REAL-TIME MOLECULAR IMAGING AND MINIMALLY-INVASIVE DETECTION IN INTERVENTIONAL CARDIOLOGY

Abstract

A catheter is disclosed for locating radiation tagged tissue within a mammalian body and treating tagged tissue or untagged tissue adjacent to the tagged tissue in a single procedure. The catheter includes in or on a distal end thereof one or more detectors for locating labeled tissue. A lumen extending from a proximal end of said tube to the distal end of said tube, includes a retractable and extendable needle positioned adjacent the distal end of said tube for delivering a liquid treatment modality. the alternative the injector for delivering the treatment modality may be placed adjacent to the catheter for delivery of the treatment.

Claims

1. A catheter for locating and treating tagged tissue within a human body comprising: a hollow conduit steerable through a vessel within the human body, said hollow conduit including in or on a distal end thereof one or more detectors for locating labeled tissue within the human body, a lumen extending from a proximal end of said hollow conduit to the distal end of said hollow conduit, and a probe with an electrically conductive tip positioned within said lumen, the electrically conductive tip adjacent the distal end of said hollow conduit and within said lumen, the electrically conductive tip configured to delivery electrical energy or provide ablation to tagged tissue to be treated.

2. The catheter of claim 1 further including a location indicator in or on a distal portion of the catheter.

3. The catheter of claim 2 wherein the location indicator is a signal transmitting position sensor.

4. The catheter of claim 3 wherein the location indicator comprises radiopaque makers.

5. The catheter of claim 2 further including a CCD camera in or on a distal portion of the catheter.

6. The catheter of claim 2 further including one or more electrodes for sensing electrical signals from the heart.

7. A catheter for locating and treating tagged tissue within a human body comprising: a first probe steerable through a vessel within the human body, said first probe including in or on a distal end thereof one or more detectors for locating labeled tissue within the human body, and a. a tube steerable through said vessel adjacent to said first probe adapted to receive a retractable and extendable second probe, said second probe having an electrically conductive tip positioned in said tube with the electrically conductive tip adjacent the distal end of said tube and steerable to a location of the labeled tissue, or b. a retractable and extendable second probe with an electrically conductive tip steerable through said vessel adjacent to said first probe, said second probe adapted to be positioned with the electrically conductive tip of the probe adjacent the labeled tissue, the electrically conductive tip configured to delivery electrical energy for providing ablation to tagged tissue to be treated.

8. A method of treating cells, tissue or organs within a mammalian body to enhance the functioning of said cells, tissue or organs, wherein said cells, tissue or organs have a deficiency or malfunction (target tissue), comprising: delivering a labelled compound to the cells, tissue or organs, said labelled compound having a specific affinity to the cells, tissue or organ so as to form tagged tissue, so that tagged tissues can be distinguished from tissue not tagged (untagged tissue), using the tagged tissue for guidance in performing a therapeutic procedure, and delivering a treatment modality to untagged or tagged tissue.

9. The method of claim 8 wherein the treatment modality comprises the delivery of cells, genes, polymers, inhibitory microRNAs, DNA, plasmids, chemicals, enzymes, growth factors, medicinal compounds or combinations thereof.

10. The method of claim 8 wherein the treatment modality comprises the use of ablation instruments.

11. The method of claim 8 wherein the procedure for producing tagged tissue comprises locating target tissue using a catheter with radiation detectors positioned in or on the distal end thereof and delivering tissue-specific radiolabeled compounds to the target tissue, the procedure including an injector integral with or adjacent to the catheter for detection.

12. The method of claim 8 wherein the procedure for producing tagged tissue comprises locating target tissue using a catheter with radiation detectors positioned in or on the distal end thereof and delivering tissue-specific radiolabeled compounds to the target tissue, the procedure including an ablation probe within or adjacent to the catheter used for detection.

13. The method of claim 8 wherein said method is performed while the mammalian body is positioned a PET scanner or Gamma camera scanner.

14. The method of claim 13 wherein images are obtained from the PET scanner or gamma camera scanner are displayed simultaneously with images of the location of the labelled tissue, the tip of the catheter, and the location of the treatment deliver injector or probe.

