Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Magnetic imaging agent
Reexamination Certificate
2001-07-11
2003-11-25
Hartley, Michael G. (Department: 1616)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Magnetic imaging agent
C424S009370, C436S173000
Reexamination Certificate
active
06652833
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
A molecular or macromolecular structure and method of use are disclosed in which an active-nucleus is functionalized in at least a transient interaction with a target carrier to form a sensor that selectively associates with a target substrate or environment to produce a detectable signal. More specifically, a functionalized active-nucleus complex sensor is described in which an active-nucleus gas such as hyperpolarized xenon, hyperpolarized helium, or sulfur hexafluoride, or active-nuclei
19
F derivatives are bound in a carrier structure having a binding region specific for a target species. Upon binding to the target species the active-nucleus produces a detectable nuclear magnetic resonance signal or is detectable as a magnetic resonance imaging contrast agent. A plurality of target specific sensors may be utilized in the assaying and screening of samples containing the plurality of targets under either in vivo or in vitro conditions.
2. Description of the Background Art
The detection of biological molecules and their interactions is a significant component of modern biomedical research. In current biosensor technologies, simultaneous detection is limited to a small number of analytes by the spectral overlap of their signals. Recent biosensor technologies exploit surface plasmon resonance (
1
), fluorescence polarization (
2
), and fluorescence resonance energy transfer as detection methods (
3
). Although the sensitivity of such techniques is excellent, it has proven challenging to extend these assays to multiplexing capabilities because of the difficulty in distinguishing signals from different binding events. While nuclear magnetic resonance (NMR) spectroscopy is able to finely resolve signals from different molecules and environments, the spectral complexity and low sensitivity of NMR spectroscopy normally preclude its use as a detector of molecular targets in complex mixtures. Notable successes (
4
,
5
) in the application of NMR to such problems are still limited by long acquisition times or a limited number of detectable analytes. Laser polarized xenon NMR benefits from good signal to noise and spectral simplicity with the added advantage of substantial chemical shift sensitivity.
U.S. Pat. No. 5,642,625 discloses a high volume hyperpolarizer for spin-polarized noble gas. A method and apparatus are presented that allow spin exchange between atoms of the noble gas and an alkali metal such as rubidium.
Described in U.S. Pat. No. 5,785,953 is a magnetic resonance imaging technique using hyperpolarized noble gases as contrast agents. In particular, hyperpolarized xenon and helium are utilized in spatial distribution studies.
The foregoing references/patents reflect the state of the art of which the applicant is aware and are tendered with the view toward discharging applicant's acknowledged duty of candor in disclosing information which may be pertinent in the examination of this application. It is respectfully submitted, however, that none of these references/patents teach or render obvious, singly or when considered in combination, applicant's claimed invention.
SUMMARY OF THE INVENTION
An object of the present invention is to disclose a sensor and method of use comprising an active-nucleus (guest) and target carrier (host) that generates an NMR and/or MRI detectable signal upon association with a biological target.
Another object of the present invention is to relate a biosensor and method of in vivo and in vitro assaying/screening use that comprises a functionalize active-nucleus complex that selectively binds to and signals the presence of a desired biological target species.
A further object of the present invention is to describe biosensors and methods of in vivo and in vitro assaying/screening use that comprises a plurality of functionalize active-nucleus complexes with each complex selectively binding to and signaling the presence of a desired biological target species or analyte.
Still another object of the present invention is to present a biosensor and method of use in which the biosensor comprises an active-nucleus bound to a target carrier in which when the target carrier binds to a target species/analyte a detectable signal is produced upon the binding or upon alterations in the target species/analyte or its environment after the binding.
Yet a further object of the present invention is to disclose a plurality of biosensors and a multiplexed method of use in which each of the biosensors comprises an active-nucleus bound to a target carrier in which when the target carrier binds to a target species/analyte a detectable signal is produced upon the binding or upon alterations in the target species/analyte or its environment after the binding, wherein all the biosensors' signals are simultaneously detectable.
Disclosed is a novel, functionalized active-nucleus sensor or biosensor that is directed to and signals the presence of a desired biological target species, often of biological origin or importance. An active-nucleus that presents a detectable signal to either nuclear magnetic resonance (NMR) or magnetic resonance imaging (MRI) techniques is utilized in conjunction with a target specific carrier that interacts with both the active-nucleus and a biological target substrate or environment. The active-nucleus is capable of at least a minimal transient binding to a targeting carrier. The targeting carrier associates with the target substrate or environment, thereby stimulating the production of or change in the detectable signal from the active-nucleus in a functionalized interaction. “Functionalized” implies that when the active-nucleus is bound, in at least a minimal transient manner, by the targeting carrier, that the active-nucleus then responds to and signals the association between the targeting carrier and the target substrate or environment.
Since the basic subject invention enables the creation of several extremely powerful and versatile sensors and techniques that have eluded researchers for many years, a number of related embodiments are disclosed below. One requirement for the subject invention is that the reporter nucleus be sufficiently “active” or capable of producing a signal that is detectable by NMR or MRI techniques. Hyperpolarized noble gases such as xenon and helium meet this requirement, as do other nuclei such as
19
F, if present in sufficiently high concentrations. Thus, “active” implies that the nucleus generates a suitable signal that is capable of detection by NMR (either in strong or weak magnetic fields) and/or MRI contrast procedures. Several relatively standard techniques now exist for hyperpolarizing noble gases and include optical pumping or spin exchange procedures.
It is important to appreciate that for the subject invention the signal produced by the functionalized active-nucleus is studied directly to follow the behavior of the biological target substrate or environment. For example, xenon (as indicated above, other suitable active-nuclei are also contemplated as being within the realm of this disclosure), has a chemical shift that is enormously sensitive to its local chemical environment. With the large xenon NMR signal created by optical pumping, the chemical shift can easily serve as a signature for the different chemical surroundings in which the xenon is found. Direct interaction between xenon and a target molecule has been observed by measuring the chemical shift and relaxation properties on xenon (in particular see, S. M. Rubin, M. M. Spence, B. M. Goodson, D. E. Wemmer, A. Pines,
Proceedings of the National Academy of Sciences of the United States of America
97, 9472-9475 (2000) that was part of the Provisional Application to which this application claims priority). However, the observation is of this direct contact may be limited by the weak binding of xenon (or other suitable active-nuclei) to many target molecules of interest. To enhance the binding of the xenon, for example, to the biological target species/substrate/molecule/analyte of i
Pines Alexander
Rubin Seth
Spence Megan
Wemmer David E.
Hartley Michael G.
O'Banion & Ritchey
Ritchey James M.
The Regents of the University of California
LandOfFree
Functionalized active-nucleus complex sensor does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Functionalized active-nucleus complex sensor, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Functionalized active-nucleus complex sensor will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3148449