Patent Application
20160124063
Magnetic relaxometry has been proposed to locate and measure solid tumors and other disease with fixed sites in vivo. See, e.g., PCT/US2010/055729; PCT/US2011/028746; PCT/US2011/039349; U.S. Ser. No. 13/870,925 filed Apr. 25, 2013; U.S. Pat. No. 8,447,379 issued May 21, 2013; each of which is incorporated herein by reference. The present invention provides methods and apparatuses for assessing disease expressed in cells or other substances circulating in a body.
Superparamagnetic nanoparticles are conjugated with antibodies or other targeting agents that preferentially bind to a disease marker, using processes known in the art and processes like those described in the references mentioned elsewhere herein. Targeting agents can comprise, as examples, antibodies that are specific to markers such as cell surface antigens on cancer cells, antibody fragments, small molecules, or any other substance that will bind the nanoparticle to a marker for disease. The specificity of the targeting agent contributes to the specificity of the invention. For example, nanoparticles using her-2 antibodies as a targeting agent will bind with cells expressing her-2; while nanoparticles using an EGFR as a targeting agent will bind with cells expressing EGFR, generally encompassing a greater number of cells and wider range of cell types.
The targeted nanoparticles (nanoparticles conjugated with a targeting agent) are introduced into the circulatory system of a subject, either animal or human. While in the circulatory system, if they encounter a fixed tumor (or other site with receptors for the targeting agent), the targeting agent will bind to the receptors and the nanoparticle will be effectively removed from circulation (at least for a time). If the site to which the nanoparticle was bound breaks free, e.g., a cancer cell breaks free of the fixed tumor and enters the circulatory system, then the nanoparticle will re-enter the circulatory system attached to the much larger cell.
If a targeted nanoparticle encounters a targeted site in the circulatory system, e.g., by encountering a circulating tumor cell, then the nanoparticle will be bound to the circulating cell and accompany it through the circulatory system.
The presence in the circulatory system of targeted cells (or other substances with receptors for the specific targeting agent) can be an indicator of disease. As an example, cancer tumors can shed cells into the circulatory system. The presence of such cells can indicate the presence of a tumor. Such circulating tumor cells can also be indicators that a tumor might metastasize to another location.
A magnetic relaxometry measurement system can be placed in proximity to the circulatory system of the subject. As an example, such a system can be placed on a wrist next to veins in that region. Other sites near blood flow can also be suitable. Such a system can also be made indwelling, and be placed within an artery or vein. Such a system can also be placed in an extracorporeal blood loop. The system can be mounted semipermanently, as with a wristwatch; can be mounted with clothing, such as gloves; and can be configured as a separate measurement device that is used to make measurements only when a subject is nearby. Since magnetic relaxometry involves measuring magnetic fields, it is generally preferable to place the sensors close to the region to be measured. If frequent, or near-continuous, monitoring is desired, then mounting such as with a wristwatch, can be preferable. The measurement system can also comprise communications with a remote system for control of the measurement system, data collection from the measurement system, analysis of data from the measurement system, or a combination thereof. For example, a wrist-mounted measurement system can be placed in wired or wireless communication with a smart phone or computer, wherein the smart phone or computer controls the measurement system and analyses data from the measurement system.
A magnetic relaxometry system involves a magnetization facility and a sensor facility. The magnetic characteristics of the nanoparticles determine the timing of the measurement. It has been found that iron oxide nanoparticles of about 25 nm in diameter are suitable for a measurement with a 0.75 second magnetization pulse followed by a magnetic field measurement over about 3 seconds. The 3 second measurement time allows Neel relaxation of nanoparticles that have bound to relatively large objects (such as cells) to be distinguished from randomization of magnetic moments to Brownian motion of nanoparticles that have not bound to such objects.
The blood flow characteristics of the region to be sampled can determine the configuration of the magnetic relaxometry system. The magnetization system and sensor system can be separated by a distance such that nanoparticles magnetized by the magnetization system are within the measurement region of the measurement system during the appropriate time after magnetization. Using the example numbers above, the sensor system can be positioned downstream from the magnetization system a distance that nanoparticles will traverse in about 0.5 to 3 seconds.
In operation, the magnetic relaxometry system can detect when nanoparticles bound to the targeted substance are in the measurement region of the magnetic relaxometry system. Such detection can be used for various purposes, depending on the targeting agent. As examples: (a) If a specific tumor antigen is targeted, then the detection of such tumor cells by the system can indicate that a tumor of that type is present, and that further tests are indicated. (b) If a tumor is known or suspected, then nanoparticles targeting that tumor type can be used. The nanoparticles will be expected to bind to the solid tumor at the fixed site. If bound nanoparticles are subsequently detected by the system, then it can be inferred that the tumor is shedding cells and possibly metastasizing, possibly indicating that more aggressive treatment is indicated. (c) A targeting agent that targets markers that are common to many disease types, e.g., EGFR or VEGF, can be used. The detection of those cells by the system can indicate that more specific tests are needed. (d) A plurality of targeting agents can be used, each specific to a type of disease to be monitored. The system can detect when any of the targeted cells or diseases have been encountered, providing a general screen for a plurality of diseases. More specific tests can be used to follow up a positive result from the more general screen.
Analysis of the results of the measurement can comprise various techniques. A basic magnetic relaxometry measurement can provide information concerning the number of bound nanoparticles that were present in the measurement region by determining the magnetic moment of the particles exhibiting the characteristic Neel relaxation. The system can look for any measurement above zero if a sensitive detection is desired. If the targeting agent targets a substance that is normally present, then the system can look for a measurement above a threshold, e.g., a predetermined threshold (as in the common PSA test) or a determined threshold (as when looking for an increase or decrease in the presence of a targeted substance). The system can also look for patterns in the measurement, such as variations that might correlate with time of day or physical exertion. The system can also look for frequency of occurrence, e.g. if a cell is detected once per day as opposed to once per hour. The system can also look for measurement changes following occurrences such as chemotherapy, specific diet choices or changes, other medications or therapies.
The magnetic properties of the nanoparticles can also be used to urge the nanoparticles, and especially the nanoparticles that have bound to targeted substances, to particular regions. For example, an appropriate magnetic field can be used to encourage nanoparticles to remain in the measurement region for extended periods. As another example, an appropriate magnetic field can be used to urge nanoparticles to the portion of the body that is being measured, e.g., an arm if a wristwatch-like configuration is used.
Using the magnetic properties to encourage the presence of the targeted substance in a predetermined region of the body can improve the effective sensitivity of the magnetic relaxometry measurement. If can also be used to enrich the region with the targeted substance, so that a blood draw for immunohistochemistry or other analysis can be done in that region and the effective sensitivity of that procedure also improved.
The presence of nanoparticles on the targeted substance can also be beneficial after blood has been drawn. The targeted substance can be preferentially removed from the blood sample for further analysis, for example by magnetic separation as described in PCT/US2010/0514417 and U.S. Ser. No. 13/399,733 filed Feb. 17, 2012; each of which is incorporated herein by reference.
The present invention has been described in connection with various example embodiments. It will be understood that the above description is merely illustrative of the applications of the principles of the present invention, the scope of which is to be determined by the claims viewed in light of the specification. Other variants and modifications of the invention will be apparent to those of skill in the art.
This application claims priority to U.S. provisional 62/072,293, filed Oct. 29, 2014, which is incorporated herein by reference.
| Number | Date | Country | |
|---|---|---|---|
| 62072293 | Oct 2014 | US |