15. A beta probe for placement within a body organ comprising a catheter having multiple radiation detectors on a tip thereof, the radiation detectors mounted on a flexible band configured to simultaneously place more than one radiation detector against a surface of the body organ.

16. The beta probe of claim 15 wherein the flexible band is configured in the form of a loop to provide additional contact with the surface of the body organ.

Description

DESCRIPTION OF DRAWING

[0027] FIG. 1A is a cut-away side view of a first embodiment of a radiation detection catheter incorporating features of the invention showing a needle in a stored position and including a plastic scintillator coupled to a solid state photomultiplier.

[0028] FIG. 1B is a cutaway end view of the catheter of FIG. 1A.

[0029] FIG. 2A is a cut-away side view of the radiation detection catheter embodiment of FIGS. 1A with the needle in an extended orientation incorporating features of the invention.

[0030] FIG. 2B is a cutaway end view of the catheter of FIG. 2A.

[0031] FIG. 3A is a cut-away side view of an embodiment of a radiation detection catheter incorporating features of the invention with a second, different shaped needle in a stored position, said catheter including a forward facing detector.

[0032] FIG. 3B is a cutaway end view of the catheter of FIG. 3A.

[0033] FIG. 4A is a cut-away side view of a third embodiment of a radiation detection catheter with two detectors, including a gamma or x-ray detector incorporating features of the invention with a third version of a needle in a stored view.

[0034] FIG. 4B is a cutaway end view of the catheter of FIG. 4A.

[0035] FIG. 5A is a cut-away side view of a fourth embodiment of a radiation detection catheter including a gamma or x-ray detector and a position sensor incorporating features of the invention with the third version of the needle in a stored view.

[0036] FIG. 5B is a cutaway end view of the catheter of FIG. 5A.

[0037] FIG. 6A is a cut-away side view of a fifth embodiment of a radiation detection catheter including a gamma or x-ray detector and a CCD camera incorporating features of the invention with the third version of the needle in a stored view.

[0038] FIG. 6B is a cutaway end view of the catheter of FIG. 6A.

[0039] FIG. 7A is a cut-away side view of a sixth embodiment of a radiation detection catheter including a gamma or x-ray detector, an electrode and a laser incorporating features of the invention with the third version of the needle in a stored view.

[0040] FIG. 7B is a cutaway end view of the catheter of FIG. 7A.

[0041] FIG. 8A is a cut-away side view of a further embodiment of a radiation detection catheter including a gamma or x-ray detector and further including an electrode for measuring heart electrical activity and a biopsy needle.

[0042] FIG. 8B is a cutaway end view of the catheter of FIG. 8A.

[0043] FIG. 9A is a cut-away side view of a further embodiment of a radiation detection catheter including two detectors, a needle for injection, a position sensor for tracking, a laser for photo-excitation, a biopsy port and an electrode for sensing and measuring heart electrical activity and devices for delivery of RF or cryo ablation.

[0044] FIG. 9B is a cutaway end view of the catheter of FIG. 9A.

[0045] FIG. 10 shows a catheter incorporating features of the invention inside the ventricle of the heart.

[0046] FIG. 11 shows a detector-catheter incorporating features of the invention inside the ventricle of the heart and a separate injection catheter.

[0047] FIG. 12A shows a flexible beta camera comprising multiple radiation detectors on a flexible backing attached to the distal end of a catheter.

[0048] FIG. 12B shows the beta camera of FIG. 12A on the end of a catheter curved into a form to match the shape of the inside wall of the myocardium.

[0049] FIG. 13 illustrates the catheter tip with beta camera positioned within the heart with the beta camera curved to contact the interior wall of the heart, therapy delivering catheter or an injector or ablation device being separately introduced adjacent thereto.

[0050] FIG. 14 illustrates the flexible beta camera in conformal apposition to the inside of the heart, and the needle positioned to deliver treatment material. Also illustrated is electrodes placed between each beta camera.

[0051] FIG. 15 is an enlarged view of the distal end of the delivery catheter with alternating electrodes and beta cameras.

[0052] FIG. 16 shows the flexible 1-dimensional beta camera and detector-catheter incorporating features of the invention inside the ventricle of the heart with a separate injection catheter prior to injection, including ablation means.

