MXPA01004375A - Method for improved imaging and photodynamic therapy - Google Patents

Abstract

The present invention is directed toan apparatus and method of imaging and treatment using at least one photodynamic therapy ("PDT") agent. The method includes administering a photoactive agent to a patient (56), imaging the patient to locate the diseased tissue or tumors (54) in the patient using an imaging device (52) such as CAT scan or MRI, and treating the imaged diseased tissue with light (60) sufficient to photo-activate the agent in the tissue.

Description

METHOD FOR IMPROVED IMAGE FORMATION AND PHOTODYNAMIC THERAPY DESCRIPTION Background and Field of the Invention The present invention relates to an apparatus and method for imaging and treatment using at least one photodynamic therapy agent (PDT). In particular, this apparatus and method are used to image and treat diseased tissue. Imaging is usually done to locate diseased tissue or tumors in a body. Once the diseased tissue is located, it is subsequently treated in some way to destroy the diseased cells within this tissue. As explained below, in the past, these were two separate procedures in a long and tedious process that was often useless. Imaging is generally performed using an imaging device such as CAT (Computed Tomography) or MRI (Magnetic Resonance Imaging) scanning. Alternatively, fluorography (using an image produced on a fluorescent screen by means of x-rays) or similar procedures may be used. Each of these imaging procedures requires a contrast agent for optimal operation. Examples of such imaging contrast agents include iodinated agents such as Omnipaque® (Iohexol) and Omniscan® (Gadodiamide) for X-ray based imaging or one of the different paramagnetic MRI contrast agents such as gadolinium DPTA. (Gd-DPTA). Once the diseased tissue has been located by imaging, it needs to be treated.

Such treatments; however, they are often unsuccessful. All current therapies for cancer (for example, radiation and chemotherapy) work by rapidly attacking cell proliferation. Unfortunately, this selection criterion does not limit the effects of treatment to cancer cells. As a consequence, such therapies are accompanied by undesirable side effects that can be life-threatening. In addition, such therapies can actually reduce natural antitumor defenses. For example, radiation and chemotherapy damage rapidly dividing immune system cells, suppressing anti-tumor and anti-infective responses.

