Magnetic probes for in vivo capture and detection of extracellular vesicles

• US 10,492,709 B2
• Filed: 10/14/2016
• Issued: 12/03/2019
• Est. Priority Date: 11/19/2015
• Status: Active Grant

• Current Assignee: Verily Life Sciences LLC (Alphabet Inc.)
• Original Assignee: Verily Life Sciences LLC (Alphabet Inc.)
• Inventors: Audeh, Mark, Klein, Joshua Simon, Giannetti, Anthony M, Morton, Stephen, Higbie, James Michael
• Primary Examiner(s): Winakur, Eric F
• Application Number:
  US15/293,558
• Publication Number:
  US 20170143233A1
• Time in Patent Office: 1,145 Days
• CPC Class Codes: A61B 2562/0223 Magnetic field sensors
• CPC Class Codes: A61B 2562/0238 Optical sensor arrangements for performing transmission measurements on body tissue
• CPC Class Codes: A61B 5/0022 Monitoring a patient using a global network, e.g. telephone networks, internet
• CPC Class Codes: A61B 5/0071 by measuring fluorescence emission
• CPC Class Codes: A61B 5/0515 Magnetic particle imaging
• CPC Class Codes: A61B 5/14546 for measuring analytes not otherwise provided for, e.g. ions, cytochromes
• CPC Class Codes: A61B 5/1455 using optical sensors, e.g. spectral photometrical oximeters
• CPC Class Codes: A61B 5/681 Wristwatch-type devices
• CPC Class Codes: A61K 49/0058 Antibodies
• CPC Class Codes: A61K 49/0093 Nanoparticle, nanocapsule, nanobubble, nanosphere, nanobead, i.e. having a size or diameter smaller than 1 micrometer, e.g. polymeric nanoparticle
• CPC Class Codes: B03C 1/288 disposed at the outer circumference of a recipient
• CPC Class Codes: B03C 1/30 Combinations with other devices, not otherwise provided for
• CPC Class Codes: B03C 2201/18 Magnetic separation whereby the particles are suspended in a liquid
• CPC Class Codes: B03C 2201/26 for use in medical applications

Abstract

Body-mountable devices are provided to detect the presence or status of an analyte in subsurface vasculature of a body by detecting fluorescent reporters that are bound to instances of the analyte in the subsurface vasculature. Such devices further operate to exert an attractive magnetic force on magnetic nanoparticle-containing probes that are configured to bind to the analyte, thus concentrating the analyte proximate the devices by magnetically exerting attractive forces on such probes that are bound to instances of the analyte. The analyte can be an extracellular vesicle that is characteristic of a cancer, and a body-mountable device as described herein could be used to detect such extracellular vesicles in a portion of subsurface vasculature such that a presence or status of a tumor could be determined based on an amount, presence, or other detected property of the extracellular vesicle.

Claims

1. A body-mountable device comprising:

a magnetic flux source that, when mounted to an external body surface, can exert an attractive magnetic force on probes disposed in a portion of subsurface vasculature, wherein the exerted magnetic force is sufficient to collect the probes within the portion of subsurface vasculature, and wherein each probe comprises one or more magnetic nanoparticles and includes multiple binding sites that enable the probe to bind to multiple instances of an analyte such that an instance of the analyte that is bound to the probe can further bind to a fluorescent reporter that is separate from the probe;

a sensor comprising a light emitter and a light detector; and

a controller operably coupled to the sensor, wherein the controller comprises a computing device programmed to perform controller operations comprising;

operating the light emitter, during a detection period, to illuminate the probes collected within the portion of subsurface vasculature, wherein the detection period is a specified period of time relative to at least one of a timing of introduction of the probes into a body to which the device is mounted, a timing of introduction of the fluorescent reporter into the body to which the device is mounted, or a timing of mounting the device to the body;

operating the light detector, during the detection period, to detect light emitted from fluorescent reporters bound to instances of the analyte that are bound to the collected probes in response to the illumination; and

detecting the analyte based on the detected light.

