MOLECULAR AND CELLULAR IMAGING USING ENGINEERED HEMODYNAMIC RESPONSES

• US 20150018665A1
• Filed: 07/15/2014
• Published: 01/15/2015
• Est. Priority Date: 07/15/2013
• Status: Abandoned Application

• Current Assignee: Massachusetts Institute of Technology
• Original Assignee: Massachusetts Institute of Technology
• Inventors: Jasanoff, Alan Pradip, Slusarczyk, Adrian Lukas, Desai, Mitul, Barch, Mariya, Westmeyer, Gil G.
• Application Number:
  US14/332,099
• Publication Number:
  US 20150018665A1
• Time in Patent Office: Days
• US Class Current: 600/410
• CPC Class Codes: A61B 5/0075 by spectroscopy, i.e. measuring spectra, e.g. Raman spectroscopy, infrared absorption spectroscopy A61B5/0071 takes precedence
• CPC Class Codes: A61B 5/02028 Determining haemodynamic parameters not otherwise provided for, e.g. cardiac contractility or left ventricular ejection fraction
• CPC Class Codes: A61B 5/026 Measuring blood flow A61B3/1233, A61B3/1241 take precedence
• CPC Class Codes: A61B 5/0261 using optical means, e.g. infrared light
• CPC Class Codes: A61B 5/0263 using NMR
• CPC Class Codes: A61B 5/14546 for measuring analytes not otherwise provided for, e.g. ions, cytochromes
• CPC Class Codes: A61B 5/24 Detecting, measuring or recording bioelectric or biomagnetic signals of the body or parts thereof
• CPC Class Codes: A61B 5/4848 Monitoring or testing the effects of treatment, e.g. of medication
• CPC Class Codes: A61K 49/14 Peptides, e.g. proteins
• CPC Class Codes: C07K 14/575 Hormones derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin C07K14/665, e.g. corticotropin C07K14/695
• CPC Class Codes: C07K 14/585 Calcitonins
• CPC Class Codes: C07K 2319/50 containing protease site

Abstract

According to some aspects, the invention relates to methods and compositions for evaluation of hemodynamic responses (e.g., using molecular imaging) with high sensitivity.

Claims

1. A method for evaluating a tissue in a subject, the method comprising:

producing a hemodynamic response in a tissue of a subject by providing an effective amount of a vasoactive agent to the tissue;

obtaining an image representation of the tissue; and

evaluating the tissue based on a hemodynamic response detected in the image representation.

2. The method of claim 1, wherein the hemodynamic response is produced by providing to the tissue an exogenous vasoactive agent in a submicromolar concentration that is effective for inducing a hemodynamic response in the tissue

3. The method of claim 1, wherein the vasoactive agent is provided to the tissue by administering the vasoactive agent to the subject.

22. The method of claim 1, wherein the hemodynamic response comprises a change in blood volume in the tissue.

23. The method of claim 1, wherein the hemodynamic response comprises an increase in blood flow in the tissue.

24. The method of claim 1, wherein the hemodynamic response comprises a decrease in blood flow in the tissue.

25. The method of claim 1, wherein the hemodynamic response comprises changes in oxy/deoxyhemoglobin balance in the tissue.

26. The method of claim 1, wherein the tissue is neuronal tissue and wherein the hemodynamic response is associated with changes in neural activity.

27. The method of claim 26 further comprising determining that the hemodynamic response is associated with excitatory neural activity in the tissue.

28. The method of claim 26 further comprising determining that the hemodynamic response is associated with inhibitory activity in the tissue.

29. The method of claim 1, wherein the vasoactive agent is a molecule having the formula X¹-L¹-X²-L²-X³, in which X¹ is a blocking domain and/or ligand binding domain, L¹ and L² are independently linkers or absent, X² is a protease recognition site and/or a ligand or analog thereof, and X³ is a vasoactive molecule.

45. The method of claim 29, wherein the vasoactive molecule is calcitonin gene-related peptide (CGRP) or an engineered derivative thereof.

46. The method of claim 29, wherein the vasoactive molecule is adrenomedullin (ADM) or an engineered derivative thereof.

47. The method of claim 29, wherein the vasoactive molecule is Maxadilan (Max) or an engineered derivative thereof.

4-21. -21. (canceled)

30-44. -44. (canceled)

48-73. -73. (canceled)

74. A method for evaluating presence of a molecular analyte in a tissue, the method comprising:

providing to a tissue a vasoactive agent, the activity of which vasoactive agent is modulated by binding to an analyte, wherein modulation of the vasoactive agent results in a hemodynamic response in the tissue;

obtaining an image representation of the tissue; and

evaluating ligand binding by assessing in the image representation presence or absence of a hemodynamic response resulting from modulation of the vasoactive agent in the tissue.

75-101. -101. (canceled)

102. An engineered vasoactive agent having the formula X¹-L¹-X²-L²-X³, in which X¹ is a blocking domain and/or ligand binding domain, L¹ and L² are independently linkers or absent, X² is a protease recognition site and/or a ligand or analog thereof, and X³ is a vasoactive molecule.

103. The engineered vasoactive agent of claim 102, wherein X¹ is a blocking domain, L¹ is a linker, L² is absent, X² is a protease recognition site, and X³ is a vasoactive molecule.

104. The engineered vasoactive agent of claim 102, wherein X¹ is a ligand binding domain, L¹ is a linker, L² is absent, X² is a ligand or analog thereof, and X³ is a vasoactive molecule.

105. A method for evaluating a tissue in a subject, the method comprising:

producing a hemodynamic response in a tissue of a subject by providing an effective amount of a vasoactive agent to the tissue;

detecting spectroscopic signals indicative of the hemodynamic response; and

evaluating the tissue based on the hemodynamic response.

106. The method of claim 105, wherein the spectroscopic signals are detected using optical spectroscopy, magnetic resonance spectroscopy, or localized spectroscopy.