In addition to producing undesirable side effects, current therapies are quite unable to achieve the desired potency of effects since they do not specifically target cancer cells. Therefore, radiation or chemotherapy alone or in combination rarely cure cancer. Thus, the primary treatment for cancer is currently the surgical removal of the tumor. This is usually done together with radiation and adjuvant chemotherapy. Therefore, to achieve a cure, the patient is surgically mutilated and poisoned by very toxic treatments in an effort to destroy all cancer cells. In an effort to minimize the invasiveness of cancer treatment and improve overall effectiveness, photodynamic therapy (PDT) has been developed. Photodynamic therapy is the combination of a photosensitive agent with specific illumination at the site to produce a therapeutic response in certain tissues, such as a tumor. The agent achieves an excited state when it absorbs a photon, and then it becomes or becomes efficient. Unfortunately, the single photon excitation (SPE) methods used for the passage of illumination in PDT have not allowed the PDT to reach its potential, mainly because (1) the high energy light required for such treatment is incapable. of penetrating deep into the tissue and (2) such illumination allows the physician a minimum spatial control of the treatment site. In contrast, the low energy light used for two-photon excitation PDT (TPE) can penetrate tissue more safely and provides three-dimensional control of treatment margins. A more detailed explanation of TPE and SPE is provided in the commonly owned application of the United States of America No. 08/739, 801 which is incorporated herein by reference. Although the use of two-photon excitation in PDT significantly improves the depth of penetration and the spatial control problems that plague conventional PDT, further improvements can be made by improving the therapeutic functioning of PDT agents and improving the specificity of the disease. in the selection of the activation site. This is the consequence of several limitations of currently used agents and activation selection attempts. The only major PDT agent authorized by the Food and Drug Administration (federal entity that controls the quality of food and medicines) of the United States of America is the Type II agent, sodium of porf ero (or PHOTOFRIN®). This porphyrin-based agent is representative of a family of related agents (such as benzoporphyrin derivative, SnEt2, and Lutex) that are normally activated by single-photon methods using light between 500 nm and 730 nm in wavelength. Such Type II agents produce a therapeutic effect through the conversion activated by light (photocatalytic conversion) of oxygen into an unstable and toxic form (singlet oxygen) which destroys biological material. Unfortunately, this mechanism requires a rich supply of oxygen at the treatment site. This supply, however, can be rapidly depleted, for example due to the supply of compromised blood (as is common at the center of a large tumor) or intense illumination (which can consume all available oxygen, preventing continued conversion to singlet oxygen) . Thus the treatment of large tumors and the use of aggressive lighting methods are not practical with such agents. In addition, porfimer sodium-like agents should typically be administered systemically (by intravenous injection) at high dose levels, advantageously before illumination (typically at least 24 hours before - increased cost and patient discomfort). Moreover, high doses required for systemic administration are very expensive (up to $ 5,000 or more per dose) and cause persistent photosensitization of the skin.The problems with porphyrin-based agents stem in part from the fact that these agents do not achieve a significant concentration in tumors. Rather, large doses administered systemically saturate all tissues. As a result, after a safety time in the hours to days scale, the excitation of a single residual agent photon at the treatment site not only produces the desired cytotoxic effect in the diseased tissue but can also damage the surrounding tissue healthy due to the agent activation there present. It is this residual agent that also explains the persistent photosensitization of the skin. Moreover, this family of agents is typified by the relatively high toxicity without activation by light (cytotoxicity without light or dark). Activation by light generally increases only marginally this toxicity (ratio of poor light to dark cytotoxicity). While the use of two-photon excitation can improve the performance of PDT with such agents, specifically by reducing or eliminating potential collateral damage during illumination, coupling TPE with an agent that has improved bioselectivity and light-to-dark cytotoxicity enhances it. importantly the safety and effectiveness of PDT. However, the ability to achieve such advantages requires that the size, location and depth of the target be accurately known so that the light used for TPE can be delivered precisely to the target. Therefore, a new method is required to identify and locate tumors or other diseased tissues quickly and precisely. Additional features of such a method should solve other current problems with PDT, including: improved ratio of light to dark cytotoxicity for the agent (and more specifically a very low dark cytotoxicity); improved accumulation of agent in diseased tissue with strong contrast between diseased tissue and healthy tissue; and ability to combine imaging and therapy (such as through photoactivation of the agent at locations formed in images). Additional features should include significant reduction of agent cost and quickly debug or eliminate the normal tissue agent. Accordingly, it is an object of the present invention to meet these characteristics and overcome the disadvantages of the foregoing methods and agents.

Summary of the invention The present invention relates to a method and apparatus for imaging and treating diseased tissue using at least one PDT agent.

One embodiment of the method of the present invention includes the steps of administering a photoactive agent, the photoactive agent being retained in diseased tissue; and treating the diseased tissue with sufficient light to photoactivate the photoactive agent in the diseased tissue. Preferably, the photoactive agent is a halogenated xanthene such as Bengal rose. A further embodiment of the method of the present invention includes the steps of administering the photoactive agent to a patient before or after imaging, the photoactive agent being retained in diseased tissue; form the patient in images to identify diseased tissue; and treating the diseased tissue formed in images with sufficient light to photoactivate the photoactive agent in the diseased tissue formed in images. In a further embodiment, the photoactive agent is capable of acting as a contrast agent for CAT scanning, fluorography or related procedures. In a further embodiment, the photoactive agent is capable of acting as a contrast agent for CAT scanning, fluorography or related procedures and is photoactive in diseased tissue.

In a further embodiment, the photoactive agent is capable of acting as a contrast agent for MRI and is photoactive in diseased tissue. In yet another embodiment, the photoactive agent is mixed with CAT scanning agents, MRI, fluorography or related contrast or selection agents before use. In another embodiment of the present invention, the light source for performing PDT is integrated into or attached to an imaging device (e.g., CAT scanner, MRI, or related devices). In a further embodiment, the method uses a light source in the combined PDT / imaging apparatus which causes two photon excitation. In an alternative embodiment, the illumination source in the combined PDT / imaging apparatus causes single-photon excitation.

Brief Description of the Figures The figure is an illustration of the chemical structure of rose Bengal. Figure lb is an illustration of the chemical structure of a halogenated xanthene.

