3 research outputs found
On the Fate of MRI Gd-Based Contrast Agents in Cells. Evidence for Extensive Degradation of Linear Complexes upon Endosomal Internalization
Commercial
Gd-containing complexes are often used as MRI reporters
in cellular labeling procedures as they are internalized into endosomes
by pinocytosis. A methodology has been applied to assess the relative
stability of three commercial Gd contrast agents following cellular
uptake in fibroblasts and macrophages. It has been found that the
acyclic series of Gd MRI contrast agents are degraded much more rapidly
than their macrocyclic analogues, following endosomal internalization
into living cells. This helps to explain their causal role in the
development of nephrogenic systemic fibrosis in renally impaired patients.
The methodology has also been applied to assess the fate of Gd-DTPA-BMA-loaded
liposomes upon their endosomal internalization. Resistant liposomes
prevent the degradation of the complex, whereas liposomes designed
to release their payload in the acidic environments show a loss of
integrity of Gd-DTPA-BMA analogous to the one observed upon internalization
of the free complex
Synthesis of High Relaxivity Gadolinium AAZTA Tetramers as Building Blocks for Bioconjugation
Molecular
imaging requires the specific accumulation of contrast
agents at the target. To exploit the superb resolution of MRI for
applications in molecular imaging, gadolinium chelates, as the MRI
contrast agents (CA), have to be conjugated to a specific vector able
to recognize the epitope of interest. Several GdÂ(III)-chelates can
be chemically linked to the same binding vector in order to deliver
multiple copies of the CA (multimers) in a single targeting event
thus increasing the sensitivity of the molecular probe. Herein three
novel bifunctional agents, carrying one functional group for the bioconjugation
to targeting vectors and four GdÂ(III)-AAZTA chelate functions for
MRI contrast enhancement (AAZTA = 6-amino-6-methylperhydro-1,4-diazepinetetraacetic
acid), are reported. The relaxivity in the tetrameric derivatives
is 16.4 ± 0.2 mM<sub>Gd</sub><sup>â1</sup> s<sup>â1</sup> at 21.5 MHz and 25 °C, being 2.4-fold higher than that of parent,
monomeric GdÂ(III)-AAZTA. These compounds can be used as versatile
building blocks to insert preformed, high relaxivity, and high density
Gd-centers to biological targeting vectors. As an example, we describe
the use of these bifunctional GdÂ(III)-chelates to label a fibrin-targeting
peptide
Synthesis and Preliminary Evaluation in Tumor Bearing Mice of New <sup>18</sup>FâLabeled Arylsulfone Matrix Metalloproteinase Inhibitors as Tracers for Positron Emission Tomography
New
fluorinated, arylsulfone-based matrix metalloproteinase (MMP)
inhibitors containing carboxylate as the zinc binding group were synthesized
as radiotracers for positron emission tomography. Inhibitors were
characterized by <i>K</i><sub>i</sub> for MMP-2 in the nanomolar
range and by a fair selectivity for MMP-2/9/12/13 over MMP-1/3/14.
Two of these compounds were obtained in the <sup>18</sup>F-radiolabeled
form, with radiochemical purity and yield suitable for preliminary
studies in mice xenografted with a human U-87 MG glioblastoma. Target
density in xenografts was assessed by Western blot, yielding <i>B</i><sub>max</sub>/<i>K</i><sub>d</sub> = 14. The
biodistribution of the tracer was dominated by liver uptake and hepatobiliary
clearance. Tumor uptake of <sup>18</sup>F-labeled MMP inhibitors was
about 30% that of [<sup>18</sup>F]Âfluorodeoxyglucose. Accumulation
of radioactivity within the tumor periphery colocalized with MMP-2
activity (evaluated by in situ zimography). However, specific tumor
uptake accounted for only 18% of total uptake. The aspecific uptake
was ascribed to the high binding affinity between the radiotracer
and serum albumin