[0053] FIG. 17A is a cutaway side view of a detector-catheter that has radioactive markers 300 attached to its body so it can be seen by PET or gamma camera and correlate it with the location of the abnormal heart tissue.

[0054] FIG. 17B is a cutaway end view of the catheter of FIG. 17A.

[0055] FIG. 18A is a further variation of the detector catheter of FIG. 17A detector catheter having and additional detector for optical, infra-red, or ultraviolet radiation.

[0056] FIG. 18B is a cutaway end view of the catheter of FIG. 18A.

[0057] FIG. 19 is a further version of FIG. 12A showing the Beta camera formed into a flexible loop.

[0058] FIG. 20 shows a nuclear image on a PET or SPECT display along with an ultrasound or x-ray image illustrating an intersection of beta ray counts from labeled heart tissue with electrophysiological results.

DETAILED DESCRIPTION

[0059] Described herein is series of theragnostic devices that feature a flexible, narrow gauge catheter with a retractable needle and, in some embodiments, a solid state beta detector capable of high sensitivity measurement of the radioactivity of the endocardial surface of tagged heart tissue. Theragnostic is a term developed to describe treatment modalities which combine diagnostic and therapeutic capabilities into a single agent, such as a single device. Disclosed herein are hybrid catheter-based system that can be delivered percutaneously to detect molecularly-targeted radiotracer signals, for example on the endocardial surface, and in such an instance direct intramyocardial delivery of therapeutics using molecular or radiotracer guidance to maximize treatment benefits. One potential application of this technology is the intramyocardial delivery of therapeutics (e.g. stem cells, therapeutic polymers, etc.) to injured myocardium following myocardial infarction.

[0060] A radiation-detection catheter can be used to enter the chambers of the heart in a minimally-invasive taken up by the tissue of the myocardial surface, or structures immediately adjacent thereto or into viable or dysfunctional heart tissue. Additionally, the catheter can contain a retractable needle connected to a flowable treatment source by a thin tube for delivery and injection of such therapeutic materials into the myocardium. These therapeutic materials can consist of cells, genes, polymers, inhibitory microRNAs, DNA, plasmids, chemicals, enzymes, growth factors, or a variety of medicinal compounds or combinations thereof. The intent of the devices and procedures shown and described herein is to provide a better means to locate tagged tissue, for example tissue tagged with a radioactive compounds, and to deliver a therapeutic composition directly to the vicinity of the tagged location in real time (in a single procedure), and is not intended to be limited by the method of tagging or the tissue treatment modality. It should be noted that tissue tagging is not limited to radiation tagging and other modalities, such as tagging with fluorescent or phosphorescent compounds can be used in conjunction with optical visualization techniques. Further, while the examples set forth herein are directed to the delivery of therapeutic material to the heart, the catheter described herein is not limited to therapeutic delivery to heart tissue and is contemplated to be useful to deliver therapeutic compositions to any tissue or organ in the body which can be reached by a catheter or similar tubular device including, but not limited to, the intestinal tract, bladder, kidney, liver, brain, lungs, etc.

[0061] In a first embodiment, the catheter contains one or more electrodes that detect the electrical signals of the myocardium and help localization during electrophysiology.

[0062] In another embodiment the catheter also contains a detector that is preferentially sensitive to beta rays.

[0063] In a further embodiment, the catheter also contains a detector that is sensitive to gamma rays and/ or x-rays.

[0064] In a still further embodiment, the catheter also contains two detectors in tandem, one for detection of beta rays and the other for detection of gamma and/or x-rays.

[0065] In still further embodiment, the catheter can also include light detectors, electrodes and/or lasers, the electrodes suitable for detecting electrical activity or delivering an electrical pulse or stimulus.

[0066] In still further embodiment, the catheter can also include a biopsy needle or other means for removing a small piece of the myocardial tissue.

[0067] In still further embodiment, the catheter can also include means to deliver RF or cryo-ablation.

