# US 10,441,668 B2 · System and method for enhanced mass spectrometry imaging

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- Number: US 10,441,668 B2
- Document ID: US10441668B2
- Status: Granted
- Kind: B2
- Application number: 15/533,799
- Filed: 2015-12-08
- Published: 2017-12-28
- Granted: 2019-10-15
- Earliest claimed: 2014-12-08
- Assignees: University Health Network
- Applicants: University Health Network
- Inventors: Arash Zarrine-Afsar; David Anthony Jaffray
- Web page: https://patentgrep.com/patent/US10441668B2

## CPC

- A61K 49/106: {the complex-forming compound being cyclic, e.g. DOTA}
- A61K 49/00: Preparations for testing in vivo
- A61K 49/0438: {Organic X-ray contrast-enhancing agent comprising an iodinated group or an iodine atom, e.g. iopamidol}
- G01N 27/00: Investigating or analysing materials by the use of electric, electrochemical, or magnetic means (G01N3/00 – G01N25/00 take precedence; measurement or testing of electric or magnetic variables or of electric or magnetic properties of materials G01R)
- G01N 33/4833: {of solid biological material, e.g. tissue samples, cell cultures (tissue in vivo A61B5/00; cell suspensions G01N33/48735)}
- G01N 33/58: involving labelled substances (G01N33/53 takes precedence)
- H01J 49/0004: {Imaging particle spectrometry}
- H01J 49/105: {using high-frequency excitation, e.g. microwave excitation, Inductively Coupled Plasma [ICP]}
- G01N 2458/15: Non-radioactive isotope labels, e.g. for detection by mass spectrometry
- G01N 2560/00: Chemical aspects of mass spectrometric analysis of biological material
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)
- H01J: ELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS (spark-gaps H01T; electric arc lamps H05B31/00; particle accelerators H05H)

## Abstract

Various embodiments are described herein for a system and a method for identifying a region of interest in tissue using mass spectrometry. An agent administration component can be provided to administer an exogenous agent to the tissue. A sampling unit can also be provided to acquire a sample from the tissue. The sample can then be provided to a high sensitivity analysis platform, such as a mass analyzer, to analyze the sample and determine a distribution of the exogenous agent or a by-product of the exogenous agent within the tissue based on the analysis. The analysis platform can then identify the region of interest based on the distribution of the exogenous agent or the distribution of the by-product.

## Claims

### Claim 1

A method of identifying a region of interest in tissue, the method comprising:
administering an exogenous agent to the tissue, the exogenous agent being capable of forming a by-product in the tissue;
analyzing a sample based on the tissue using a high sensitivity platform comprising a mass spectrometer;
determining a distribution, optionally quantitative, of the by-product of the exogenous agent within the tissue based on the analysis of the sample; and
identifying the region of interest within the tissue based on the determined distribution of the by-product of the exogenous agent relative to tissue surrounding the region of interest.

### Claim 2 (depends on 1)

The method of claim 1, wherein the determining act further comprises determining a distribution of the exogenous agent in addition to the by-product of the exogenous agent.

### Claim 3 (depends on 2)

The method of claim 2, further comprising:
identifying a boundary of the region of interest based on the distribution of at least one of the exogenous agent, and the by-product of the exogenous agent relative to tissue surrounding the region of interest; and
displaying an image of the tissue with the boundary marked.

### Claim 4 (depends on 1)

The method of claim 1, wherein prior to the analyzing act the method comprises
acquiring the sample from the tissue after administration of the exogenous agent to the tissue; and
transporting the sample to the mass spectrometer using a transfer line by applying a positive pressure on the transfer line at a first end proximate to the tissue.

### Claim 5 (depends on 4)

The method of claim 4, wherein acquiring the sample comprises desorbing the sample from the tissue, the desorbing act selected from applying laser ablation vaporization, desorption electrospray ionization, or radio frequency ablation.

### Claim 6 (depends on 4)

The method of claim 4, further comprising ionizing the sample using inductively-coupled plasma, rapid evaporative ionization, or electrospray ionization prior to analyzing the sample unless the administered exogenous agent includes charged particles, or becomes ionized as an adduct.

### Claim 7 (depends on 1)

The method of claim 1, wherein prior to the analyzing act the method comprises obtaining the sample from the tissue using an ex vivo sampling technique.

