Systems and methods for high-resolution in vivo imaging of biochemical activity in a living organism

Abstract

This invention relates to multifunctional detection agents useful for providing high-resolution, in vivo imaging of biochemical activity in a living organism. Methods of using these multifunctional detection agents may comprise administering them into a living organism, and then estimating the localization of the detection agent using one modality (i.e., MRI), while concurrently estimating the level of biological activity using a second modality (i.e., optical imaging). One of the multifunctional detection agents comprises a magnetic resonance component and an optical imaging component. The magnetic resonance component comprises a contrast agent that is always activated or “on”. The optical imaging component comprises a plurality of activatable contrast agents or dyes, at least two of which are different from one another, wherein at least one of the activatable contrast agents can be activated or turned “on” only in the presence of a particular event.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation-in-part of U.S. application Ser. No. 10 / 252,311 filed Sep. 23, 2002, the entire contents of which are incorporated herein by reference.FIELD OF THE INVENTION[0002]The present invention relates generally to the field of medical diagnostic imaging. More particularly, the present invention relates to the design and synthesis of multifunctional contrast agents that are operable for both magnetic resonance imaging (“MRI”) and optical imaging, and methods of using such agents to obtain high-resolution in vivo images of biochemical activity in a living organism.BACKGROUND OF THE INVENTION[0003]Magnetic resonance imaging (“MRI”) was established over two decades ago as a medical diagnostic technique that offers high-resolution anatomical information about the human body, and has since been used for the detection of a multitude of diseases. MRI creates images of a body using the principles of nuclear magnetic reso...

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Benefits of technology

[0015]Accordingly, the above-identified shortcomings of existing contrast agents and methods of using them are overcome by embodiments of the present invention. Embodiments of the present invention provide systems and methods that aid in the early detection of disease. These systems and methods allow for high-resolution in vivo imaging of the localization of biochemical activity in a living organism. Embodiments of the present invention may comprise multifunctional contrast agents that can be utilized in two different modalities concurrently. One embodiment comprises a multifunctional contrast agent that may be utilized in both MRI and optical imaging concurrently. Embodiments of these multifunctional contrast agents may comprise an always-activated first component for obtaining enhanced anatomical information and an activatable second component for obtaining enhanced functional information. In embodiments, these multifunctional contrast agents may comprise one activatable component that is activatable only in the presence of a predetermined event.

[0017]In accordance with the needs outlined above, embodiments of the present invention provide multifunctional detection agents, each comprising at least one activatable optical contrast agent or dye covalently linked to at least one magnetic resonance contrast agent. In one embodiment, the multifunctional detection agent comprises a magnetic resonance contrast agent covalently linked to both an optical dye and a quencher molecule, wherein the dye and quencher are linked such that when the multifunctional detection agent is excited with light of a certain wavelength, the quencher efficiently absorbs the emitted light so as to reduce the amount of light being detected by the optical detector. The magnetic resonance contrast agent may comprise a chelated gadolinium complex (i.e., Gd-DTPA or Gd-DOTA), a coated iron oxide nanoparticle, or the like. The linker can be designed so that close proximity of the dye and quencher molecule is achieved either through chemical bonds or through space. Furthermore, the linker may be designed such that, as the result of some biological or signaling process (i.e., enzyme cleavage), the proximity of the dye and the quencher is compromised (i.e., the distance between the dye and the quencher is increased), thereby allowing light to be emitted and detected by an optical imaging device.

[0019]One aspect of the present invention relates to the co-localization of the multifunctional agent. This co-localization is possible because the magnetic resonance contrast agent and the optical contrast agent / dye are covalently bound together. Another aspect of embodiments of the present invention is that the magnetic resonance component and the optical component are also covalently bound to a quencher molecule that, due to its close proximity to the dye, efficiently absorbs the emitted light of the excited optical contrast agent. Yet another aspect of the present invention is that the magnetic resonance contrast agent and the optical dye remain covalently bound while a biological signaling process (i.e., enzyme cleavage) diminishes the close proximity of the quencher molecule, thereby activating the optical contrast agent and turning it “on”. The optical signal produced by the activatable optical contrast agent is directly related to the biological signaling process, thereby allowing functional information to be detected.

[0020]The present invention has all the advantages associated with anatomical imaging using current magnetic resonance contrast agents, but also allows functional information to be obtained simultaneously via optical imaging. The multifunctional MRI / optical imaging contrast agents of the present invention make the simultaneous gathering of high-resolution anatomical and functional information possible. Preferably, the optical component of these contrast agents is only activated in the presence of a particular event (i.e., only when a particular enzyme is present in a person's body and light of a specific wavelength excites the optical contrast agent).

[0024]The activatable optical imaging component of the present invention comprises at least one optical dye, and may also comprise at least one quencher (which may also be a dye). As noted above, the optical dye and the quencher are different from one another. The magnetic resonance imaging component of the present invention allows enhanced anatomical information to be obtained, while the activatable optical imaging component allows enhanced functional / metabolic information to be obtained. Herein, “enhanced” means that the image or information obtained by using the multifunctional contrast agent is of improved quality over the image or information that would be obtained by using no contrast agent.

Problems solved by technology

Furthermore, the linker may be designed such that, as the result of some biological or signaling process (i.e., enzyme cleavage), the proximity of the dye and the quencher is compromised (i.e., the distance between the dye and the quencher is increased), thereby allowing light to be emitted and detected by an optical imaging device.

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