In vivo fluorescence sensors, systems, and related methods operating in conjunction with fluorescent analytes

• US 7,778,695 B2
• Filed: 02/19/2009
• Issued: 08/17/2010
• Est. Priority Date: 02/19/2003
• Status: Active Grant

• Current Assignee: SNC Holdings Corp.
• Original Assignee: Sicel Technologies, Inc.
• Inventors: Black, Robert D., Bolick, Natasha
• Primary Examiner(s): Casler; Brian
• Assistant Examiner(s): RAMIREZ, JOHN FERNANDO
• Application Number:
  US12/389,012
• Publication Number:
  US 20090180962A1
• Time in Patent Office: 544 Days
• Field of Search: 424/9.1, 424/9.6, 424/426, 600/476
• US Class Current: 600/476
• CPC Class Codes: A61B 5/0002 Remote monitoring of patients using telemetry, e.g. transmission of vital signals via a communication network A61B5/07 takes precedence; transmission systems for measured values G08C; transmission H04B; transmission of digital information H04L; wireless communication networks H04W
• CPC Class Codes: A61B 5/0071 by measuring fluorescence emission
• CPC Class Codes: A61B 5/0084 for introduction into the body, e.g. by catheters A61B5/1459 takes precedence
• CPC Class Codes: A61B 5/417 the bone marrow
• CPC Class Codes: A61K 49/0041 Xanthene dyes, used in vivo, e.g. administered to a mice, e.g. rhodamines, rose Bengal in vivo G01N
• CPC Class Codes: A61K 49/0058 Antibodies

Abstract

Methods, systems, devices and computer program product include: (i) administering a fluorescent analyte to a subject; (ii) repetitively emitting excitation light from an implanted sensor over a desired monitoring period; (iii) detecting fluorescence intensity in response to the excitation light using the implanted sensor that outputs the excitation light; and (iv) using data associated with the detected fluorescence intensity to perform at least one of: (a) calculate the concentration or dose of the analyte received proximate to the implanted sensor site; (b) evaluate the pharmacodynamic or pharmacokinetic activity of the fluorescent analyte; (c) confirm Ab attachment to a tumor site; (d) monitor a non-target site to confirm it is not unduly affected by a therapy; (e) monitor for changes in cellular properties; (f) use the calculated dose or concentration data to adjust or customize a therapeutic amount of the analyte administered to the subject; (g) confirm micelle concentration at a target site and then stimulate toxin release based on the confirmation; and (h) monitor for the expression of a protein produced from a gene therapy modification.

In particular embodiments, the intensity of the excitation signals emitted to the localized tissue can be varied in a predetermined manner to generate optical profiling data of the response of the tissue proximate the sensor.

Claims

1. A method for determining in vivo fluorescent activity in a subject, comprising:

positioning at least one sensor in tissue in a region of interest in the body;

administering a fluorescent analyte to a subject, the fluorescent analyte including at least one of a fluorescently pre-labeled analyte, a naturally fluorescent analyte and an analyte that exhibits fluorescence when internally administered to the subject, wherein the fluorescent analyte is administered from a source other than the at least one sensor;

emitting at least one excitation light signal from the at least one sensor to localized tissue proximate the at least one sensor, wherein the sensor projects the at least one excitation light signal outside the sensor at a distance sufficient to probe fluorescent activity at locations away from the sensor of several millimeters, wherein the excitation light signal has a wavelength that is between about 400 nm to about 900 nm;

detecting in vivo from the at least one sensor a signal corresponding to fluorescence in the subject responsive to the administering and emitting steps;

relaying the signal to a location external of the subject'"'"'s body;

electronically monitoring the relayed signal over time to electronically generate a time-dependent measurement profile of fluorescence in the localized tissue; and

determining in vivo fluorescent activity of the subject based on the monitoring step.

2. A method according to claim 1, wherein the administrating step comprises administering the fluorescently pre-labeled analyte, wherein the excitation light is able to penetrate tissue that is up to about 20 mm away, and wherein the excitation light signal wavelength is between about 630 to about 660 nm and generates fluorescence response wavelengths of from about 665 to about 695 nm.

3. A method according to claim 1, wherein administering comprises administering the fluorescently pre-labeled analyte, wherein the excitation light is able to penetrate tissue that is up to about 20 mm away, and wherein the excitation light signal wavelength is between about 400 to about 660 nm and generates fluorescence response wavelengths of from about 400 to about 695 nm.

4. A method according to claim 1, wherein the at least one sensor is adapted to be implanted in the body at subsurface depths up to about 25 cm.

5. A method according to claim 1, wherein the excitation light signal is generated by a pulsed laser diode.

6. A method according to claim 5, wherein the pulsed laser diode is operated with a frequency that is between about 10 Hz to about 1 KHz and with a duty cycle of between about 1 to about 10 percent.

7. A method according to claim 6, wherein the excitation signal has an associated operating level of from about 1 to about 20 mW.

8. A method according to claim 1, wherein the at least one excitation signal comprises a plurality of signals having a predetermined variation in output intensity, and wherein the detecting and monitoring steps are carried out to generate optical profiling data.

9. A method according to claim 1, wherein the at least one sensor is configured as a cylindrical encapsulated body having a cylindrical optical filter that selectively allows light associated with the fluorescent wavelengths of interest to travel into the interior of the sensor body.