Figure 2 is an illustration of the two photon cross section for several examples of halogenated xanthenes. Figure 3 illustrates the CAT scanner image of Bengal rose test tubes, X-ray contrast agents and a control. Figure 4 illustrates a CAT scanner of a concentration scale of the solutions of Figure 3. Figure 5 is a graph of energy versus X-ray cross-section for halogens. Figure 6 illustrates a combined imaging and treatment device according to the present invention.

Detailed Description of the Currently Preferred Modality The present invention relates to the apparatus and use of at least one PDT agent in the imaging and treatment of diseased tissue. The first embodiment of the present invention relates to an improved method for photodynamic therapy that improves performance by the use of a photoactive agent that has superior light-to-dark cytotoxicity. This modality includes treating the diseased tissue with light to photoactivate the photoactive agent in the diseased tissue, thus destroying diseased tissue. The step of administering a photoactive agent (PDT) to a patient is included in this modality. The PDT agent will preferentially accumulate in diseased tissue. Each of these steps, the PDT agent and additional embodiments of the present invention based thereon, will be discussed in more detail below. A PDT agent that can be used in the present invention is Bengal Rose (4,5,6,7-tetrachloro-2 ', 4', 5 ', 7' tetraiodofluorescein); (see 10 in figure la). Rose Bengal is a Type I PDT agent that is known to preferentially accumulate in (ie select) some tumors and other diseased tissues. Type I agents produce a cytotoxic response through direct photochemical conversion to toxic substances, and their photodynamic action Type I is thus independent of oxygen. In the presence of oxygen, rose Bengal is also capable of the efficient production of singlet oxygen (type II action), further strengthening its photodynamic potential. In fact, the inventors of the present application have found that Rose Bengal is a highly efficient PDT agent when compared to conventional PDT agents (such as porfimer sodium and other porphyrin-based agents that are limited to only the mechanism of Type I or Type II action). For example, in in vitro tests it has been shown that Bengal rose at a concentration < 10 μg / ml is capable of killing 107 bacteria / ml within 5 seconds of illumination. Under similar conditions, porfimer sodium requires several hours to kill only a small percentage of these bacteria. Therefore, with respect to porfimer sodium, rose Bengal has an extremely high light-induced cytotoxicity. What's more, the dark cytotoxicity of rose Bengal is negligible. Therefore, Bengal rose has all the characteristics of a desirable replacement for porphyrin-based PDT agents: excellent bioselectivity and high proportion of light-to-dark cytotoxicity. Rose Bengal is a specific example of a class of photoactive agents that are preferably used in the present invention. These agents are referred to as halogenated xanthenes and are illustrated in Figure lb, where the symbols X, Y, and Z represent various elements present at the designated positions, and the symbols R1 and R2 represent various functionalities present at the designated positions. The physical and photochemical properties of representative halogenated xanthenes are summarized in the attached table 1. Porfimer sodium, the most common PDT agent currently in use, is also listed for comparison of related properties.

In general, halogenated xanthenes are characterized by low dark cytotoxicity, high light cytotoxicity, high single photon cross section ranging from about 300 nm to 600 nm, and photochemical properties that remain substantially unchanged by the environment local chemical or the union of functional derivatives in positions R1 and R2. Furthermore, halogenated xanthenes will select some diseased tumors based on selective partition properties. The ease with which halogenated xanthenes select specific tissues or other sites can be improved by binding specific functional derivatives at positions R1 and R2, so as to change the chemical partition or biological activity of the agent. For example, the binding of one or more selection portions at the R1 or R2 positions can improve the selectivity for specific tissues, such as tissues of cancerous tumors or sites of localized infection. These selectable portions include DNA, RNA, amino acids, proteins, antibodies, ligands, haptens, carbohydrate receptors or complexing agents, lipid receptors or complexing agents, protein receptors or complexing agents, chelators, and encapsulation vehicles.

