Magnetic Resonance Imaging Detection of Tumor Cells by Targeting Low-Density Lipoprotein Receptors with Gd-Loaded Low-Density Lipoprotein Particles

Abstract

Gd-DO3A-diph and Gd-AAZTAC17 are lipophilic magnetic resonance imaging (MRI) agents that display high affinity for low-density lipoprotein (LDL) particles. However, on binding to LDL, Gd-DO3A-diph shows a decreased hydration that results in a lower enhancement of water proton relaxation rate. Conversely, Gd-AAZTAC17 displays a strong relaxation enhancement at the imaging fields. Each LDL particle can load up to 100 and 400 UNITS of Gd-DO3A-diph and Gd-AAZTAC17, respectively. Their LDL adducts are taken up by human hepatoblastoma G2 (HepG2) and melanoma B16 tumor cells when added to the incubation medium. T(1) measurements of the labeled cells indicate that Gd-AAZTAC17 is significantly more efficient than Gd-DO3A-diph. Furthermore, it has been found that HepG2 hepatoma cells can internalize higher amounts of Gd-AAZTAC17 than B16 cells and the involvement of LDL receptors (LDLRs) has been demonstrated in competition assays with free LDL. Gd-AAZTAC17/LDL adduct proved to be an efficient probe in the magnetic resonance (MR) visualization of subcutaneous tumors in animal models obtained by injecting B16 melanoma cells into the right flank of mice. Finally, confocal microscopy validation of the distribution of LDL-based probes in the tumor has been obtained by doping the Gd-AAZTAC17/LDL adduct with a fluorescent phospholipid moiety.

Stability and Toxicity of Contrast Agents

“…Since then, several other AAZTA derivatives (Chart 4.5) including some bifunctional versions were also prepared and suggested for the chelation of Ln 3+ and Mn 2+ [80][81][82][83]. In spite of the lower denticity and negative charge of AAZTA compared to DTPA, the stability constants of its complexes are very similar to those of the Ln(DTPA) 2 [69,75,76] log β 014 = 24.…”

Recombinant high-density lipoprotein nanoparticles containing gadolinium-labeled cholesterol for morphologic and functional magnetic resonance imaging of the liver

“…7,13,[30][31][32][33][34][35] LDL nanoparticles containing lipophilic gadolinium complexes such as Gd-AAZTAC17 are also utilized as MRI probes for tumor cells in vitro and in vivo. 9 Similarly, many HDL nanoparticles have also been developed as drug or gene delivery systems, with many targeted to the liver, to which natural HDL is targeted. 10,11,36,37 Hepatocytes express high levels of HDL receptors (scavenger receptor class B, type I, SR-BI) that interact with the apoA-I protein on HDL surfaces.…”

“…Significant efforts have been devoted to the use of recombinant lipoprotein-like nanoparticles as drug delivery vehicles and diagnostic agents, because most of these particles resemble natural lipoprotein structures and are considered highly biocompatible and safe. [7][8][9][10][11][12] While most LDL-like nanoparticles have been studied as drug delivery or imaging agents for malignant cells expressing LDL receptors, 13 HDL nanoparticles have been used to target hepatocytes and atherosclerotic plaque because the natural function of HDL is to transport cholesterol from the peripheral tissues to the liver through the reverse cholesterol transport pathway. 14 Frias et al prepared HDL-like nanoparticles containing gadolinium-DTPA-conjugated phospholipid and apolipoprotein A-I (apoA-I) proteins or apoA-I mimetic peptides, 18A and 37pA.…”

In Vitro and In Vivo Studies Glycosylated Gadolinum Nanomagnetic Particleas (GD-DTPA-DG) as New Potential Metabolic Contrast Agent in MMRI

“…This agent has a long history of use in MRI (9). The main disadvantages Gd-DTPA are related to a lower cellular uptake and nonspecific contrast agent, reducing its ability to assist in gathering information about cellular physiology or molecular pathology (10,11). For this reason, new contrast agents that target specific organs or body tissues and/or aggregate in specific regions of tumors are needed (12).…”