Nanotemplate-engineered nanoparticles containing gadolinium for magnetic resonance imaging of tumors.
ABSTRACT To design nanoparticles containing accessible gadolinium atoms (Gd-NPs) as a contrast agent for magnetic resonance imaging of tumors.
Nanoparticles containing phospholipid-chelates (phosphoethanolamine diethylenetriaminepentaacetate) and DSPE-PEG (MW5000) were prepared from Brij 78 and stearyl alcohol using the nanotemplate engineering approach. After addition of GdCl3, the presence of gadolinium on the surface of nanoparticles was quantified using inductively coupled plasma atomic emission spectroscopy. The in vitro relaxivities of the Gd-NPs in phosphate buffered saline were assessed at 4.7 T. The conditional binding constants of nanoparticle formulations were determined spectrophotometrically by competitive titration. Transmetallation kinetics of Gd from nanoparticles with Cu2+ and Zn2+ as the competing ions was measured in acetate buffer. The biodistribution profiles, pharmacokinetics, and contrast enhancement in tumor region was studied after administration of Gd-NPs to nude mice bearing A549 lung carcinoma xenografts.
Gd-NPs with an average diameter of 138 nm possessing surface chelating functions were prepared from GRAS (generally regarded as safe) materials. The longitudinal relaxivity (r1) and transverse relaxivity (r2) of Gd-NPs in 10% fetal bovine serum at 4.7 T were 7.1 (+/-0.2) and 13.0 (+/-0.7) 1/mM/s, respectively. These pegylated Gd-NPs had enhanced relaxivities and exhibited particle size stability, sufficient binding affinity, and kinetic inertness under physiologic conditions. The contrast enhancement in tumors was demonstrated 40, 120, and 360 minutes after intravenous injection of Gd-NPs at a dose of 0.1 mmol Gd/kg. The Gd plasma concentration of Gd-NPs over a period of 24 hours fit a two-compartmental model with Cl sys = 0.89 mL/h and MRT = 5.93 h. The amount of Gd that accumulated in the tumor region was consistent with the estimated value obtained by T1 measurements using MR imaging.
Pegylated nanoparticles composed of biocompatible, biodegradable materials and possessing accessible Gd ions on their surface induce relaxivities in the bulk water signal and accumulated sufficiently in tumors, demonstrating their utility as potential magnetic resonance imaging tumor contrast enhancement agents.
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ABSTRACT: The enzyme phosphoglucomutase can be used as a metal ion indicator to measure the concentrations of free Mg2+ and free Zn2+ in physiological fluids. In horse plasma, the concentration of free Mg2+ is close to 0.5 mM, whereas that of free Zn2+ is about 2 X 10(-10) M, although numerous physiological roles for Zn2+ have been postulated that would require free Zn2+ concentration orders of magnitude higher than this. A titration of plasma with Zn2+ shows that the fractional increase in free Zn2+ is essentially the same as the fractional increase in total exchangeable Zn2+, and the results are consistent with a model in which essentially all of the Zn2+ in plasma is bound to albumin. Regardless of the model, the buffering capacity of plasma for free Zn2+ is intrinsically low; however, its capacity relative to the total (exchangeable) Zn2+ present is maximal. The implications of this type of buffering for homeostasis of plasma Zn2+ are considered. Treatment of plasma with a strong reducing agent such as dithiothreitol (0.1 mM) substantially increases the apparent binding of Zn2+ and thus reduces the free Zn2+ concentration. However, the concentration of free Zn2+ appears to be insensitive to decreases in the physiological concentrations of reduced glutathione and cysteine. The concentrations of free Zn2+ and free Mg2+ in plasma are similar to those that have been reported for muscle tissue (rabbit). Their ratio is about 4 X 10(-7). The physiological implications of these concentrations are considered. In some cases, if the Zn2+ and Mg2+ complexes of an uncharacterized vertebrate protein exhibit significantly different properties, their relative importance under physiological conditions can be approximated by evaluating those of the mixed complexes present in a solution that contains the physiological concentration of free Mg2+, plus Zn2+ buffered with histidine, at the appropriate pH and ionic strength. Other metal ion/chelon systems that come close to reproducing the concentrations of free Mg2+ and free Zn2+ in horse plasma also are considered.Journal of Biological Chemistry 09/1987; 262(23):11140-8. · 4.65 Impact Factor
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ABSTRACT: The intracellular metabolism of receptor-targeted 153Gd-DTPA-glycoproteins was studied in vitro and in vivo. These agents bound to cell surface receptors, underwent receptor mediated endocytosis, and were rapidly degraded to a metabolite which co-migrated with a 153Gd-DTPA-lysine standard on thin layer chromatography. The rates of dissociation of 153Gd and 111In from a glycoprotein-chelate conjugate were determined in vitro. Gadolinium readily dissociated, in a pH-sensitive manner, from glycoprotein-DTPA, and to a lesser degree glycoprotein-MX-DTPA. The biodistribution of targeted and blood pool 153Gd/111In labeled proteins also suggested that gadolinium dissociates from protein-DTPA and protein-MX-DTPA and their metabolites leading to an accumulation of gadolinium in bone. Metal-DTPA-glycoprotein agents targeted to cell surface receptors can still produce very high concentrations of radioactive or paramagnetic metals within the lysosome due to the high rate of accumulation afforded by receptor mediated endocytosis and the low release rate of metabolites such as metal-DTPA-lysine. However, the continued development of gadolinium based macromolecular agents will require improvements in bifunctional chelates.Magnetic Resonance Imaging 02/1995; 13(2):201-14. · 2.06 Impact Factor
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ABSTRACT: Nephrogenic systemic fibrosis (NSF) is a rare acquired disorder that was first recognized in 1997. Presented is a retrospective review of 6 cases of NSF diagnosed by skin biopsy in our institution during the past 4 years and their relationship to gadodiamide exposure. Patient age ranged from 23 to 71 years. The onset of symptoms consistent with NSF was between 19 days and 2 months after gadodiamide exposure. Five patients had severe renal impairment and started dialysis around the period of gadodiamide exposure (1 day before the 37 days after contrast administration). The sixth patient had a clotted access at the time of a contrast-enhanced magnetic resonance venogram and was hence not being adequately dialyzed. The dose of gadodiamide ranged from 16 to 40 mL (0.11 to 0.36 mmol/kg). Despite having normal serum bicarbonate, 5 of the 6 patients had an elevated anion gap metabolic acidosis. In our 6 patients, all had either failing native or transplant kidneys at the time of gadodiamide exposure. The development of NSF was temporally related to gadodiamide injection, suggesting as the etiology dechelation of the agent and thus emphasizing the need for change in clinical practice.Investigative Radiology 03/2007; 42(2):139-45. · 5.46 Impact Factor