Thus, an example of this configuration would be to combine Rose Bengal with a lipid (in the R ?, position by esterification), to increase the lipophilicity of Rose Bengal, and therefore modify its selectivity properties in the patient. Such a modified agent could be administered directly as a suspension of micelles, or delivered together with a delivery vehicle, such as a surfactant, and could show increased selectivity to the tumor cells. Suitable formulations for such an agent include topical creams and lotions, and fluids for intravenous, parenteral or intratumoral injection. In addition to having desirable SPE characteristics, halogenated xanthenes have attractive properties for TPE. Specifically, this class of agent offers a wide and intense TPE spectral response during a scale of wavelengths ranging from as much as 730 nm to less than 1100 nm, as shown in Figure 2. More specifically, the union of portions at positions R1 and R2 cause negligible changes in the spectral properties of TPE, as is clear, for example, by comparison of the spectral response of Eosin Y (where R1 = Na) and Ethyl Eosin (where R1 = OCH2CH3). Thus, the binding of selection agents is possible without significantly affecting the photochemical properties of the agent. Accordingly, halogenated xanthenes constitute excellent PDT agents for both PDT and TPE activation mechanisms, and can be used directly or in derivatized form to improve, for example, solubility or bioselectivity through the binding of various functionalities in the positions R1 and R¿. Thus, in a preferred embodiment of the present invention, at least one halogenated xanthene or halogenated xanthene derivative is used as a PDT agent. The PDT agent can be administered orally, systemically (for example by injection), or topically, in a well-known manner in the medium. It is also preferred that Bengal rose be used as the PDT agent. Such an agent can be activated using excitation of a single photon, or preferably excitation of two photons. In a further embodiment of the present invention, the photodynamic activation selectivity is improved by the use of conventional imaging methods to identify diseased tissue targets. For example, imaging based on X-rays, such as computerized axial tomography, is used.

