Calcium Fluoride Nanocrystals: Tracers for In Vivo ¹⁹F Magnetic Resonance Imaging

Abstract

Inorganic nanocrystals (NCs) have been extensively developed for av ariety of uses.T he ability to obtain highresolution NMR signals from the core nuclei of NCs in solution could offer new opportunities in materials sciences and MR imaging.Herein, we demonstrate that small, water-soluble 19 Fionic NCs can average out homonuclear dipolar interactions, enabling one to obtain high-resolution 19 FNMR signals in solution that reflect the MR properties of F À in the crystal core. Decorating 19 F-NC surfaces with ab iocompatible poly(ethylene glycol) coating maintains colloidal stability in water while preserving the NC high-resolution 19 FNMR properties,e ven after further functionalization. The high content and magnetic equivalence of the fluorides within the NCs enable their use as imaging tracers for in vivo 19 FMRI by facilitating a"hot-spot" displayoft heir distribution.

Inducing Defects in 19F-Nanocrystals Provides Paramagnetic-free Relaxation Enhancement for Improved In Vivo Hotspot MRI

“…Notably, by shortening the T 1 values of the nanofluorides by one order of magnitude, we were able to detect low 19 F concentrations down to 5 mM, 10 times lower than the detectability level of the highly crystalline CaF 2 . 20 For example, an SNR of 28 in the 19 F-MRI of the studied phantom was obtained with a 5 mM 19 F-concentration (equivalent to 1.2 × 10 16 fluorine spins) with a voxel size of 4 mm 3 , a level of 19 F-MRI detectability comparable to that of the commonly used PFC nanoemulsions. 42 The very long T 2 values of PFCs, however, allows us to acquire their 19 F-MRI data using multi-echo-based schemes (i.e., RARE or FSE) and thus provide them with essential improved sensitivity for a given time of data acquisition when directly compared to PL-OP-CaF 2 NCs ( Figure S9 and Table S1 ).…”

“…Nanosized inorganic fluoride (specifically, CaF 2 ) 20 NCs have been recently designed and implemented as imaging tracers benefiting from the advantageous background-free 19 F-MRI. 21 − 25 Their small size (<10 nm) and their inorganic solid core make them a unique category of 19 F-MRI tracers, distinct from the extensively developed and frequently used perfluorocarbon (PFC) nanoemulsions, 22 , 23 with the potential to be further developed for applications where small-sized NCs and tunable morphologies are essential.…”

“…This 10-fold reduction in T 1 should allow significant improvement in the sensitivity of 19 F-MRI studies when using OP-CaF 2 compared to OA-CaF 2 NCs. Note that the short T 2 that is characteristic to nanofluorides was similar in both fabrications ( Figure S3c,d ); nevertheless, such limitation could be overcome by using an MRI scheme such as ultrashort TE (UTE) or zero TE (ZTE), found to be applicable to both nanofluorides 20 and paramagnetic PFCs. 29 …”

“…Indeed, a four times higher SNR was obtained in 19 F-MRI for the tube containing the PL-OP-CaF 2 as compared to that of PL-OA-CaF 2 NCs ( Figure 4 b,c), acquired with a UTE sequence to detect the 19 F-MR signal of the fluorides in the NCs. 20 The 10-fold shorter T 1 of the fluorides in PL-OP-CaF 2 allowed us to shorten dramatically the repetition time (TR) and, thus, to increase the number of signal averages for a given time of acquisition or to shorten the total scan time for a given number of signal averages. Note that in order to obtain a comparable 19 F-MRI SNR from the crystalline PL-OA-CaF 2 NCs, a much longer TR was needed, and consequently, a more than 1 h acquisition time to allow the same number of signal averages would be required (compared to the 6.5 min needed for TR = 4.2 ms, Figure 4 b,c).…”

A Fluorinated Ionic Liquid-Based Activatable 19F MRI Platform Detects Biological Targets

“…to construct nanoprobes in their molten state by stably confining them in hollow mesoporous silica (HMS) spheres and then sealing the pores with stimuli-responsive copolymers. The entrapment of the ILs in HMS spheres restricts their molecular mobility and accelerates transverse relaxation, [33][34][35] turning 19 F signals ''off'' (Figure 1A). Their 19 F signals would be significantly enhanced once the trapped ILs are released after the probes respond to a specific stimulus (e.g., tumor-related factors including low pH and matrix metalloproteinase (MMP) secretion), 36,37 thus turning on the 19 F signal.…”