### Claim 8 (depends on 1)

The method of claim 1, wherein the method comprises selecting the exogenous agent so that the at least one of the exogenous agent and the by-product of the exogenous agent has at least one of a mass to charge ratio peak and an elemental mass peak that is not endogenous to the tissue.

### Claim 9 (depends on 1)

The method of claim 1, further comprising selecting the agent from chelated metal containing agents and tumour specific metalloporphyrins, or chelated metal containing agents being Gadolinium based, ion oxide based, iron-platinum based, manganese based, or chromium based.

### Claim 10 (depends on 1)

The method of claim 1, further comprising selecting the exogenous agent from at least one of a metallic element, a heavy atom, and an isotopic variant that is not endogenous to the tissue, a metabolic precursor, an isotopic variant of a metabolic precursor, a moiety of a metabolic precursor or a plurality of exogenous sub-agents.

### Claim 11 (depends on 10)

The method of claim 10, wherein the at least one isotopic variant comprises an isotopic variant of an endogenous metabolic precursor, and the method comprises determining the distribution of a by-product of the isotopic variant of the endogenous metabolic precursor.

### Claim 12 (depends on 1)

The method of claim 1, wherein the exogenous agent is administered encapsulated in a lipidic structure.

### Claim 13 (depends on 1)

The method of claim 1, wherein the sample comprises a tissue sample, an ablated tissue sample, an ablation plume, a liquefied tissue sample, an extraction of the exogenous agent, or an extraction of the by-product of the exogenous agent.

### Claim 14

A system for identifying a region of interest in tissue, the system comprising:
a sampling unit configured to acquire a sample based on the tissue after administration of an exogenous agent to the tissue, the exogenous agent being capable of forming a by-product in the tissue; and
a high sensitivity platform comprising a mass spectrometer, the high sensitivity platform being coupled to the sampling unit to analyze the sample, the high sensitivity platform being configured to determine a distribution, optionally quantitative, of a by-product of the exogenous agent within the tissue based on a spectral analysis of the sample to determine spectral peaks due to the by-product of the exogenous agent that are not endogenous to the tissue and to identify the region of interest based on the determined distribution of the by-product of the exogenous agent relative to tissue surrounding the region of interest.

### Claim 15 (depends on 14)

The system of claim 14, wherein the high sensitivity platform is configured to determine a distribution of the exogenous agent in addition to the by-product of the exogenous agent based on a spectral analysis of the sample to determine spectral peaks due to the exogenous agent that are not endogenous to the tissue, and the exogenous agent and the by-product of the exogenous agent having at least one of a mass to charge ratio peak and an elemental mass peak that is not endogenous to the tissue.

### Claim 16 (depends on 14)

The system of claim 14, wherein the at least one isotopic variant comprises an isotopic variant of an endogenous metabolic precursor, and the high sensitivity platform is configured to determine the distribution of a by-product of the isotopic variant of the endogenous metabolic precursor.

### Claim 17 (depends on 14)

The system of claim 14, wherein the sampling unit comprises at least one of a desorption component configured to desorb the sample from the tissue, a vaporization component configured to vaporize the sample from the tissue, the desorption component comprises a laser ablation device; and an ionization device configured to ionize the sample from the tissue, the ionization device comprising an inductively-coupled plasma ionization device.

### Claim 18 (depends on 17)

The system of claim 17, further comprising a transportation unit including a transfer line configured to couple the sampling unit and the mass spectrometer to transport the sample to the mass analyzer unit, wherein the transfer line houses the at least one of the desorption component and the vaporization component.

### Claim 19 (depends on 14)

The system of claim 14, further comprising a transportation unit including a transfer line that is configured to couple the sampling unit and the mass spectrometer to transport the sample to the mass analyzer unit and the transfer line is configured to apply a positive pressure on the transfer line at a first end of the transfer line, the first end being proximate the tissue from which the sample is acquired.

### Claim 20 (depends on 19)

The system of claim 19, wherein at least one of the sampling unit and the transfer line comprises trackable markings; and the high sensitivity platform is configured to track the trackable markings to identify a location of the tissue where the sample was acquired.

### Claim 21 (depends on 14)

The system of claim 14, further comprising a display device; wherein the high sensitivity platform is further configured to identify a boundary of the region of interest; and the display device is configured to display an image of the tissue with the boundary marked.