(CAT scan), fluorography or other related procedures, or magnetic resonance imaging (MRI) to detect the location of diseased tissue. Such imaging works by detecting abnormalities in the distribution or properties of tissue components (such as density), the presence or absence of certain materials, or the capture or exclusion of contrast agents for imaging. The diseased tissue is then used as the target for the selective optical activation of the photodynamic agent administered to the patient, whereby diseased tissue is selectively destroyed. The inventors of the present invention have discovered that certain PDT agents, and more specifically halogenated xanthenes, substantially do not activate photodynamically or destroy by exposure to the energies commonly used for MRI or X-ray imaging. Thus, these agents they are safe for administration before such diagnostic procedures. Accordingly, the PDT agent can be administered to the patient prior to diagnosis (potentially reducing the delay between diagnosis and treatment) or after diagnosis (thereby reducing unnecessary administration of the agent in cases where no disease is detected). ). Accordingly, a preferred embodiment of the present invention comprises the steps of MRI or X-ray imaging by conventional means to detect the presence of diseased tissue.; administering a PDT agent, preferably a halogenated xanthene, before or during detection of the diseased tissue, and directing light, suitable for methods of activating SPE or preferably TPE, as discussed below, on or to such a sufficient diseased tissue to activate the PDT agent and thereby selectively destroy practically only the diseased tissue. In a further embodiment of the present invention, the efficiency of the detection or imaging step in the preceding embodiment is enhanced by the use of a contrast agent to image. In particular, the PDT agent, and more specifically, a halogenated xanthene, is mixed with a contrast agent for imaging, such as, for example, X-ray contrast agents such as Omnipaque® (Iohexol) and Omniscan® (Gadodiamide ) or one of several MRI paramagnetic contrast agents such as gadolinium DPTA (Gd-DPTA). For example, Bengal rose is compatible in solution with agents such as Omnipaque®, Omniscan®, and Gd-DPTA, and exhibits similar bioselection properties. The mixture is then administered to the patient. After administration of a mixture of contrast agent and PDT agent, conventional imaging (such as, for example, CAT or MRI scanning) is used to locate diseased tissue based on the response of the conventional contrast agent, then the PDT agent, co-localized in the diseased tissue, is activated at the site of the diseased tissue detected using SPE or more preferably TPE to destroy such diseased tissue. The inventors have shown that Bengal rose is capable of selective photodynamic activation in a liver model, after administration of the agent in solution. It is also known that such a model accumulates conventional X-ray contrast agents and MRI. Thus, the inventors have shown that it is feasible to administer conventional imaging contrast agents and PDT agents to target tissues, and that such agents will maintain their respective activities in the selected tissues, allowing the combined detection and treatment of diseased tissue in the tissues. locations indicated by the imaging based on the detected image formation contrast agents. Accordingly, a preferred embodiment of the present invention is to administer together, either sequentially (eg, by injections or intravenous drip) or more preferably as a single mixed and single solution, one or more X-ray contrast agents or MRI with one or more PDT agents, preferably a halogenated xanthene agent, and then direct the activation of the one or more PDT agents based on imaging data obtained using at least one or more contrast agents. In another embodiment of the present invention, the PDT agent also acts as a contrast agent for imaging. The use of the same agent for both imaging and for the treatment procedures is very advantageous. For example, this eliminates the need for a second dose of an agent. Said second dose requires additional time between imaging and treatment, because the second agent, after it is administered, must accumulate in the diseased tissue before the treatment can begin. In addition, the use of a second agent makes the process more expensive and requires that the patient be subjected to a second application of a foreign substance. More specifically, the chemical structure of halogenated xanthenes, which have a high electron density due to their significant halogen content, gives them dark to X-rays. For example, Bengal rose is very dark to X-rays used for CAT scanning or normal X-ray imaging. Figures 3 and 4 illustrate the opacity of Bengal rose against normal X-ray contrast agents and a control. These figures are drawings of real images of experiments made by the inventors of the present invention. For example, the CAT scan image of test tubes containing several solutions shown in Figure 3 demonstrates that iodine 40 (350 mg / ml in aqueous base), rose Bengal 42 (225 mg of halogen / ml in saline), and Omnipaque® 44 (350 mg / ml Iohexol) have similar X-ray densities. In addition, these densities are considerably higher than that of a control 46 (saline). A CAT scan image of several dilutions of these same solutions (kept in cavities in a 96-well sample plate) illustrated in the drawing in Figure 4 further demonstrates that Bengal Rose 42 shows response comparable to that of the agents , 44 X-ray contrast through a range of concentrations. Figure 5 shows that strong absorption by halogens occurs well below the energies used for normal X-ray diagnostic devices that generally use energies greater than 50 keV. Accordingly, the halogen content of the halogenated xanthenes makes this class of contrast photodynamic agents potent X-ray contrast agents. In view of the fact that the X-ray cross-section increases substantially in the order F <; Cl < Br < I, it is preferred that those halogenated xanthenes with a large content of I or Br are used for X-ray contrast. For example, Table 1 indicates that Bengal rose, B floxin, Erythrosin B, and Eosin Y will have lightning cross sections. X larger than Red Solvent or Eosin B as a consequence of respective differences in halogen content, and will therefore be preferred for use as X-ray contrast agents. More preferably, the high content of Bengal Rose iodine makes this agent the most attractive for X-ray contrast agent of this class. Thus, certain special PDT agents, preferably the halogenated xanthenes, can be used as contrast agents for tissue detection and tissue imaging based on X-rays for the detection of disease. This is based on the tissue specificity of such agents and their high density for X-rays. Therefore, it is a further preferred embodiment to use such agents as contrast agents for X-rays. Such agents will in general retain their photodynamic ability under such conditions. It can be used consistently for X-ray detection for the detection of diseased tissue followed by photodynamic activation guided by imaging, using SPE activation methods or preferably TPE, to selectively destroy such diseased tissue. In view of the fact that both the X-ray density and the photodynamic efficiency are greater for those halogenated xanthenes with a large content of iodine or bromine, such agents will be optimal and preferred for combined X-ray imaging and subsequent activation of specific PDT of the site based on the results of such imaging. Table 1 shows that Bengal rose, Floxin B, Erythrosin B, and Eosin Y, for example, have high efficiency in the generation of singlet oxygen, and are also highly effective PDT agents. Thus, it is a further preferred embodiment of the present invention to use halogenated xanthenes, and more preferably iodated or brominated halogenated xanthenes, as combined PDT and X-ray contrast agents, wherein X-ray imaging is used for subsequent direct activation of such an agent using SPE activation methods or preferably TPE. In addition to the aforementioned use of halogenated xanthenes as X-ray contrast agents, the unique structural characteristics of these agents make such attractive candidates attractive as MRI contrast agents. Although non-paramagnetic like most conventional MRI contrast agents, halogenated xanthenes contain aromatic protons which show characteristic MRI identifications based on the chemical change of such protons. In addition, the presence of substantial aromatic halide densities in the halogenated xanthenes constitutes a unique and useful identification of additional MRI based on the detection of resonances of such aromatic halides. Since nuclear magnetic resonance of proton and halogen are relatively sensitive phenomena (for example, F, Br and iodine are often more sensitive in relation to carbon 13 NMR, as shown in Table 2), the detection of MRI and the Imaging based on the presence of halogenated xanthenes in diseased tissue represents a unique and attractive additional medical application for such agents. Therefore, it is a further preferred embodiment of the present invention to use the halogenated xanthenes as MRI contrast agents, and to use the imaging database in the detection of such agents to selectively direct the subsequent photoactivation of such agents present in diseased tissue using SPE activation methods and preferably TPE. Since most MRI devices installed are based on proton resonance detection, it is further preferred that such MRI detection be performed based on resonance of aromatic protons present in the halogenated xanthenes. After imaging in the present invention, light is applied by a light source to the site of the disease to photoactivate the agent associated with the diseased tissue. Preferably, laser light is used. Alternative sources of illumination include light emitting diodes, microllasers, monochromic or continuous lasers or lamps for the production of activating light, and pulsed lasers or continuous wave or lamps. Both single-photon or two-photon excitation methods can be used for agent activation. A more detailed explanation of such excitation methods is given in the commonly assigned application, serial No. 08 / 739,801 filed October 30, 1996, which is incorporated herein by reference. The excitation of the photoactive agent initiates a process which eventually kills the cells in the diseased tissue. In a further embodiment of the present invention, the light source used for photodynamic activation is integrated into or onto the image forming device, such as an MRI system or X-ray imaging device. An example of such a device for imaging and treatment 50 is illustrated in Figure 6. Such a combined imaging and treatment device allows a more accurate delivery of treatment to diseased tissue based on improved registration accuracy between imaging data and treatment objectives. . For example, Figure 6 shows a conventional imaging unit 52, such as an MRI system or CAT scanner, used to identify a lesion 54 present in a patient 56. Imaging of this lesion can be done by means of one of the methods discussed above or by other known methods for forming images. This lesion 54 then serves as the target for an integrated activation unit 58 which selectively serves to photoactivate the PDT agent present in the lesion. The activation unit 58 preferably includes a light source 60, such as, for example, a laser capable of SPE activation of the agent and more preferably a laser capable of TPE activation of such an agent, such as a YLF titanium: sapphire laser or neodymium with mode insurance. Preferably, the activation unit 58 also includes a pointing system 62, such as, for example, a mirror-based galvanometer (reflection) or other optical scanning system.

