Water relaxation-based sensors

• US 20060269965A1
• Filed: 05/09/2006
• Published: 11/30/2006
• Est. Priority Date: 05/09/2005
• Status: Abandoned Application

• Current Assignee: The General Hospital Corporation (Mass General Brigham, Inc.)
• Original Assignee: The General Hospital Corporation (Mass General Brigham, Inc.)
• Inventors: Sun, Yi, Weissleder, Ralph, Josephson, Lee
• Application Number:
  US11/431,247
• Publication Number:
  US 20060269965A1
• Time in Patent Office: Days
• US Class Current: 435/7.100
• CPC Class Codes: A61B 5/14503 invasive, e.g. introduced into the body by a catheter or needle or using implanted sensors A61B5/1459, A61B5/1464, A61B5/1473, A61B5/1482, A61B5/14865 take precedence
• CPC Class Codes: G01N 27/745 for detecting magnetic beads used in biochemical assays concerning the assays G01N33/54326; sensors therefor G01R33/1269; automatic analysers therefor G01N35/0098
• CPC Class Codes: G01N 33/54326 Magnetic particles
• CPC Class Codes: G01N 33/54366 Apparatus specially adapted for solid-phase testing
• CPC Class Codes: G01R 33/465 applied to biological material, e.g. in vitro testing
• CPC Class Codes: G01R 33/50 based on the determination of relaxation times , e.g. T1 measurement by IR sequences; T2 measurement by multiple-echo sequences

Abstract

This invention relates to magnetic resonance-based sensors and related methods.

Claims

1. A water relaxation-based sensor for detecting the presence of an analyte in a sample, the sensor comprising:

(i) a walled enclosure enveloping a chamber, wherein the wall comprises an opening for passage of the analyte into and out of the chamber;

(ii) a plurality of magnetic nanoparticles located within the chamber, each nanoparticle having at least one moiety that is covalently or noncovalently linked to the nanoparticle; and

optionally,

(iii) at least one binding agent located within the chamber;

wherein the opening is smaller in size than the nanoparticles, and is larger in size than the analyte; and

wherein the moiety and the analyte each bind reversibly to the binding agent, when present;

or the analyte binds reversibly to the moiety.

2. The sensor of claim 1, wherein the opening is smaller in size than the binding agent.

3. The sensor of claim 1, wherein the wall comprises a plurality of openings for passage of the analyte into and out of the chamber, wherein each of the openings is smaller in size than the nanoparticles and the binding agent, and each of the openings is larger in size than the analyte.

4. The sensor of claim 1, wherein the moiety comprises a carbohydrate, an antibody, an amino acid, a nucleic acid, an oligonucleotide, a therapeutic agent or a metabolite thereof, a peptide, or a protein.

5. The sensor of claim 1, wherein the moiety comprises a molecular fragment of the analyte being detected or a molecular fragment of a derivative, isostere, or mimic of the analyte being detected.

6. The sensor of claim 1, wherein the moiety is linked to the nanoparticle by a functional group comprising —

NH—

, —

NHC(O)—

, —

(O)CNH—

, —

NHC(O)(CH₂)_nC(O), —

(O)C(CH₂)_nC(O)NH—

, —

NHC(O)(CH₂)_nC(O)NH—

, —

C(O)O—

, —

OC(O)—

, or —

SS—

, and wherein n is 0 to 20.

7. The sensor of claim 6, wherein the functional group is —

NHC(O)(CH₂)_nC(O)NH—

.

8. The sensor of claim 7, wherein n is 2.

9. The sensor of claim 1, wherein the binding agent is absent.

10. The sensor of claim 9, wherein the moiety comprises a protein.

11. The sensor of claim 9, wherein:

(a) when the analyte is absent, the chamber comprises substantially disaggregated nanoparticles; and

(b) when the analyte is present, the chamber comprises a nanoparticle aggregate, wherein the nanoparticle aggregate comprises nanoparticles bound to the exogenous analyte through the moiety.

12. The sensor of claim 1, wherein the binding agent is present.

13. The sensor of claim 12, wherein the binding agent comprises a protein or a monoclonal antibody.

14. The sensor of claim 12, wherein the moiety comprises a molecular fragment of the analyte being detected or a molecular fragment of a derivative, isostere, or mimic of the analyte being detected.

