ABSTRACT
The objective of this study was to evaluate the potential of a high-relaxivity macromolecular gadolinium (Gd) chelate to target folate receptors (FRs). P866 is a dimeric high-relaxivity Gd chelate coupled to a folate moiety. Binding affinity, in vivo biodistribution studies in KB tumor-bearing mice at 1, 4, and 24 h, and dynamic contrast-enhanced (DCE)-MRI (2.35 T) over 4 h were assessed. Binding and internalization of P866 through the FR was demonstrated. Due to the high molecular volume of P866, the binding affinity compared to free FA was decreased (K(D) = 59.3 +/- 1.8 nM and 5.9 +/- 0.2 nM, respectively). Tumor/muscle (T/M) uptake was 5.4 +/- 1.0, 4 h after injection of 15 micromol/kg. Competition with free FA was less effective when the dose was increased due to a saturation of FR. At a dose of 5 micromol/kg, a 70% difference in signal enhancement was observed between P866 and the nonspecific reference compound, thus demonstrating the specificity of FR targeting. While this high-relaxivity folate-Gd chelate has demonstrated its potential capacity to target in vivo FR on tumors, the sensitivity is probably limited to a certain extent by the saturation of the FR and by the decrease in the apparent relaxivity of the internalized part of P866 in the tumor cells.
Subject(s)
Carrier Proteins/metabolism , Drug Delivery Systems/methods , Gadolinium DTPA/pharmacokinetics , Nasopharyngeal Neoplasms/diagnostic imaging , Nasopharyngeal Neoplasms/metabolism , Receptors, Cell Surface/metabolism , Animals , Cell Line, Tumor , Chelating Agents/pharmacokinetics , Contrast Media/pharmacokinetics , Folate Receptors, GPI-Anchored , Humans , Metabolic Clearance Rate , Mice , Organ Specificity , Radionuclide Imaging , Tissue DistributionABSTRACT
Ultrasmall superparamagnetic iron oxide (USPIO) particles are efficient contrast agents used in vivo to enhance relaxation differences between healthy and pathological tissues. Detailed understanding of their physicochemical properties in suspension is necessary to guarantee the quality and safety of biological USPIO particles application. The ferrofluids stability against aggregation and gravitational settling affects their biodistribution and consequently the resulting contrast. In this study, the stability of iron oxide particles was investigated by dynamic light scattering (DLS) at different NaCl concentrations in order to monitor the evolution of the hydrodynamic radius of the particles with time. The results were interpreted using the classical DLVO theory of colloidal stability. The electrophoretic mobility and the models generally used to convert it to zeta potential were discussed and related to the stability results.
Subject(s)
Colloids/chemistry , Drug Stability , Iron/chemistry , Oxides/chemistry , Coated Materials, Biocompatible/chemistry , Dextrans , Electrophoresis , Ferrosoferric Oxide , Light , Magnetite Nanoparticles , Osmolar Concentration , Particle Size , Polyethylene Glycols , Scattering, Radiation , Sodium ChlorideABSTRACT
Ultrasmall superparamagnetic iron oxide (USPIO) particles are maghemite or magnetite nanoparticles currently used as contrast agent in magnetic resonance imaging. The coatings surrounding the USPIO inorganic core play a major role in both the in vitro stability and, over all, USPIO's in vivo fate. Different physicochemical properties such as final size, surface charge and coating density are key factors in this respect. Up to now no precise structure--activity relationship has been described to predict entirely the USPIOs stability, as well as their pharmacokinetics and their safety. This review is focused on both the classical and the latest available techniques allowing a better insight in the magnetic core structure and the organic surface of these particles. Concurrently, this work clearly shows the difficulty to obtain a complete physicochemical characterization of USPIOs particles owing to their small dimensions, reaching the analytical resolution limits of many commercial instruments. An extended characterization is therefore necessary to improve the understanding of the properties of USPIOs when dispersed in an aqueous environment and to set the specifications and limits for their conception.