Constructed and operated in this manner, the imaging unit 52 can be made to guide the application of light 64 produced by the activation unit 58, for example under the manual control of a physician or more preferably under automated or semi-automated computer control, such that the activating light 64 is substantially applied only to the site of the lesion 54 detected, thus improving the safety and efficacy of the treatment process. A titanium: sapphire laser with mode lock is a preferred embodiment for lighting source for the integrated activation unit. Such a laser is capable of producing a rapid series of pulses of high power peaks of NIR light which are very suitable for TPE of halogenated xanthenes. Standard titanium: sapphire lasers with commercially available mode safe, are able to provide pulse with safe mode with durations < 200 fs with pulse energies of approximately 1-20 nJ at pulse repetition frequencies of more than 75 MHz. This constitutes an almost continuous beam of light that has a relatively low average power (up to several watts) but high peak power (in the order of 100 kW) that is continuously adjustable by a band NIR wavelength of approximately 690-1080 nm. The pulse train of such a source is easily aimed using normal optical means, such as reflective or refractive optical lenses, so that they are directed on or in a lesion or other localized treatment target. Other sources of suitable lighting for the activation of photodynamic agents include: pulsed or continuous wave lamps, diode light sources, semiconductor lasers; other types of gas lasers, dye lasers, and continuous solid-state, pulsed or mode-safe lasers, including: argon ion lasers; krypton ion lasers; helium-neon lasers; helium-cadmium lasers; ruby lasers; Nd: YAG, Nd: YLF, Nd: YAP, Nd: YV04, Nd: Glass, and Nd lasers: CrGsGG; Lasers of Cr: LiSF; Er: YAG lasers; center-F lasers; Ho lasers: YAF and Ho lasers: YLF; copper vapor lasers; nitrogen lasers; parametric optical oscillators, amplifiers and generators; regeneratively amplified lasers; amplified lasers of screeching pulse; and sunlight. This description has only been offered for illustrative purposes and is not intended to limit the invention of this application, which is defined in the following claims. What is claimed as new and desired to be protected by a patent document is set forth in the appended claims.

