Movatterモバイル変換

[0]ホーム
URL:

Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
Thehttps:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

NIH NLM Logo
Log inShow account info
Access keysNCBI HomepageMyNCBI HomepageMain ContentMain Navigation
pubmed logo
Advanced Clipboard
User Guide

Full text links

American Chemical Society full text link American Chemical Society Free PMC article
Full text links

Actions

Share

.2017 Jul 13;60(13):5543-5555.
doi: 10.1021/acs.jmedchem.7b00234. Epub 2017 Jun 27.

Synthesis and Preclinical Characterization of a Cationic Iodinated Imaging Contrast Agent (CA4+) and Its Use for Quantitative Computed Tomography of Ex Vivo Human Hip Cartilage

Affiliations

Synthesis and Preclinical Characterization of a Cationic Iodinated Imaging Contrast Agent (CA4+) and Its Use for Quantitative Computed Tomography of Ex Vivo Human Hip Cartilage

Rachel C Stewart et al. J Med Chem..

Abstract

Contrast agents that go beyond qualitative visualization and enable quantitative assessments of functional tissue performance represent the next generation of clinically useful imaging tools. An optimized and efficient large-scale synthesis of a cationic iodinated contrast agent (CA4+) is described for imaging articular cartilage. Contrast-enhanced CT (CECT) using CA4+ reveals significantly greater agent uptake of CA4+ in articular cartilage compared to that of similar anionic or nonionic agents, and CA4+ uptake follows Donnan equilibrium theory. The CA4+ CECT attenuation obtained from imaging ex vivo human hip cartilage correlates with the glycosaminoglycan content, equilibrium modulus, and coefficient of friction, which are key indicators of cartilage functional performance and osteoarthritis stage. Finally, preliminary toxicity studies in a rat model show no adverse events, and a pharmacokinetics study documents a peak plasma concentration 30 min after dosing, with the agent no longer present in vivo at 96 h via excretion in the urine.

PubMed Disclaimer

Conflict of interest statement

Competing Interest

MWG is a co-founder of Ionic Pharmaceuticals and MW was an employee of Ionic Pharmaceuticals. Ionic Pharmaceuticals paid for the radiolabeled study. AG is President of BICL, LLC and Consultant to Sanofi Aventis, GE Healthcare, AstraZeneca, TissueGene, OrthoTrophix, Pfizer, and MerckSerono.

Figures

Figure 1.
Figure 1.
Chemical structures of the cationic (CA4+) as well as commercially available negatively charged (ioxaglate) and neutral (iodixanol) contrast agents.
Figure 2.
Figure 2.
Diffusion trajectories of cationic (CA4+), anionic (ioxaglate), and nonionic (iodixanol) contrast agents in bovine articular cartilage. (A) Average CECT attenuation values (reported in Hounsfield Units, HU) over the 48-hour time course of diffusion into the cartilage of bovine osteochondral plugs. Each point is reported as the average of six samples (mean ± standard deviation). Each contrast agent was fit to a nonlinear diffusion model (Equation 1). The arrow marks the time when 95% of the equilibrium attenuation is reached. (B) Equilibrium CECT attenuation (normalized by concentration) for each contrast agent in bovine osteochondral plugs (*p<0.0001).
Figure 3.
Figure 3.
μCT images of a bovine osteochondral plug visualized in color maps. All images are taken of the same plug cross section. The color map ranges from air in red (each image bottom), to cartilage in yellow, green and blue, & bone in dark blue and purple (each image top). The contrast agents diffuse into cartilage over time and the color turns from yellow to green to blue indicating higher CT attenuation.
Figure 4.
Figure 4.
Donnan equilibrium modelling showing the partition coefficient of CA4+ as a function of sodium ion partition coefficient. Nonlinear least-squares best fits suggest a valence (Z) on the CA4+ as Z = 3.71, compared to the theoretical value (Z = 4).
Figure 5.
Figure 5.
CECT attenuation correlates strongly with GAG content (A) and equilibrium compressive modulus (B) using both CA4+ and ioxaglate.
Figure 6.
Figure 6.
CECT attenuation correlates moderately with coefficients of friction for ioxaglate (A) and CA4+ (B).
Figure 7.
Figure 7.
(A) IV and IA plasma concentrations (male and female). (B) Kidney, liver, and lung concentrations (1, 8 and 24 h post-dose). (C) Urine and feces concentrations.
Figure 8.
Figure 8.
Osteochondral cores (7 mm diameter) were harvested from various locations around the femoral head surfaces.
Scheme 1.
Scheme 1.
Large scale synthesis of the chloride salt of CA4+5.
Scheme 2.
Scheme 2.
Synthesis of14C-labeled CA4+5*.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Hallouard F; Anton N; Choquet P; Constantinesco A; Vandamme T Iodinated Blood Pool Contrast Media for Preclinical X-Ray Imaging Applications – A Review. Biomaterials 2010, 31 (24), 6249–6268. - PubMed
    1. Hasebroock KM; Serkova NJ Toxicity of MRI and CT Contrast Agents. Expert Opin. Drug Metab. Toxicol 2009, 5 (4), 403–416. - PubMed
    1. Kün-Darbois J-D; Manero F; Rony L; Chappard D Contrast Enhancement with Uranyl Acetate Allows Quantitative Analysis of the Articular Cartilage by microCT: Application to Mandibular Condyles in the BTX Rat Model of Disuse. Micron 2017, 97, 35–40. - PubMed
    1. Lee N; Choi SH; Hyeon T Nano-Sized CT Contrast Agents. Adv. Mater 2013, 25 (19), 2641–2660. - PubMed
    1. Mattrey RF; Aguirre DA Advances in Contrast Media Research. Acad. Radiol 2003, 10 (12), 1450–1460. - PubMed

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full text links
American Chemical Society full text link American Chemical Society Free PMC article
Cite
Send To

NCBI Literature Resources

MeSHPMCBookshelfDisclaimer

The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.

[8]ページ先頭
©2009-2025 Movatter.jp