[0068] FIG. 1A shows the tip and distal end of a catheter 20 with side viewing capability. FIG. 1B is a cut-away end view of the same catheter The catheter contains a hollow conduit, preferably a micro plastic tube 1, such as a Tygon plastic tube, that is connected to a needle 2 (for example a 30 gauge needle). The detector comprises a plastic scintillator 3 connected to a solid state photomultiplier 4. A plastic scintillator is preferred due to its selective sensitivity to beta rays and insensitivity to gamma rays.

[0069] FIGS. 2A and 2B illustrate the same catheter 20 as in FIGS. 1A and 1B with the needle 2 extended forward, as best shown in the front view, FIG. 2B. The outside jacket of the catheter 6 is stiff enough for guidance. However, if necessary, a guidewire can be used and the catheter can have an additional lumen for receiving the guidewire used to aid in placement of the catheter. Cables or electrical conduits 5 carry the signals from the detector to an outside monitor (not shown) for measurement, display and placement guidance.

[0070] FIGS. 3A and 3B show a catheter 30 with a front-viewing detector 12 mounted on the distal end thereof. The needle, or ablation tool 9 in its retracted position can be seen in the front view 3B. One skilled in the art will recognize that once the catheter is positioned adjacent the tissue to be treated the needle or ablation tool can be extended for injecting the treatment modality, or electrical or cryo ablation directly into the targeted tissue. Also shown is the tube 1 attached to the needle 9 that carries the treatment material for injection.

[0071] FIGS. 4A and 4B show a different needle or ablation tool arrangement comprising a straight needle or ablation tool in a dual detector catheter 40. A second detector 13 sensitive to gamma or x-rays is connected to a multi-wire cable 12. Once the labeled tissue 106, 113, 123, 144 (see FIGS. 10, 11, 13 and 16) is located the needle or the ablation tools can be extended to inject the treatment material into the labeled tissue or deliver electrical ablation or cryo-ablation.

[0072] FIGS. 5A and 5B show a catheter 50 containing fiber optics 14 that is capable of detecting luminescence light emitted by a tracer that was injected into the tissue or systemically delivered and preferentially absorbed by target tissue.

[0073] FIGS. 6A and 6B show a catheter 60 containing a small CCD camera 15 that is capable of detecting luminescence light emitted by a tracer that was injected into the tissue or, alternatively providing a visual image of targeted tissue.

[0074] FIGS. 7A and 7B show a catheter 70 containing an electrode 16 for measurement of the electrical activity of the heart tissue, or delivering electrical stimulation to the heart, as well as a laser 17 to activate fluorescent compounds that can be injected, or otherwise placed, into the tissue. Alternatively, the laser can be used to deliver ionizing radiation to the tissue or to ablate the tissue surface.

[0075] FIGS. 8A and 8B show a catheter 70 containing an electrode 16 for measurement of the electrical activity of the heart tissue, as well as an electromagnetic position sensor 18 to track the position of the catheter and correlate it to the position of other catheters or devices being used in the procedure.

[0076] FIGS. 9A is a cut-away side view of a further embodiment of a radiation detection catheter including two detectors, a needle for injection, position sensor for tracking, a laser for photo excitation, a biopsy port, an electrode for sensing electrical activity, and a mean for delivery of RF or cryo-ablation 19.

[0077] FIG. 9B is a cutaway end view of the catheter of FIG. 9A.

[0078] FIG. 10 shows a detector-catheter 101 incorporating features of the invention positioned inside the left ventricle 103 of the heart 105. This detector catheter has one detector 104 and incorporates a tube and needle 102 for injecting medicinal compounds, therapeutic cells, or genetic material.

[0079] FIG. 11 is a variation of the detector-catheter 110 and its position sensor 111 and detector 112, inside the left ventricle of the heart. The injection catheter or ablation tool 114 is not part of the detector 112 but is placed separately into the left ventricle so the operator has more control of the placement of location of the lesion 113, and injection or ablation procedures by utilizing the information provided by the position sensor 115.

[0080] FIG. 12A shows a 1-Dimensional beta camera 118 with radiation detectors 117 attached to the end of a placement catheter 116. A position sensor 119 is also shown.

