Novel Gd Nanoparticles Enhance Vascular Contrast for High-Resolution Magnetic Resonance Imaging

Abstract

BackgroundGadolinium (Gd), with its 7 unpaired electrons in 4f orbitals that provide a very large magnetic moment, is proven to be among the best agents for contrast enhanced MRI. Unfortunately, the most potent MR contrast agent based on Gd requires relatively high doses of Gd. The Gd-chelated to diethylene-triamine-penta-acetic acid (DTPA), or other derivatives (at 0.1 mmole/kg recommended dose), distribute broadly into tissues and clear through the kidney. These contrast agents carry the risk of Nephrogenic Systemic Fibrosis (NSF), particularly in kidney impaired subjects. Thus, Gd contrast agents that produce higher resolution images using a much lower Gd dose could address both imaging sensitivity and Gd safety.Methodology/Principal FindingsTo determine whether a biocompatible lipid nanoparticle with surface bound Gd can improve MRI contrast sensitivity, we constructed Gd-lipid nanoparticles (Gd-LNP) containing lipid bound DTPA and Gd. The Gd-LNP were intravenously administered to rats and MR images collected. We found that Gd in Gd-LNP produced a greater than 33-fold higher longitudinal (T1) relaxivity, r1, constant than the current FDA approved Gd-chelated contrast agents. Intravenous administration of these Gd-LNP at only 3% of the recommended clinical Gd dose produced MRI signal-to-noise ratios of greater than 300 in all vasculatures. Unlike current Gd contrast agents, these Gd-LNP stably retained Gd in normal vasculature, and are eliminated predominately through the biliary, instead of the renal system. Gd-LNP did not appear to accumulate in the liver or kidney, and was eliminated completely within 24 hrs.Conclusions/SignificanceThe novel Gd-nanoparticles provide high quality contrast enhanced vascular MRI at 97% reduced dose of Gd and do not rely on renal clearance. This new agent is likely to be suitable for patients exhibiting varying degrees of renal impairment. The simple and adaptive nanoparticle design could accommodate ligand or receptor coating for drug delivery optimization and in vivo drug-target definition in system biology profiling, increasing the margin of safety in treatment of cancers and other diseases.

Anti-HIV Drug-Combination Nanoparticles Enhance Plasma Drug Exposure Duration as Well as Triple-Drug Combination Levels in Cells Within Lymph Nodes and Blood in Primates

“…While dose-ranging and multiple-dose studies are needed to optimize dose and dosing frequency, our predictive model indicates that once weekly dosing with anti-HIV LNPs is feasible. Studies evaluating intracellular drug levels in lymph nodes throughout the body and lipid-particle distribution using gadolinium tracers 28 are planned, but are beyond the scope of this report. a Animals were administered anti-HIV LNPs or free drug at a normalized dose of 25 mg/kg LPV, 14.3 mg/kg RTV, and 17.1 mg/kg PMPA subcutaneously.…”

Influence of different cleaning processes on the surface chemistry of gold nanoparticles

“…% sucrose density gradient with a disc speed of 22 000 rcf. Each sample injection of 100 ll was preceded by a calibration step using certified poly(vinyl chloride) particle size standards with a modal size of 380 nm and a density of 1.325 g/ cm 3 . The AuNPs' size was also measured by SEM (FEI6000, FEI, Japan), DLS (Zetasizer ZS-Nano, Malvern Instruments, Malvern, UK), while the gold concentration in AuNPs was estimated from UV-vis spectroscopy data (Thermo Electron Corporation, Nicolett Evolution 300 instrument).…”

“…As a consequence, this revolutionary field of science and technology is being intensively studied as a possible means to help satisfy future societal needs. 1 In this context, metallic, 2 semiconductors, 3,4 oxides, 5,6 polymeric, 7,8 and carbon-based 9,10 nanoparticles have been receiving much attention due to their unique and fascinating properties. 11 Among the different metallic nanoparticles, gold nanoparticles (AuNPs) are probably the most studied because of their particular optical and electronic properties, 12 the relative simplicity of their synthesis processes, [13][14][15] and the wide range of possible surface modifications achievable via thiol based chemistry.…”

MRI with Gadolinium‐Based Nanoparticles

“…Gd 3+ liposomes have been reported to accumulate in the liver and spleen regardless of the size and allowed detection of tumors in the liver with better results for the smaller particles [127]. Because of their large size, they exhibit a longer blood circulation time than single Gd 3+ chelates, especially when derivatized with peG, allowing visualization of fine vasculature [128,129]. Also, paramagnetic lipid-based agents are the object of a growing interest for the visualization of atherosclerotic plaque by various mechanisms [130][131][132][133].…”