10. A method according to claim 1, wherein administering comprises administering the fluorescently pre-labeled analyte, wherein the analyte is a therapeutic pharmaceutical drug configured to treat a selected physiologic or biologic condition, impairment, or disease, and wherein the fluorescence label is substantially transparent to the physiologic or biologic reaction of the drug in the body, and wherein said monitoring and determining steps are carried out to predict and/or assess the in vivo clinical efficacy and/or localized dose of a selected treatment.

11. A method according to claim 1, wherein the administrating step comprises administering the fluorescently pre-labeled analyte, wherein the analyte comprises an antibody configured to treat a selected physiologic or biologic condition, impairment, or disease, and wherein the fluorescence label is substantially transparent to the physiologic or biologic reaction of the antibody in the body, and wherein said monitoring and determining steps are carried out to:

(a) predict or assess the in vivo clinical efficacy of the antibody treatment;

(b) measure a localized dose of the antibody; and

/or (c) adjust a therapeutic dose amount administered to the subject.

12. A method according to claim 1, wherein the administrating step comprises administering the fluorescently pre-labeled analyte, wherein the pre-labeled analyte is a fluor-labeled pharmaceutical grade version of a gene therapy analyte configured for administration to a human subject, the labeled version of being substantially transparent to the in vivo behavior of the non-labeled version.

13. A method according to claim 12, wherein the determining step is carried out to determine the expression of a protein resulting from the administered gene therapy.

14. A method according to claim 1, wherein the determining step determines whether at least one of uptake and retention of the fluorescent analyte in the localized region is above a predetermined threshold level and/or a rate of the increase and decay in signal strength of the relayed signal over time.

15. A method according to claim 1, wherein the determining step comprises determining a phenotypic response to the fluorescent analyte.

16. A method according to claim 1, wherein said determining step determines an amount of time the detected relayed signal remains above a threshold level, a time the relayed signal takes to reach a peak level, a time the relayed signal takes to decay to below a threshold value, and a rate of decay of the relayed signal from a peak to a threshold value.

17. A method according to claim 1, wherein said monitoring step monitors, over a period of at least about 1 hour from a time said administering step is initiated, wherein the determining step comprises electronically generating a time-response profile with at least one predictor variable derived therefrom associated with uptake and/or retention of fluorescence in localized tissue, the predictor variable including at least one of:

(a) a time at which the detected peak fluorescence count occurs;

(b) a rate of increase of detected fluorescence;

(d) a rate of decrease of detected fluorescence;

(e) a time at which the detected fluorescence falls a predetermined amount below a threshold or the peak detected value;

(f) a duration that the detected signal increases in strength; and

(g) a time during the monitored period when the detected signal begins to decay.

18. A method according to claim 1, wherein the fluorescent analyte is administered to the subject as a first test dose amount, wherein the determining step predicts whether the response of the subject to the first dose indicates a the likelihood of a favorable response to a selected treatment, and wherein said method further comprises the step of administering a second therapeutic dose of the analyte to the subject if a favorable response is indicated, and wherein the second therapeutic dose amount is greater than the first test dose amount.

19. A method according to claim 1, wherein administering comprises administering the fluorescently pre-labeled analyte and wherein said determining step electronically assesses a behavior of the labeled analyte in vivo in the localized tissue and generates a predictive treatment outcome of a corresponding non-labeled analyte based on the behavior of the labeled analyte.

20. A method according to claim 1, wherein the sensor is disposed proximate or in a cancerous tumor, and wherein said determining step comprises determining cancer cell sensitivity or receptiveness to the fluorescent analyte.

21. A method according to claim 1, wherein at least one of the at least one sensors is positioned in the body so as to be proximate a tumor, and wherein said administering step is first carried out at a time which is proximate to a first planned therapeutic treatment, and wherein said determining step further comprises determining if the tumor is likely to be responsive to the planned treatment, said method further comprising the steps of:

administering a therapeutic treatment to the subject after the fluorescent analyte administering step;

repeating said step of administering the fluorescent analyte after said step of administering a therapeutic treatment wherein the determining step is carried out to monitor changes in cell kinetics following the therapeutic treatment.

22. A method according to claim 1, wherein the step of positioning is carried out so that the sensor is chronically implanted in the subject.

23. A method according to claim 1, wherein the at least one sensor is a plurality of sensors, each positioned in different locations in the body of the subject, and wherein each of the plurality of sensors can be serially polled.

24. A method according to claim 1, wherein the step of positioning is carried out so that at least one sensor is positioned proximate to cancerous tissue and another sensor is positioned proximate to normal tissue, and wherein said determining step evaluates biokinetics of both normal and cancerous tissue.

25. A method according to claim 1, wherein at least one of said sensors is implanted in localized tissue in the target region of interest and configured to operate wirelessly such that said relaying step is carried out telemetrically.

26. A method according to claim 1, wherein administering comprises administering the fluorescently pre-labeled analyte, wherein the labeled analyte is a labeled version of a pharmaceutical product undergoing clinical evaluation, and wherein the determining step comprises determining whether the pharmaceutical product reaches the region of interest and/or the pharmacodynamics and/or pharmacokinetics thereof.

27. A method according to claim 1, wherein said detecting step is at least periodically performed over a period of time extending for at least between about 24-48 hours.

28. A method according to claim 1, wherein said detecting step is at least periodically performed over a period of time extending from about several seconds to about several minutes.

29. A method according to claim 1, wherein said determining step serially determines fluorescent intensity of the fluorescent analyte in the localized tissue at a plurality of points in time and then determines at least one of the pharmacokinetic, the pharmacodynamic, the biokinetic response to the fluorescent analyte and/or the bioactivity in tissue in the region of interest.