[0081] FIG. 12B shows the 1-Dimensional beta camera 118 in a deployed position. The beta cameras are mounted on a flexible backing which can be bent to take the form of the myocardium inner wall by pulling on a cable 120 attached to the distal end of the flexible backing, the cable extending through the length of the placement catheter 116.

[0082] FIG. 13 shows the 1-Dimensional beta camera 122 deployed into the heart, the flexible backing bent to conform to the myocardium inner wall in order to find the radiolabeled lesion 123. A position sensor 124 is attached to this beta camera. In FIG. 13 the injector or ablation tool 125 is shown as separate from the detector catheter with its position sensor 126.

[0083] FIG. 14 shows a variation of the flexible 1-Dimensional beta camera 127 of FIGS. 12A and 12B with radiation detectors 128 and the injector needle or ablation tool 129 extending from a lumen in the delivery catheter. The device shown also includes position sensors 111, 115, 119, 124, 126 (see FIGS. 11, 12A, 13) on or adjacent to the beta camera or treatment needle or ablation tool.

[0084] FIG. 15 is an enlarged view of the distal end of the placement catheter with the 1-Dimensional beta camera in its bent configuration, with electrodes 130 positioned between each radiation detector 131 for mapping electrical activity of the heart or delivering ablation.

[0085] FIG. 16 is another view of the 1-Dimensional beta camera 145 deployed in the heart 143 for detecting the radioactive tagged portions 144 thereof, and an integral injection needle 146 (or ablation device).

[0086] FIG. 17A is a cutaway side view of a detector-catheter 70 that has radioactive markers 200, (see FIG. 17B) attached to its body so it can be seen by PET or a gamma camera and correlated with the location of the abnormal heart tissue.

[0087] FIG. 17B is a cutaway end view of the catheter of FIG. 17A.

[0088] FIG. 18A is a further variation of the detector catheter of FIG. 17A detector catheter having an additional detector 300 for optical, infra-red, or ultraviolet radiation.

[0089] FIG. 18B is a cutaway end view of the catheter of FIG. 18A.

[0090] FIG. 19 is a further version of FIG. 12A showing the beta camera formed on a flexible loop. Two 1-Dimensional beta cameras similar to the one depicted in FIGS. 12A and 12B, are shown joined together to form a loop. The beta cameras 61 on the loop are pivoted around the central axis of the catheter when deployed in the heart. They are mounted on a flexible backing which can be bent to take the form of the myocardium inner wall by pulling on a cable 62 attached to the distal end of the flexible backing, the cable extending through the length of the placement catheter. The two portions of the loop of beta cameras each touch separate portions of the wall of the heart chamber to provide better apposition.

[0091] FIG. 20 illustrates the co-registered combined information of external nuclear imaging with PET or SPECT, displaying the results of electrophysical study together with the results of beta ray count rates, to provide a comprehensive map for guiding therapy.

[0092] A computer 701 is used to co-register the nuclear image of the heart with the x-ray and ultrasound image 702 and display them on a display screen 703 along with the results of the electrophysiological study 704 and the results of beta ray count rates 705 This provides a simultaneous, comprehensive map of electrophysiologic and molecular activity of the heart for guided therapy.

[0093] Described below are various novel methods for therapy using the catheters described herein based on real-time characterization of myocardial tissue utilizing radiopharmaceuticals.

EXAMPLE 1

Evaluation of a Single-Detector Catheter in a Pig Heart with Infarct

[0094] As an evaluation of the method and the instrument described and discussed in regard to FIG. 1, a flexible theragnostic beta-detection catheter was constructed by coupling a 11 mm piece of plastic scintillator to a silicon photomultiplier and mounting the combination on a catheter as described below with flexible 60 cm long conduit extending the length of the catheter. The plastic scintillator was selected for its high efficiency positron detection and minimal gamma ray sensitivity, which reduces background signals and increases spatial resolution. A Tygon tube with outer diameter of 1.5 mm was also placed in the thin-walled catheter together with the detector and the flex circuit. The catheter tip also included a retractable 25 G needle for therapeutic delivery, which can be accessed via an attached injection port at the catheter base.

