Water relaxation-based sensors

• US 8,535,949 B2
• Filed: 11/04/2009
• Issued: 09/17/2013
• Est. Priority Date: 05/09/2005
• Status: Active Grant

• Current Assignee: The General Hospital Corporation (Mass General Brigham, Inc.)
• Original Assignee: The General Hospital Corporation (Mass General Brigham, Inc.)
• Inventors: Josephson, Lee, Sun, Yi, Weissleder, Ralph
• Primary Examiner(s): BROWN, MELANIE YU
• Application Number:
  US12/612,126
• Publication Number:
  US 20100120174A1
• Time in Patent Office: 1,413 Days
• Field of Search: 436/518, 436/524, 436/525, 436/526, 436/536, 977/840, 977/953, 977/960, 435/7.1, 435/283.1, 435/287.2, 600/300, 600/309, 600/316
• US Class Current: 436/526
• 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 method of detecting an analyte in an aqueous sample for periodic or continuous remote monitoring of an analyte concentration in a subject, the method comprising:

(i) providing a water relaxation sensor comprising;

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

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

optionally,

(c) 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, to cause a reversible aggregation or disaggregation of the nanoparticles within the chamber in an equilibrium controlled process, wherein the equilibrium is dependent upon, and changes with, analyte concentration;

(ii) implanting the sensor into a subject subcutaneously; and

(iii) following step (ii), measuring the spin-spin (T2) relaxation time of a fluid within the chamber, wherein the spin-spin (T2) relaxation time measurement indicates the analyte concentration.

2. The method of claim 1, wherein the wall comprises one or more 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.

3. The method 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.

4. The method of claim 1, wherein the binding agent is absent.

5. The method of claim 4, wherein:

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

(b) when the analyte is present, the chamber comprises one or more nanoparticle aggregates, wherein the nanoparticle aggregate comprises nanoparticles bound to the analyte through the moiety.

6. The method of claim 1, wherein the binding agent is present.

7. The method of claim 6, 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.

8. The method of claim 1, wherein the nanoparticle aggregate has an overall size of at least about 100 nm.

9. The method of claim 1, wherein the change in nanoparticle aggregation between (i) and (ii) alters the proton relaxation of water inside the chamber, but does not substantially alter the proton relaxation of water outside the chamber.

10. The method of claim 1, wherein the change in nanoparticle aggregation between (i) and (ii) produces a measurable change in the T2 relaxation times of water inside the chamber.

11. The method of claim 1, further comprising the following steps:

(iv) following step (iii), measuring a second spin-spin (T2) relaxation time within the chamber; and

(v) on the basis of the difference between the T2 relaxation time of step (iii) and the second T2 relaxation time, determining whether the amount of analyte in the sample has changed,

wherein a fluctuation in the observed T2 relaxation time within the chamber indicates a fluctuation in the concentration of analyte.

12. The method of claim 1, wherein the T2 relaxation times is measured using a magnetic resonance imaging method.

13. The method of claim 1, further comprising providing a plurality of water relaxation sensors for detection of two or more analytes.