Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – X-ray contrast imaging agent
Reexamination Certificate
2001-11-09
2003-12-09
Hartley, Michael G. (Department: 1616)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
X-ray contrast imaging agent
C424S009420, C424S009450, C423S44500R, C516S901000
Reexamination Certificate
active
06660248
ABSTRACT:
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
Not Applicable.
FIELD OF THE INVENTION
This invention relates to a new contrast agent for medical use in diagnostic x-ray imaging and method for making the same. The compound comprises an x-ray contrast agent based on a fullerene (C
60
) scaffolding material.
BACKGROUND OF THE INVENTION
Since the fortuitous discovery of X-rays by Wilhelm C. Röntgen in 1895, X-ray radiography has evolved into the foundation of contemporary medical imaging. The term “X-ray radiography” can be taken to encompass all of the technology involved in the creation of medically useful images, from the production of X-ray radiation to the processing of raw photographic, or more recently, digital data. Although the past two decades have experienced an explosive growth in ultrasound and magnetic resonance imaging (MRI) modalities (due largely to the advent of the microchip), approximately 75-80% of all imaging procedures still entail the use of X-rays.
Contemporary X-ray radiography is intimately dependant upon the use of X-ray contrast agents (also called X-ray contrast media, radiopaque agents, and roentgenographic agents). With the exception of orally ingested barium salt slurries for gastrointestinal imaging, all commonly employed X-ray contrast agents (CA) are based on the 1,3,5-triiodinated-5-aminoisophthalic acid substructure. The substructure, along with a typical, commercially available X-ray contrast agent, Iohexol, is shown in FIG.
1
. Administered intravenously, the agents enhance radiographic image contrast by increasing x-ray attenuation via their multiple electron-rich iodine atoms. In the U.S. alone, iodinated contrast agents are used in approximately 20 million procedures annually.
The fractional decrease in X-ray radiation intensity (X-ray attenuation) upon passing through a tissue of interest can be expressed by Equation 1:
I/I
o
=e
−&mgr;&khgr;
(1)
where I and I
o
are the transmitted and incident radiation intensities, respectively. The tissue thickness is &khgr;, and &mgr; is the linear attenuation coefficient. In terms of interactions with the tissue of interest, &mgr; increases with (i) an increase in tissue density and (ii) an increase in the mean atomic number, Z
eff
, of the tissue. The relationship between Z
eff
and &mgr; is a complex function due to atomic absorption edges.
The coefficient &mgr; has three contributions at the clinical X-ray energies of 20-150 keV, each specifying an independent interaction of the X-ray radiation with matter: Rayleigh or coherent scattering (&ohgr;), Compton or incoherent scattering (&dgr;), and the photoelectric event (&tgr;). Thus, &mgr; is simply a summation of each type of interaction as expressed in Equation 2:
&mgr;=&ohgr;+&dgr;+&tgr; (2)
The contribution from coherent scattering is usually never more than 10% and generally considered negligible. Therefore the major contributors to X-ray attenuation are incoherent scattering and the photoelectric event, especially in the absence of contrast agent. In applications involving the use of X-ray contrast agent, however, &tgr; is the dominant term. Equation 3 shows the proportionality of &tgr; with Z
eff
:
&tgr;∝Z
eff
3
(3)
Thus, in the presence of relatively high atomic weight iodinated contrast agents (Iodine, Z=53), the approximation in Equation 4 holds true:
&mgr;∝Z
eff
3
(4)
The proportionality of the linear attenuation coefficient to the cube of the effective atomic number explains the significant contrast enhancement that is seen in the final radiographs due to the presence of the contrast agent.
Angiography, or imaging of the blood vessels is one of the most common radiographic procedures. Typically, an aqueous commercial contrast agent formulation is injected rapidly via catheter directly into the blood stream. As the contrast agents in the injected material are carried through the blood vessels, their presence makes it possible to make images of those vessels.
Unfortunately, conventional contrast agents are absorbed out of the blood fairly quickly, so that they are only effective as imaging agents for about one minute. In addition, in the human circulatory system each blood cell circulates through the heart about once every two minutes. These two factors mean that it is desirable to inject conventional contrast agents very near to the area of interest and to acquire images almost immediately thereafter. Hence, when it is desired to acquire contrast agent-enhanced images of a patient's heart, it is necessary to use a catheter having its tip at or even in the heart. The catheter is typically inserted through a vessel in the thigh or groin and threaded through vessel until it reaches the heart. This is procedure is quite invasive and one that would be preferable to avoid. In addition, conventional contrast agents are often not suitable for use in the field because of the need to rapidly inject the contrast agent and obtain the image. For example, contrast agent-enhanced images of the blood flow through the hearts of stroke victims cannot be obtained in the field because of the impossibility of catheterizing the victim in the field and injecting the contrast agent near the heart.
Diffusion of the contrast agent through the intercellular junctions of the vascular endothelium, known as “extravasation” or “partial extravasation,” occurs everywhere except where an organ/blood barrier exists (e.g. brain and prostate). Image quality is lost due to extravasation, which causes a loss of contrast between the blood vessels and the surrounding tissues. Contrast agents that do not allow or minimize extravasation are called “blood pool contrast agents.”
Today's X-ray contrast agent have evolved the point where it is unlikely that simple modification of the R groups in
FIG. 1
will lead to an improvement in tolerability or performance. Other applications that can be enhanced by the use of contrast agents include imaging of the urinary tract, sinuses, and salivary gland ducts. In each application, however, there continues to be a need for an effective, non-toxic contrast agent that will not be absorbed in to the body. As a result, new contrast agents are currently being investigated that may be delivered less invasively and have a longer circulation time in the body.
SUMMARY OF THE INVENTION
The present invention utilizes a fullerene scaffold to support an iodinated moiety and, preferably, a water solubilizing moiety for use as an improved contrast agent that can be delivered less invasively and have a longer circulation time in the body. The fullerene scaffold may comprise empty fullerenes or endohedral fullerenes.
In a preferred embodiment, the present invention comprises an agent for therapeutic or diagnostic treatment that includes a fullerene scaffold and an iodinated moiety bonded to the scaffold. In some embodiments, a plurality of water solubilizing moieties is also preferably bonded to the scaffold.
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Article entitled: “New non-ionic, highly water-soluble derivatives of C60 designed for biological compatibility,” by Tim Wharton et al., Department of Chemis
Sagman Uri
Wharton John T.
Wilson Lon J.
Conley & Rose, P.C.
Hartley Michael G.
William Marsh Rice University
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