[0095] Myocardial infarctions (MI) were created in Yorkshire pigs (n=4) via 90 min balloon occlusions of the distal left circumflex arteries. Pigs were then injected with 0.5 mCi/kg 18FDG 1 week post-MI and sacrificed 90 min following injection. Hearts were imaged ex vivo via PET/CT. 18FDG signals of infarct/periinfarct zones were measured using the above described theragnostic catheter and a gamma well counter.

[0096] Catheter-based endocardial measurements of 18FDG injected intramyocardially in biologically-relevant activities at depths of 1 mm in a bovine heart, have been demonstrated. The catheter device demonstrates a concentration-dependent relation to signal strength, recording values of 2 and 21 counts per second (CPS) for the 1 and 10 micro Ci samples, respectively. The sensitivity of the detector was 3000 CPS/micro Ci when in direct contact with a 1 mm.sup.2 source of 18FDG. The difference in magnitude of signals detected in direct contact and in tissue (1 mm deep injections) reflects the limited range of 18F positrons in tissue (Rmax=2.4 mm). This contributes to high spatial resolution radiotracer detection to guide therapeutic delivery.

[0097] The beta-detection catheter registered consistently reproducible signals on the endocardial surface following post-MI injection of 18FDG. Myocardial sections containing infarct and peri-infarct tissue demonstrated heterogeneous 18FDG uptake at 1 week post-MI. Beta-detection catheter measurements show reasonable visual agreement with 18FDG PET/CT images and good visual and numerical correlation with gamma well counting data. The beta-detection catheter registered consistently reproducible signals on the endocardial surface following post-MI injection of 18FDG. Myocardial sections containing infarct and peri-infarct tissue demonstrated heterogeneous 18FDG uptake at 1 week post-MI.

[0098] In another procedure a post-MI patient was injected with F-18 labeled Annexin-V one or two hours prior to the procedure. Annexin-V accumulates in tissue that is undergoing apoptosis. The catheter includes at least one detector that is predominantly sensitive to positrons. After the area of myocardium that has highest uptake of Annexin-V is located using this detector, therapeutic compounds are injected into the myocardium. The injector can be an integral part of the detector catheter or a separate simultaneously positioned injector. Because the Annexin-V has accumulated in tissue that is undergoing apoptosis, the injected compound containing stem cells or angiogenic genes or factors can result in rehabilitation of the infarcted tissue, or the peri-infarcted tissue, and improve the heart's function.

[0099] Other radiolabeled compounds that are specific to infarcted or peri-infarcted tissue can also be used in this method. Alternatively, F-18 labeled FDG, which is attracted to health tissue, can be used and the probe will locate areas of the myocardium that has low or no FDG as areas of chronic infarction for injection with the therapeutic compound. Alternatively, F-18 FDG can be high in regions of acute reperfusion injury following myocardial infarction, or in other chronic inflammatory states like sarcoidosis or myocarditis. Once located, acute myocardial infarction can be treated with local therapies to promote repair and reduce adverse post-MI remodeling, including cell, gene and polymer therapies. In the cases of sarcoidosis or myocarditis the device can be used to direct a myocardial biopsy for diagnostic purposes.

[0100] Further, the therapeutic cells can be labeled with a radioactive isotope that emit gamma rays, such as Tc-99m. A few minutes after injection of these cells, a gamma probe catheter can be used to verify the accumulation of these therapeutic cells in the myocardium and not into the blood pool. Another way to verify the intra-myocardial injection is to mix a colloidal radioactive solution into the therapeutic injectant. Alternatively, a fluorescent colloidal solution can be added to the injectant, and an appropriate light detector placed into the myocardium can be used to verify the implantation of the therapeutic cells or other materials into the appropriate tissues. This light detector can be a part of the original radioactive detector catheter or paced as a separate device. In the above method a detector catheter can be used that contains an electrode to examine the electrical signals of the heart tissue and further verify that the tissue that is being injected is infarcted or peri-infarcted tissue.

[0101] In another such method, the patient can be injected with a positron emitting labeled matrix metalloproteinase inhibitor that accumulates in the regions of the heart that are causing arrhythmia. Examples of this isotope include Ga-68, I-124, I-131, Re-186, Re-188, Cu-62 and Zr-89. Other radiolabeled compounds that have specific uptake characteristic to the abnormal tissue can also be used in this method.

