IN VIVO FLUORESCENCE SENSORS, SYSTEMS, AND RELATED METHODS OPERATING IN CONJUNCTION WITH FLUORESCENT ANALYTES

• US 20090180962A1
• Filed: 02/19/2009
• Published: 07/16/2009
• 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
• Granted Patent: US 7,778,695 B2
• Time in Patent Office: Days
• US Class Current: 424/9.200
• 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 the in vivo clinical efficacy of a treatment 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;

emitting at least one excitation light signal from the at least one sensor to tissue proximate the at least one sensor;

detecting in vivo from the at least one sensor a signal corresponding to the fluorescence in the region of interest in the subject responsive to the administering step;

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

monitoring the signal over time to determine the localized fluorescence response of the subject to the administered fluorescently pre-labeled analyte, naturally fluorescent analyte and/or analyte that exhibits fluorescence when in the subject.

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 label is an excitation wavelength of from about 630 to about 660 nm that 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 label is an excitation wavelength of from about 400 to about 660=m that 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 detected fluorescence is used 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 a 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 is 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 is carried out to:

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

(b) measure the localized dose; and

/or (c) adjust the 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 monitoring is carried out to determine the expression of a protein resulting from the administered gene therapy.

14. A method according to claim 1, further comprising the step of processing the relayed signal to electronically generate a time-dependent measurement profile of fluorescence in the localized tissue.

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

16. A method according to claim 1, further comprising determining a phenotypic response to the fluorescent analyte based on said monitoring step.

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

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

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

(b) the rate of increase of detected fluorescence;

(d) the rate of decrease of detected fluoresence;

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

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

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

19. A method according to claim 1, wherein the fluorescent analyte is administered to the subject as a first test dose amount, said monitoring step predicts whether the response of the subject to the first dose indicates 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 fluorescent 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.

20. A method according to claim 1, wherein administering comprises administering the fluorescently pre-labeled analyte and wherein said monitoring step assesses the 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 monitored behavior of the labeled analyte.

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

22. 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 detecting step further comprises determining if the tumor is likely to be responsive to the planned treatment based on said detecting and monitoring steps, said method further comprising the steps of:

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

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

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

24. 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.

25. 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 detecting step detects the biokinetics of both normal and cancerous tissue.

26. 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.

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

28. 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.

29. 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.

30. A method according to claim 1, wherein said monitoring step serially determines the 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.