Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – X-ray contrast imaging agent
Reexamination Certificate
1998-12-08
2001-03-20
Hollinden, Gary E. (Department: 1616)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
X-ray contrast imaging agent
C424S009420, C424S009430, C424S009440
Reexamination Certificate
active
06203778
ABSTRACT:
BACKGROUND OF THE INVENTION
X-ray imaging techniques, including radiography, fluoroscopy and computed tomography (CT) x-ray imaging are well known and extremely valuable tools for the detection and diagnosis of various disease states in the human body. In CT, the usual x-ray film image is replaced by sets of digitized matrices which represent the x-ray attenuation through the body. CT imaging allows 2-dimensional cross-sectional images of the body's organs and interior spaces to be acquired. In addition to its ability to produce cross-sectional images, CT imaging provides greater sensitivity to attenuation differences between tissues than conventional x-ray imaging. In spite of its sensitivity to attenuation differences, it is still quite common to perform CT imaging in conjunction with administering a radiopaque contrast agent.
Many different types of tissue and tumors can be imaged by CT imaging, including, but not limited to, brain, lungs, heart, and any solid tumor found in any soft tissue in the body (including liver, pancreas, ovaries, etc.). Contrast enhanced CT imaging can be used to enhance the visibility of vascular structures of in and around tumors, such as breast, lung, prostate, head and neck (squamous), rectal, testicular, bladder and ovarian carcinomas, soft tissue and central nervous system tumors.
Radiopaque contrast agents provide a means to vary image contrast and to improve the differentiation between pathological and physiological phenomena. An excellent background on contrast agents and media in medical imaging is provided by D. P. Swanson et al., PHARMACEUTICALS IN MEDICAL IMAGING, 1990, MacMillan Publishing Company, the disclosure of which is hereby incorporated by reference in its entirety. Briefly, in x-ray imaging techniques, transmitted radiation is used to produce an image or a series of images based upon overall tissue attenuation characteristics. X-rays pass through various tissues and are attenuated by scattering (i.e., reflection or refraction) or energy absorption. However, certain body organs, vessels and anatomical sites exhibit so little absorption of x-ray radiation that images of these body portions are difficult to obtain. To overcome this problem, radiologists routinely introduce an x-ray absorbing contrast medium into such body organs, vessels and anatomical sites.
Several classes of compounds have been explored as potential contrast agents. For CT, these classes include both small molecule and particulate contrast media. See, for example, Lin, “Radiopaques,” In, KIRK-OTHMER ENCYCLOPEDIA OF CHEMICAL TECHNOLOGY, Volume 20, pp. 907-930, John Wiley and Sons, New York, 1996. There currently exist classes of small molecule radiographic contrast agents useful for a broad range of diagnostic techniques, including angiography, arteriography, aortography, ventriculography, venography, urography, myelography, cholecystography, cholangiography, gastointestinal radiography, arthography and hysterosalpingography. Currently available x-ray contrast agents generally exhibit a lack of site directed delivery or compartmentalization. Consequently, large quantities of agent are normally required for imaging. It is, therefore, desirable to restrict the contrast agent to specific biological or anatomical compartments, particularly the blood pool, liver, kidney or spleen. This would reduce the overall amount of agent administered to achieve the desired contrast enhancement.
When small molecular contrast agents are used, maximum enhancement of major blood vessels takes place during the so-called vascular phase of contrast medium kinetics which occurs within about the first two minutes following the intravascular infusion or bolus injection of the contrast medium. This is because the plasma concentration of an intravascular contrast medium decreases rapidly as a result of vascular mixing, transcapillary diffusion of the medium from the circulation into the interstitial spaces, and renal excretion. Consequently, imaging of blood vessels must take place within a narrow time window, typically within a few minutes after infusion or injection of the x-ray contrast agent.
Currently, there is no commercially available x-ray contrast agent for imaging blood vessels which provides good contrast images of the vasculature for an extended period of time. Therefore, multiple injections are often required to visualize the vasculature adequately. Furthermore, arteriography, as currently practiced, typically requires percutaneous or surgical catheterization, fluoroscopic localization and multiple bolus arterial administrations to adequately visualize a given vascular region.
Although certain particulate radiopaque contrast agents are known in the art, these have principally been used to achieve improved visualization of the liver, kidney and through accumulation of the agent by the mononuclear phagocyte system (MPS) of the reticuloendothelial system (RES). The operative design principle behind these agents is control of particle size and surface coating to ensure phagocytization.
Particles that are rapidly phagocytized by the MPS are typically greater than 100 nanometers in size. For example, See, Violante et al.,
Acta Radiol Suppl.
374: 153-156 (1990); and Rubin etal.,
Invest Radiol
. Suppl 2: S280-S283 (1994). Another factor affecting the rate of phagocytization is the nature of the coating on the particle. For example, particles which do not acquire a serum protein coat, such as those coated with neutral dextran, healthy red cells and fat particles, are not phagocytized quickly, but remain longer in the blood pool. See, for example, U.S. Pat. No. 5,543,158, to Gref et al.; Knisely et al.,
I. Det, kgl. Danske Vidensk. Selskab, Biol. Skrifter
4: 1 (1948); and Violante and Fischer, “Particulate Suspensions as Contrast Media,” in, Handbook of Experimental Pharmacology, Vol. 73, RADIOCONTRAST AGENTS, Chapter 13.
Recent reports from the field of magnetic resonance imaging (MRI) have demonstrated that contrast agents that remain largely confined to the intravascular space in healthy tissue (i.e., macromolecular contrast agents) can be used to detect areas of injury and/or disease. The underlying mechanism allowing this detection is the transit of a predominantly intravascular agent through a region of metabolically or structurally altered or diseased vasculature into the interstitium of the surrounding tissue. This passive diffusion into the interstitium results in a pooling of the contrast agent in the interstitium. This pooling is reflected in an increase in the contrast medium concentration in the tissue relative to the blood concentration over time. See, for example, Ogan et al.,
Invest. Radiol.
22: 665-671 (1987); van Dijke et al.,
Radiology
198: 813-818 (1996); Schwickert et al.,
Radiology
198: 893-898 (1996); and Cohen et al.,
Invest. Radiol.
29: 970-977 (1995). In spite of its potentially far-ranging utility, this technique has yet to be exploited in the field of x-ray, and particularly CT imaging.
A method which utilized CT imaging in conjunction with a radiopaque contrast agent that remained principally confined to the intravascular space in healthy tissue, but which pass across the endothelial membrane of abnormal vasculature and pool in the interstitium in altered or diseased tissue would provide a significant advance in the field of medical diagnostic imaging. Surprisingly, the present invention provides such a method.
SUMMARY OF THE INVENTION
Because the microvascular endothelium of tumors and injured tissues exhibits high permeability rates relative to normal tissue, particulate agents passively diffuse from the intravascular space into the extravascular interstitial compartments of these tissues. The poorly developed or absent lymphatic system of tumors and some tissues limits the rate of movement of particles out of these tissues. This combination (enhanced permeability and retention) is used during imaging of these tissues. The tumors and injured tissues are seen by imaging as a time-dependent increased signal intensity in the interstitial s
Hollinden Gary E.
The Regents of the University of California
Townsend and Townsend / and Crew LLP
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