[0102] Catheters incorporating features of the invention preferably contains at least one detector that is predominantly sensitive to beta rays. After locating the area of myocardium that has highest beta emitting uptake using the detector, a variety of local therapies can be administered.

[0103] As shown in the FIGS. 1A-10, 14, 16 and 17A-18B, the injector for delivery of medicinal therapy can be an integral part of the detector-catheter. However, as discussed below and shown in the FIGS. 11 and 13 it is also contemplated that the injector can be a totally separate device that can be positioned separate from the sensing catheter.

[0104] A further example of medicinal therapy is the local delivery of a recombinant tissue inhibitor of matrix metalloproteinase-3 (TIMP-3), or a TIMP-3 releasing hydrogel, or activatable polymer that releases TIMP-3 in presence of MMP activity,; activation leads to enhanced degradation of the polymer and release of TIMP-3 or other modulator of MMP activation TIMP-3 is known to moderate the pro-inflammatory status of macrophages. (Gill S E, Gharib S A, Bench E M, Sussman S W, Wang R T, Rims C, Birkland T P, Wang Y, Manicone A M and McGuire J K. Tissue Inhibitor of Metalloproteinases-3 Moderates the Proinflammatory Status of Macrophages, American Journal Of Respiratory Cell And Molecular Biology, (2013);49:768-777) and play a critical role in modulating post-MI remodeling. Eckhouse et al. have demonstrated that intramyocardial injection of TIMP-3 releasing hydrogel within the infarct region at the time of acute surgical-induced MI in pigs can reduce post-MI remodeling. (Eckhouse S R, Purcell B P, McGarvey J R, Lobb D, Logdon C B, Doviak H, O'Neill J W, Shuman J A, Novack C P, Zellars K N, Pettaway S, Black R A, Khakoo A, Lee T, Mukherjee R, Gorman J H, Gorman R C, Burdick J A and Spinale FG.Local Hydrogel Release Of Recombinant TIMP-3 Attenuates Adverse Left Ventricular Remodeling After Experimental Myocardial Infarction, Sci Transl Med. (2014) 6:223ra21). These studies demonstrated an increase in wall thickness within the infarct region, a decrease in wall stress, and a reduction in LVEDV. The local and sustained release of recombinant TIMP-3 over several weeks from their MMP-activatable hydrogel resulted in a reduction in regional MMP activity, and a number of other inflammatory markers including; IL-8, MCP-1, and MIP-1a. (Eckhouse S R, Purcell B P, McGarvey J R, Lobb D, Logdon C B, Doviak H, O'Neill J W, Shuman J A, Novack C P, Zellars K N, Pettaway S, Black R A, Khakoo A, Lee T, Mukherjee R, Gorman J H, Gorman R C, Burdick J A and Spinale F G. Local Hydrogel Release Of Recombinant TIMP-3 Attenuates Adverse Left Ventricular Remodeling After Experimental Myocardial Infarction. Sci Transl Med. (2014) 6:223ra21.).

[0105] The methods discussed herein can be performed while the patient is undergoing a PET scan or a gamma camera scan. These external imaging modalities can facilitate accurate localization and delivery of therapy. For example, in one embodiment, the catheters include radioactive or radiopaque markers at their tip or along their axis (FIGS. 18A, 18B) so they can be seen in the external images, and enable correlation with the radiolabeled tissues. In another embodiment, the catheters can contain position trackers at their tip or along their axis so images of the catheters can be used to correlate their location in an external images with the radiolabeled tissues as shown in FIG. 20.

[0106] With reference to FIG. 16, various non-drug therapies that can be delivered in conjunction with the label sensing catheter described herein, such as radiofrequency ablation or cryo-ablation, which are current methods of therapy for treating arrhythmias. In one embodiment of the detector-catheters for mapping radioactive distribution, electrodes are also utilized to examine the electrical signals of the heart tissue.

