 80 mM -1 s -1 per Gd 3+ ion at 1.5 T and 24 mM -1 s -1 per Gd 3+ ion even at 7 T, which are much higher than those of a clinical CA Dotarem®. Further experiments reveal that the relaxivity of the NC micelles decreases as the hydrodynamic size increases.…”

“…In 2016, Almutairi et al reported small compact nanocrystal (NC) micelles formed by coating NaGdF 4 nanocrystals (ca. 3 nm in diameter) with 1,2‐distearoyl‐sn‐glycero‐3‐phosphoethanolamine‐poly(ethylene glycol) (DSPE‐PEG) at a w/w ratio of 1:40 as a novel type of T 1 CA . Remarkably, these NaGdF 4 NC micelles could achieve a high T 1 relaxivity up to 80 m m –1 s –1 per Gd 3+ ion at 1.5 T and 24 m m –1 s –1 per Gd 3+ ion even at 7 T, which are much higher than those of a clinical CA Dotarem®.…”