Water relaxation-based sensors

Abstract

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

What is claimed is: 
     
         1 . A system for detecting an analyte in an aqueous sample for periodic or continuous remote monitoring of an analyte concentration in a subject, the system comprising a water relaxation sensor for use in combination with a magnetic resonance relaxometer, the water relaxation sensor comprising:
 (a) a walled enclosure enveloping a well, wherein the wall comprises an opening for passage of the analyte into and out of the well;   (b) a plurality of superparamagnetic nanoparticles located within the well, each superparamagnetic nanoparticle comprising at least one moiety that is covalently or noncovalently linked to the nanoparticle; and, optionally   (c) at least one binding agent located within the well, wherein the opening is smaller in size than the nanoparticles, and is larger in size than the analyte;   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 well in an equilibrium controlled process, wherein the equilibrium is dependent upon, and changes with, analyte concentration; and wherein the water relaxation sensor is implanted subcutaneously in a subject; and   wherein the magnetic resonance relaxometer is used to measure spin-spin (T2) relaxation time of a fluid within the well and the spin-spin (T2) relaxation time measurement indicates a concentration of the analyte.   
     
     
         2 . The system of  claim 1 , wherein the wall comprises one or more openings for passage of the analyte into and out of the well, 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 system 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 system of  claim 1 , wherein the binding agent is absent. 
     
     
         5 . The system of  claim 4 , wherein:
 (a) when the analyte is absent, the well comprises substantially disaggregated nanoparticles; and   (b) when the analyte is present, the well comprises one or more nanoparticle aggregates, wherein the nanoparticle aggregate comprises nanoparticles bound to the analyte through the moiety.   
     
     
         6 . The system of  claim 1 , wherein the binding agent is present. 
     
     
         7 . The system of  claim 6 , wherein:
 (a) when the analyte is absent, the well 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 well comprises substantially disaggregated nanoparticles.   
     
     
         8 . The system of  claim 1 , wherein the nanoparticle aggregate has an overall size of at least about 100 nm. 
     
     
         9 . The system of  claim 1 , wherein a change in aggregation or disaggregation of the nanoparticles within the well alters the proton relaxation of water inside the well, but does not substantially alter the proton relaxation of water outside the well. 
     
     
         10 . The system of  claim 1 , wherein the reversible aggregation or disaggregation produces a measurable change in the T2 relaxation times of water inside the well. 
     
     
         11 . The system of  claim 10 , wherein the system is configured to (i) monitor fluctuation in the observed T2 relaxation time within the well, and (ii) determine the concentration of the analyte from the fluctuation. 
     
     
         12 . The system of  claim 1 , further comprising a plurality of water relaxation sensors for detection of two or more analytes. 
     
     
         13 . A method for detecting a target analyte in an aqueous sample by nuclear magnetic resonance, the method comprising:
 a. providing a mixture of a plurality of superparamagnetic nanoparticles, wherein each superparamagnetic nanoparticle comprises at least one moiety that is covalently or noncovalently linked to the superparamagnetic nanoparticle and, optionally, a binding agent;   b. contacting the mixture with a fluid sample suspected of containing the target analyte in a well, 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 well in an equilibrium controlled process, wherein the equilibrium is dependent upon, and changes with, analyte concentration;   c. exposing the well to a T2 measuring pulse sequence to produce a nuclear magnetic resonance relaxation signal and measuring one or more echoes in the signal;   d. identifying the height value of a single echo obtained in step (c); and   e. based on the height value of the one or more echoes, determining the presence or absence of target analyte-nanoparticle aggregates.   
     
     
         14 . The method of  claim 13 , 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. 
     
     
         15 . The method of  claim 13 , wherein the binding agent is absent. 
     
     
         16 . The method of  claim 15 , wherein:
 (a) when the analyte is absent, the well comprises substantially disaggregated nanoparticles; and   (b) when the analyte is present, the well comprises one or more nanoparticle aggregates, wherein the nanoparticle aggregate comprises nanoparticles bound to the analyte through the moiety.   
     
     
         17 . The method of  claim 13 , wherein the binding agent is present. 
     
     
         18 . The method of  claim 17 , wherein:
 (a) when the analyte is absent, the well 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 well comprises substantially disaggregated nanoparticles.   
     
     
         19 . The method of  claim 13 , wherein the nanoparticle aggregate has an overall size of at least about 100 nm. 
     
     
         20 . A method for detecting a target analyte in an aqueous sample by nuclear magnetic resonance, the method comprising:
 a. providing a mixture of a plurality of superparamagnetic nanoparticles, wherein each superparamagnetic nanoparticle comprises at least one moiety that is covalently or noncovalently linked to the superparamagnetic nanoparticle and, optionally, a binding agent;   b. contacting the mixture with a fluid sample suspected of containing the target analyte in a well, 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 well in an equilibrium controlled process, wherein the equilibrium is dependent upon, and changes with, analyte concentration;   c. exposing the well to a shifting magnetic field strength while measuring a nuclear magnetic resonance relaxation signal of the sample to produce a proton absorption peak; and   d. based on a broadness of the proton absorption peak, determining the presence or absence of target analyte-nanoparticle aggregates.   
     
     
         21 . The method of  claim 20 , 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. 
     
     
         22 . The method of  claim 20 , wherein the binding agent is absent. 
     
     
         23 . The method of  claim 22 , wherein:
 (a) when the analyte is absent, the well comprises substantially disaggregated nanoparticles; and   (b) when the analyte is present, the well comprises one or more nanoparticle aggregates, wherein the nanoparticle aggregate comprises nanoparticles bound to the analyte through the moiety.   
     
     
         24 . The method of  claim 20 , wherein the binding agent is present. 
     
     
         25 . The method of  claim 24 , wherein:
 (a) when the analyte is absent, the well 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 well comprises substantially disaggregated nanoparticles.   
     
     
         26 . The method of  claim 20 , wherein the nanoparticle aggregate has an overall size of at least about 100 nm. 
     
     
         27 . A method for detecting a target analyte in an aqueous sample by nuclear magnetic resonance, the method comprising:
 a. providing a mixture of a plurality of superparamagnetic nanoparticles, wherein each superparamagnetic nanoparticle comprises at least one moiety that is covalently or noncovalently linked to the superparamagnetic nanoparticle and, optionally, a binding agent;   b. contacting the mixture with a fluid sample suspected of containing the target analyte in a well, 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 well in an equilibrium controlled process, wherein the equilibrium is dependent upon, and changes with, analyte concentration; and   c. exposing the well to a T2 measuring pulse sequence to produce a nuclear magnetic resonance relaxation signal and measuring the free induction decay of the sample; and   d. based on a free induction decay of the sample, determining the presence or absence of target analyte-nanoparticle aggregates.   
     
     
         28 . The method of  claim 27 , 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. 
     
     
         29 . The method of  claim 27 , wherein the binding agent is absent. 
     
     
         30 . The method of  claim 28 , wherein:
 (a) when the analyte is absent, the well comprises substantially disaggregated nanoparticles; and   (b) when the analyte is present, the well comprises one or more nanoparticle aggregates, wherein the nanoparticle aggregate comprises nanoparticles bound to the analyte through the moiety.   
     
     
         31 . The method of  claim 27 , wherein the binding agent is present. 
     
     
         32 . The method of  claim 31 , wherein:
 (a) when the analyte is absent, the well 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 well comprises substantially disaggregated nanoparticles.   
     
     
         33 . The method of  claim 27 , wherein the nanoparticle aggregate has an overall size of at least about 100 nm.