[0107] In another embodiment, the catheter can also contain position sensors for tracking. In one method of use, the ablation catheters are guided to the abnormal tissue location using the detector-catheter. Alternatively, structure for delivering the radiofrequency or cryoablation can be incorporated into the detector-catheter. In another embodiment a separate ablation tool having a position-sensor is navigated to the location that is identified by the detector-catheter.

[0108] Theragnostic catheters developed for both radiation detection and molecularly-targeted therapeutic injection is shown in FIGS. 1A-10, 14, 16 and 17A-18B. In a preferred construction the diameter of the flexible catheter is 2.4 mm. The detector on the catheter tip consists of a plastic scintillators (BC-412, St. Gaugin, Fr) coupled to a 1 mm1 mm solid state photodiode (Hamamatsu Photonics, Japan). The plastic scintillator was selected for its high efficiency detection of beta rays and minimal sensitivity to gamma rays, which reduces signals from background radiation and increases spatial resolution. The catheter also includes a retractable 25 G needle for therapeutic delivery, which can be accessed via an injection port on the catheter base. Basic feasibility experiments were conducted to assess the prototype device's sensitivity and ability to measure signals from intramyocardial beta-emitting radiotracers. Fifty (50) L quantities of serially diluted aqueous .sup.18FDG were injected locally into sections of an ex vivo pig heart at depths of 1 mm from the endocardial surface. .sup.18FDG signals were assessed by collecting counts with the catheter tip in direct endocardial contact.

EXAMPLE 2

[0109] A multi-detector catheter (see FIG. 19) similar to basket-shaped catheters used in electrophysiology studies, which will reduce the time needed for intraventricular mapping of radionuclide detection by incorporating multiple detectors on a single catheter that can be deployed to provide direct contact with the endocardial surface of the heart.

[0110] The detector on the catheter tip consists of a plastic scintillator (BC-412, St. Gaubain, France) coupled to a 1 mm1 mm Solid State photomultiplier SSPM (Hamamatsu Photonics, Japan). The theragnostic catheter developed for both beta detection and targeted therapeutic delivery is shown in the FIGS. 1A, 1B. The preferred diameter of the flexible catheter is 2.4 mm. The prototype catheter was shortened significantly for simplicity; a longer catheter is required for percutaneous arterial access to the heart. The catheter tip also features a retractable 25 G needle for therapeutic delivery, which can be accessed via an injection port on the catheter base. A guidewire system is added to this catheter as well to facilitate placement within the left ventricle.

[0111] The detector portion of the catheter described can include both beta and gamma detectors (FIGS. 2A, 2B), to more effectively isolate beta particles from background gamma emissions. In variations of the systems described in vivo mapping is provided by the addition of an electrode for detection of electrical activity. A multi detector system can be provided by using several solid state photomultiplyers (such as 8 SSPMs) attached to a flexible Kapton printed circuit board (1 mm wide and 40 mm long) (FIG. 15). These SSPM's are 1x1 mm in dimension and each are coupled to 1.51.5 mm piece of plastic scintillator.

[0112] In summary, described herein are various novel methods for locating labeled tissue within the body and delivering therapy to the labeled tissue based on real-time characterization of myocardial tissue. Radiopharmaceuticals, fluorescing materials and other known techniques and materials can be used to tag the target tissue. The catheters described therein are then used to locate the tagged tissue and deliver and inject into the target tissue a treatment modality including, but no limited to. cells, genes, polymers, inhibitory microRNAs, DNA, plasmids, chemicals, enzymes, growth factors, or a variety of medicinal compounds or combinations thereof.

[0113] In the methods described herein a detector catheter can be used that contains an electrode to examine the electrical signals of the heart tissue and further verify that the tissue that is being injected into is infarcted or peri-infarcted tissue.

[0114] Another therapy is the use of radiofrequency ablation alone or in combination with directly delivered drug therapy. A detector catheter can be used that contains electrodes to examine the electrical signals of the heart tissue and to then deliver electrical energy for ablation.

[0115] The methods discussed above can be performed under a PET scanner of a gamma camera. These external imaging modalities can further facilitate accurate localization and delivery of therapy.

[0116] The catheters can also include radioactive or radiopaque markers at their tip or along their axis so they can be seen by external imaging devices, and enable correlation with the position of the radiolabeled/tagged tissues.