15. The sensor of claim 12, wherein:

(a) when the analyte is absent, the chamber comprises a nanoparticle aggregate, wherein the nanoparticle aggregate comprises nanoparticles bound to the binding agent through the moiety; and

(b) when the analyte is present, the nanoparticles are displaced from the binding agent by the analyte, and the chamber comprises substantially disaggregated nanoparticles.

16. The sensor of claim 1, wherein the opening has a size of from about 1 kDa to about 3 kDa.

17. The sensor of claim 1, wherein each of the nanoparticles has an overall size of from about 30 nm to about 60 nm.

18. The sensor of claim 11 or 15, wherein the nanoparticle aggregate has a an overall size of at least about 100 nm.

19. The sensor of claim 11 or 15, wherein the change in nanoparticle aggregation between (a) and (b) alters the proton relaxation of water inside of the chamber, but does not substantially alter the proton relaxation of water outside of the chamber.

20. The sensor of claim 19, wherein the change in nanoparticle aggregation between (a) and (b) produces a measurable change in the T2 relaxation times of water inside the chamber.

21. The sensor of claim 1, wherein the moiety comprises a chiral compound.

22. The sensor of claim 1, wherein the moiety comprises a carbohydrate.

23. The sensor of claim 1, wherein the moiety comprises the structure:

24. The sensor of claim 1, wherein the binding agent is a protein that comprises at least two binding sites.

25. The sensor of claim 1, wherein the binding agent is a protein that comprises at least four binding sites.

26. The sensor of claim 1, wherein the binding agent is a protein that binds to a carbohydrate.

27. The sensor of claim 26, wherein the carbohydrate is glucose.

28. The sensor of claim 27, wherein the protein is conconavalin A.

29. The sensor of claim 1, wherein the binding agent comprises a monoclonal antibody, a polyclonal antibody, or a oligonucleotide.

30. The sensor of claim 1, wherein the magnetic nanoparticles each comprise a magnetic metal oxide.

31. The sensor of claim 30, wherein the magnetic metal oxide comprises a superparamagnetic metal oxide.

32. The sensor of claim 30, wherein the metal oxide comprises iron oxide.

33. The sensor of claim 32, wherein each of the magnetic nanoparticles is an amino-derivatized cross-linked iron oxide nanoparticle.

34. The sensor of claim 1, wherein the nanoparticles are substantially aggregated.

35. A method of detecting an analyte in an aqueous sample, the method comprising:

(i) providing the sensor of claim 1;

(ii) measuring relaxation times of the water inside of the chamber of the sensor in the absence of the analyte or under conditions that mimic the absence of the analyte;

(iii) contacting the sensor with the sample;

(iv) measuring relaxation times of the water inside of the chamber of the sensor; and

(v) comparing the T2 relaxation times measured in step (ii) and step (iv);

wherein a change in T2 relaxation times measured in step (iv) relative to the T2 relaxation times measured in step (ii) indicates the presence of the analyte.

36. The method of claim 35, wherein the analyte is a monovalent analyte.

37. The method of claim 35, wherein the analyte is a multivalent analyte.

38. The method of claim 35, wherein the change in the T2 relaxation times is measured using a magnetic resonance imaging method.

39. The method of claim 35, wherein the change in the T2 relaxation times is measured using a magnetic resonance non-imaging method.

40. The method of claim 35, wherein the analyte is a carbohydrate.

41. The method of claim 35, wherein the analyte is glucose.

42. The method of claim 35, wherein the analyte is chiral.

43. The method of claim 42, wherein the chiral analyte is present together with one or more optically active moieties in the sample.

44. The method of claim 43, wherein the chiral analyte is present together with a stereoisomer of the chiral analyte in the sample.

45. The method of claim 44, wherein the chiral analyte is present together with an enantiomer of the chiral analyte in the sample.

46. The method of claim 42, wherein the chiral analyte is an amino acid.

47. The method of claim 35, wherein the analyte is a nucleic acid or an oligonucleotide.

48. The method of claim 35, wherein the analyte is a therapeutic agent or a metabolite of a therapeutic agent.

49. The method of claim 35, wherein the analyte is peptide or a protein.

50. The method of claim 35, wherein steps (ii) and (iv) comprise measuring T2 relaxation times.

51. The method of claim 50, wherein an increase in T2 relaxation times measured in step (iv) relative to the T2 relaxation times measured in step (ii) indicates the presence of the analyte.