1. A composition for imaging a cell having a first biomarker and a second biomarker that is different than the first biomarker, the composition comprising:
a first imaging probe comprising a first targeting moiety that is linked to a first reporter moiety via a linker region, the first targeting moiety specifically complexing with the first biomarker; and
a second imaging probe comprising a second targeting moiety that is linked to an second reporter moiety via a linker region, the second targeting moiety being different than the first targeting moiety and specifically complexing with the second biomarker;
wherein the first reporter moiety and the second reporter moiety form a signaling complex that produces a detectable signal when the first imaging probe and second imaging probe complex with first and second biomarkers of the cell.
2. The composition of claim 1, at least one of the first and second biomarkers being extracellular.
3. The composition of claim 1, at least one of the first and second biomarkers being intracellular.
4. The composition of claim 1, at least one of the first and second biomarkers being a cellular protease, a kinase, a protein, a cell surface receptor, fatty acid, or lipid.
5. The composition of claim 1, the first and second biomarkers being cell surface receptors associated with cancer.
6. The composition of claim 1, the targeting moiety being selected from the group consisting of synthetic compounds, natural compounds, macromolecular entities, bioengineered molecules, and small entities.
7. The composition of claim 6, the targeting moiety being selected from the group consisting of polypeptides, polynucleotides, lipids, small molecules, elemental compounds, antibodies, and antibody fragments.
8. The composition of claim 1, the linker region comprising at least one of a chemical or biological moiety.
9. The composition of claim 8, the chemical moiety being a polymer.
10. The composition of claim 8, the biological moiety comprising at least one peptide linker.
11. The composition of claim 10, the at least one peptide linker comprising a biotin-streptavidin-biotin linkage.
12. The composition of claim 1, the first reporter moiety comprising a contrast agent.
13. The composition of claim 12, the contrast agent being at least one of EgadMe or GB 137.
14. The composition of claim 1, the second reporter moiety including an activating molecule, the activating molecule comprising an enzyme.
15. The composition of claim 14, the enzyme being at least one of horseradish peroxidase, alkaline phosphatase, \u03b2-galactosidase, luciferase, or acetylcholinesterase, \u03b2-lactamase, alpha-secretases, or matrix metalloproteinases.
16. The composition of claim 14, the second imaging probe including first and second activating molecules.
17. A composition for determining a molecular signature of a cell having a first biomarker and a second biomarker that is different than the first biomarker, the composition comprising:
a first imaging probe comprising a first targeting moiety that is linked to a first reporter moiety via a linker region, the first targeting moiety specifically complexing with the first biomarker; and
a second imaging probe comprising a second targeting moiety that is linked to a second reporter moiety via a linker region, the second targeting moiety being different than the first targeting moiety and specifically complexing with the second biomarker;
wherein the first reporter moiety and the second reporter moiety form a signaling complex that produces a detectable signal when the first imaging probe and second imaging probe complex with first and second biomarkers of the cell;
wherein the molecular signature comprises the detectable signal.
18. The composition of claim 17, at least one of the first and second biomarkers being extracellular.
19. The composition of claim 17, at least one of the first and second biomarkers being intracellular.
20. The composition of claim 17, at least one of the first and second biomarkers being a cellular protease, a kinase, a protein, a cell surface receptor, fatty acid, or lipid.
21. The composition of claim 17, the first and second biomarkers being cell surface receptors associated with cancer.
22. The composition of claim 17, the targeting moiety being selected from the group consisting of synthetic compounds, natural products, macromolecular entities, and small entities.
23. The composition of claim 22, the targeting moiety being selected from the group consisting of polypeptides, polynucleotides, lipids, small molecules, elemental compounds, antibodies, and antibody fragments.