2. The body-mountable device of claim 1, wherein the analyte is related to a presence or status of a tumor in the body.

3. The body-mountable device of claim 1, wherein the analyte comprises a particular type of extracellular vesicle that is produced by a tumor.

4. The body-mountable device of claim 3, wherein each probe is configured to selectively bind to multiple different types of extracellular vesicles including the particular type of extracellular vesicle.

5. The body-mountable device of claim 4, wherein each probe includes at least one of an anti-CD81 antibody, an anti-CD63 antibody, an anti-CD9 antibody, or an anti-ALIX antibody.

6. The body-mountable device of claim 1, wherein each probe selectively binds to the analyte.

7. The body-mountable device of claim 6, wherein the probes and the fluorescent reporters comprise respective different binding agents that selectively bind to the analyte.

8. The body-mountable device of claim 1, wherein the controller is operably coupled to the magnetic flux source, and wherein the controller operations further comprise:

operating the magnetic flux source, during a first period of time, to exert a first magnetic force, wherein the first magnetic force is insufficient to collect the probes proximate the magnetic flux source; and

operating the magnetic flux source, during a second period of time, to exert a second attractive magnetic force that that is sufficient to collect the probes proximate the magnetic flux source.

9. The body-mountable device of claim 1, wherein the body-mountable device comprises a wearable device.

10. A method comprising:

introducing probes into a body, wherein each probe comprises one or more magnetic nanoparticles and includes multiple binding sites that enable the probe to bind to multiple instances of an analyte such that an instance of the analyte that is bound to the probe can further bind to a fluorescent reporter that is separate from the probe;

introducing the fluorescent reporter into the body, wherein the fluorescent reporter selectively binds to the analyte;

applying a magnetic flux to the body to exert an attractive magnetic force the probes in a portion of subsurface vasculature of the body, wherein the exerted magnetic force is sufficient to collect the probes within the portion of subsurface vasculature;

illuminating the probes collected within the portion of subsurface vasculature;

detecting light emitted from fluorescent reporters bound to instances of the analyte that are bound to the collected probes in response to the illumination; and

detecting the analyte based on the detected light.

11. The method of claim 10, wherein the analyte is related to a presence or status of a tumor in the body.

12. The method of claim 11, further comprising:

providing an indication of a presence or status of the tumor in response to detecting the analyte.

13. The method of claim 10, wherein the analyte comprises a particular type of extracellular vesicle that is produced by a tumor.

14. The method of claim 13, wherein each probe is configured to selectively bind to multiple different types of extracellular vesicles including the particular type of extracellular vesicle.

15. The method of claim 14, wherein each probe includes at least one of an anti-CD81 antibody, an anti-CD63 antibody, an anti-CD9 antibody, or an anti-ALIX antibody.

16. The method of claim 10, wherein each probe selectively binds to the analyte.

17. The method of claim 16, wherein the probes and the fluorescent reporters comprise respective different binding agents that selectively bind to the analyte.

18. The method of claim 10, wherein the magnetic flux is applied by a body-mountable device that comprises:

a magnetic flux source that is operable to produce the applied magnetic flux; and

a sensor comprising a light emitter and a light detector, wherein illuminating the probes collected within the portion of subsurface vasculature comprises operating the light emitter to produce the illumination, and wherein detecting light emitted from fluorescent reporters in response to the illumination comprises operating the light detector to detect the emitted light.

19. The method of claim 18, wherein the method further comprises:

operating the magnetic flux source, during a first period of time, to exert a first magnetic force, wherein the first magnetic force is insufficient to collect the probes in the portion of subsurface vasculature proximate the magnetic flux source; and

operating the magnetic flux source, during a second period of time, to exert a second attractive magnetic force that that is sufficient to collect the probes in the portion of subsurface vasculature proximate the magnetic flux source.