Ultrasmall Mixed Eu–Gd Oxide Nanoparticles for Multimodal Fluorescence and Magnetic Resonance Imaging of Passive Accumulation and Retention in TBI

Abstract

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. TBI can have a long-term impact on the quality of life for survivors of all ages. However, there remains no approved treatment that improves outcomes following TBI, which is partially due to poor delivery of therapies into the brain. Therefore, there is a significant unmet need to develop more effective delivery strategies that increase the accumulation and retention of potentially efficacious treatments in the injured brain. Recent work has revealed that nanoparticles (NPs) may offer a promising approach for site-specific delivery; however, a detailed understanding of the specific NP properties that promote brain accumulation and retention are still being developed. Multimodal imaging plays a vital role in the understanding of physicochemical properties that initiate the uptake and accumulation of NPs in the brain at both high spatial (e.g., fluorescence imaging) and temporal (e.g., magnetic resonance imaging, MRI) frequency. However, many NP systems that are currently used in TBI only provide contrast in a single imaging modality limiting the imaging data that can be obtained, and those that offer multimodal imaging capabilities have complicated multistep synthesis methods. Therefore, the goal of this work was to develop an ultrasmall NP with simple fabrication capable of multimodal imaging. Here, we describe the development, characterization, accumulation, and retention of poly­(ethylene glycol) (PEG)-coated europium–gadolinium (Eu–Gd) mixed magnetic NPs (MNPs) in a controlled cortical impact mouse model of TBI. We find that these NPs having an ultrasmall core size of 2 nm and a small hydrodynamic size of 13.5 nm can be detected in both fluorescence and MR imaging modalities and rapidly accumulate and are retained in injured brain parenchyma. These NPs should allow for further testing of NP physicochemical properties that promote accumulation and retention in TBI and other disease models.

Smooth muscle cells affect differential nanoparticle accumulation in disturbed blood flow-induced murine atherosclerosis

“…FA-Gd NPs were formulated using a modified polyol synthesis method [ 21 ]. The NPs were formed by adding 2 mmol gadolinium chloride hydrate (GdCl 3 xH 2 O) into 30 mL of triethylene glycol and heated to 80°C until the dissolution of precursors was achieved.…”

“…DCE-MRI was performed on mice herein as previously described [ 21 , 22 ]. Briefly, mice were induced with 2% isoflurane gas and breathing rates were monitored by a pressure-based sensor (SA Instruments), maintaining 50 to 80 breaths per minute over the course of the imaging sequence.…”

Recent Advances in Fluorescence Imaging of Traumatic Brain Injury in Animal Models

“…Multimodal imaging enables rapid and accurate imaging at specific target sites to provide a comprehensive assessment of functional, structural, and metabolic changes in vivo (Feng et al, 2019). Therefore, the development of multimodal probes for TBI has become the focus of research (Guo et al, 2019;Bony et al, 2020;Schomann et al, 2020). Among them, fluorescence/MRI bimodal probes have attracted much attention with the superior advantages of high tissue resolution and imaging sensitivity.…”

“…Among them, fluorescence/MRI bimodal probes have attracted much attention with the superior advantages of high tissue resolution and imaging sensitivity. A feasible attempt is to use the mixed lanthanide oxide magnetic nanoparticles (MNPs) containing europium (Eu) for fluorescence imaging and gadolinium (Gd) for MRI in TBI (Bony et al, 2020). Moreover, these Eu-Gd NPs can be modified with different functional poly(ethylene glycol) (PEG) to not only tune their hydrodynamic dimensions and surface charge, but also to improve targeting ability and biocompatibility.…”

The Renal Clearable Magnetic Resonance Imaging Contrast Agents: State of the Art and Recent Advances

“…Generally, there are two protocols for the synthesis of inorganic Gd 3+ NDs: (1) direct synthesis of hydrophilic Gd 3+ NDs in water or polyol using a stabilizing agent which allows for crystal growth, followed by ligand exchange with a more robust stabilizing agent to improve the colloidal stability of Gd 3+ NDs in complex matrixes [62][63][64][65][66][67][68][69][70][71][72][73][74][75][76][77][78][79][80][81], and (2) preparation of hydrophobic Gd 3+ NDs in high boiling organic solvents by the pyrolysis methods, and subsequent transfer of the hydrophobic Gd 3+ NDs into aqueous phase by using a hydrophilic/amphiphilic ligand to render them water-dispersible [82][83][84][85][86][87][88][89][90] 6) [69]. Because the magnetic dipole interaction between surface Gd 3+ and 1 H is impeded by the PAA, both r 1 and r 2 values of Gd 2 O 3 NDs are decreased with increasing the molecular weight of PAA (Mw = 1200, 5100 and 15,000 Da).…”