24. The composition of claim 17, the linker region comprising at least one of a chemical or biological moiety.
25. The composition of claim 24, the chemical moiety being a polymer.
26. The composition of claim 24, the biological moiety comprising at least one peptide linker.
27. The composition of claim 26, the at least one peptide linker comprising a biotin-streptavidin-biotin linkage.
28. The composition of claim 17, the first reporter moiety comprising a contrast agent.
29. The composition of claim 28, the contrast agent being at least one of EgadMe or GB 137.
30. The composition of claim 17, the second reporter moiety comprising an enzyme.
31. The composition of claim 30, the enzyme being at least one of horseradish peroxidase, alkaline phosphatase, \u03b2-galactosidase, luciferase, or acetylcholinesterase, \u03b2-lactamase, alpha-secretases, or matrix metalloproteinases.
33. The composition of claim 30, the second imaging probe including first and second activating molecules.
34. A method for imaging a cell having a first biomarker and a second biomarker that is different than the first biomarker, the method comprising the steps of:
contacting the cell with an imaging composition comprising first and second imaging probes, the first imaging probe comprising a first targeting moiety that is linked to a first reporter moiety via a linker region, the first targeting moiety specifically complexing with the first biomarker, the second imaging probe comprising a second targeting moiety that is linked to a second reporter moiety via a linker region, the second targeting moiety being different from the first targeting moiety and specifically complexing with the second biomarker, the first reporter moiety and the second reporter moiety forming a signaling complex that produces a detectable signal when the first imaging probe and second imaging probe complex with first and second biomarkers of the cell; and
detecting a signal, the signal being generated when the first imaging probe and second imaging probe complex with first and second biomarkers of the cell.
35. The method of claim 34, the cell being contacted with the imaging composition in vivo.
36. The method of claim 34, the cell being contacted with the imaging composition ex vivo.
37. The method of claim 34, the signal being detected by at least one imaging modality selected from the group consisting of optical, nuclear, and magnetic resonance imaging techniques.
38. A method for determining a molecular signature of a cell that is associated with a disease, the cell having a first biomarker and a second biomarker that is different than the first biomarker, the method comprising the steps of:
contacting the cell with an imaging composition, the imaging composition comprising first and second imaging probes, the first imaging probe comprising a first targeting moiety that is linked to a first reporter moiety via a linker region, the first targeting moiety specifically complexing with the first biomarker, the second imaging probe comprising a second targeting moiety that is linked to a second reporter moiety via a linker region, the second targeting moiety being different than the first targeting moiety and specifically complexing with the second biomarker, the first reporter moiety and the second reporter moiety forming a signaling complex that produces a detectable signal when the first imaging probe and second imaging probe complex with first and second biomarkers of the cell;
detecting a signal, the signal being generated when the first imaging probe and second imaging probe complex with first and second biomarkers of the cell; and
producing the molecular signature of the cell based on the detectable signal, the molecular signature indicating at least one of the type, stage, or severity of the disease.
39. The method of claim 38, the cell being contacted with the imaging composition in vivo.
40. The method of claim 38, the cell being contacted with the imaging composition ex vivo.
41. The method of claim 38, the signal being detected by at least one imaging modality selected from the group consisting of optical, nuclear, and magnetic resonance imaging techniques.
42. The method of claim 38, the molecular signature being indicative of a stage of the cell’s cell cycle.
43. The method of claim 38, the molecular signature being indicative of a type, stage, or severity of cancer.
44. The method of claim 38, the molecular signature being indicative of a type, stage, or severity of inflammation.
45. A method for treating a disease in a subject, the method comprising the steps of:
contacting a cell of the subject with an imaging composition, the cell having a first biomarker and a second biomarker that is different than the first biomarker, the imaging composition comprising first and second imaging probes, the first imaging probe comprising a first targeting moiety that is linked to a first reporter moiety via a linker region, the first targeting moiety specifically complexing with the first biomarker, the second imaging probe comprising a second targeting moiety that is linked to a second reporter moiety via a linker region, the second targeting moiety being different from the first targeting moiety and specifically complexing with the second biomarker, the first reporter moiety and the second reporter moiety forming a signaling complex that produces a detectable signal when the first imaging probe and second imaging probe complex with first and second biomarkers of the cell;
detecting a signal, the signal being generated when the first imaging probe and second imaging probe complex with first and second biomarkers of the cell;
producing the molecular signature of the cell based on the detected signal; and
treating the subject based on the molecular signature.
46. The method of claim 45, the molecular signature indicating at least one of the type, stage, or severity of the disease.
47. The method of claim 45, the step of treating the subject based on the molecular signature further comprising administering an effective amount of a therapeutic agent to the subject.
48. The method of claim 45, the cell being contacted with the imaging composition in vivo.
49. The method of claim 45, the cell being contacted with the imaging composition ex vivo.
50. The method of claim 45, the signal being detected by at least one imaging modality selected from the group consisting of optical, nuclear, and magnetic resonance imaging techniques.
51. The method of claim 45, the molecular signature being indicative of a stage of the cell’s cell cycle.
52. The method of claim 45, the molecular signature being indicative of a type, stage, or severity of cancer.
53. The method of claim 45, the molecular signature being indicative of a type, stage, or severity of inflammation.
54. A composition for imaging a cell having a first biomarker and a second biomarker that is different than the first biomarker, the composition comprising:
a first imaging probe comprising a first targeting moiety that is linked to an enzyme activated magnetic resonance contrast agent via a streptavidin linker, the first targeting moiety specifically complexing with the first biomarker; and
a second imaging probe comprising a second targeting moiety that is linked to a enzyme molecule or fragment thereof via a linker region, the second targeting moiety being different than the first targeting moiety and specifically complexing with the second biomarker;
wherein the enzyme activated magnetic resonance contrast agent of the first imaging probe and the enzyme or fragment thereof of the second imaging probe form a signaling complex that produces a detectable signal when the first imaging probe and second imaging probe complex with first and second biomarkers of the cell.
55. The composition of claim 54, the enzyme comprising \u03b2-galactosidase.
56. The composition of claim 55, the \u03b2-galactosidase activated magnetic resonance contrast agent of the first imaging probe being conjugated to biotin, the biotin linking the \u03b2-galactosidase activated magnetic resonance contrast agent to the streptavidin.
57. The composition of claim 56, the \u03b2-galactosidase activated magnetic resonance contrast agent conjugated to biotin being selected from the group consisting of:
wherein the coordinate metal ion (indicated by the circle) can include Gd(III), Fe(III), Mn(III), Y(III), Cr(III), Eu(III), Tb(III), andor Dy(III), and X can comprise a linker group.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
I claim:
1. A logic gate, comprising:
an input terminal for receiving an input signal with two possible logic signal values;
an output terminal for outputting an output signal with two possible logic signal values assigned two different logic voltage levels;
a logic circuit connected between said input terminal and said output terminal and supplied by a supply potential exceeding the logic voltage levels;
said logic circuit having a plurality of switching elements configured to operate according to the logic voltage levels, said logic circuit having an output path connected to said output terminal, said output path having at least two switching elements configured to operate according to the logic voltage levels, connected in series, and acting as a voltage divider.
2. The logic gate according to claim 1, wherein said switching elements are switching transistors.
3. The logic gate according to claim 1, wherein said output path is one of two reciprocally operating output paths with switching elements constructed and operating complementarily with respect to one another.
4. The logic gate according to claim 1, wherein said output path is one of two output paths constructed symmetrically with respect to one another and said output terminal forming a point of symmetry thereof.
5. The logic gate according to claim 1, wherein said output path is one of two output paths each having a further switching element connected in series with said at least two switching elements.
6. The logic gate according to claim 1, wherein said output path is one of two output paths each having a protective diode device for discharging leakage currents from said switching elements.
7. The logic gate according to claim 1, wherein the two logic voltage levels are substantially 3.6 volts and substantially 1.4 volts, and the supply potential is substantially 5 volts.
8. The logic gate according to claim 1, wherein said switching elements of said logic circuit are CMOS devices rated at 3.3 volt.
9. The logic gate according to claim 1, wherein said logic circuit is a circuit selected from the group consisting of a NOT gate, AND gate, NAND gate, OR gate, EXOR gate, NOR gate, and transmission gate.