Table 1: Physical and Photochemical Properties of Examples of Halogenated Xanthines Table I: Magnetic Resonance Properties of Elements

Claims (63)

1. A method for imaging and treating diseased tissue characterized in that it comprises the steps of: administering a photoactive agent to a patient prior to imaging, a portion of the photoactive agent being retained in diseased tissue; form the patient in images to identify diseased tissue; and treating the diseased tissue formed in images with sufficient light to photodynamically photoactivate the photoactive agent retained in the diseased tissue formed in images, wherein the photoactive agent is a halogenated xanthene.

2. The method of compliance with the claim 1, characterized in that the halogenated xanthene is rose Bengal.

3. The method of compliance with the claim 1, characterized in that the halogenated xanthene includes as functional derivative a selector portion selected from the group comprising deoxyribonucleic acid (DNA), ribonucleic acid (RNA), amino acids, proteins, antibodies, ligands, haptens, carbohydrate receptors or complexing agents, receptors of lipids or complexing agents, protein receptors or complexing agents, chelators, and encapsulation vehicles. •

4. The method according to claim 1, characterized in that the imaging is performed at 5 through a method selected from the group comprising computerized axial tomography, fluorography and magnetic resonance imaging.

5. The method according to claim 1, characterized in that the photoactive agent is mixed with a? Imaging contrast agent before the step of administering.

The method according to claim 5, characterized in that the contrast agent is selected from the group comprising Omnipaque® (Iohexol), Omniscan® 15 (Gadodiamide) and one of the different paramagnetic MRI contrast agents including gadolinium DPTA (Gd-DPTA).

The method according to claim 5, characterized in that the step of imaging using the contrast agent imaging 20 produces data to direct the photoactivation of the photoactive agent in the step of treating.

8. The method according to claim 1, characterized in that the photoactive agent acts as an imaging contrast agent.

9. The method according to claim 8, characterized in that the contrast agent for imaging is an X-ray contrast agent.

The method according to claim 8, characterized in that the contrast agent for imaging is a contrast agent for magnetic resonance imaging (MRI).

11. The method according to claim 8, characterized in that the imaging contrast agent is a halogenated xanthene.

The method according to claim 11, characterized in that the halogenated xanthene is selected from the group consisting of halogenated iodinated and brominated xanthenes.

13. The method according to the claim 11, characterized in that the halogenated xanthene is selected from the group comprising Rose Bengal, Floxin B, Erythrosin B and Eosin Y.

The method according to claim 11, characterized in that the detection of halogenated xanthene contrast imaging It is based on resonance of aromatic protons in the halogenated xanthene.

The method according to claim 11, characterized in that the detection of the halogenated contrast imaging xanthene is based on resonance of aromatic halides in the halogenated xanthene.

16. The method according to claim 1, characterized in that the step of treating with light promotes excitation of two photons of the photoactive agent.

17. The method according to claim 16, characterized in that the excitation of two photons is simultaneous excitation of two photons.

18. The method according to claim 1, characterized in that the step of treating with light promotes excitation of a single photon.

19. The method according to claim 1, characterized in that the imaging and treatment steps use an integrated imaging and treatment device.

20. The method of compliance with the claim 19, characterized in that the integrated imaging and treatment device includes an imaging unit and a light source for photodynamic activation.

21. The method according to the claim 20, characterized in that the illumination source is a laser.

22. A method for treating diseased tissue comprising the steps of: administering a photoactive agent to a patient, a portion of the photoactive agent being retained in diseased tissue; and treating the diseased tissue with light in order to dynamically photoactivate the photoactive agent retained in the diseased tissue, wherein the photoactive agent is a halogenated xanthene.

23. The method according to claim 22, characterized in that the halogenated xanthene is bengal rose.

24. The method according to claim 22, characterized in that the halogenated xanthene includes as a functional derivative a selector portion selected from the group containing DNA, RNA, amino acids, proteins, antibodies, ligands, haptens, carbohydrate receptors or complexing agents, lipid receptors or complexing agents, protein receptors or complexing agents, chelators, and encapsulation vehicles.

25. The method of compliance with the claim 22, characterized in that the step of treating with light promotes excitation of two photons of the photoactive agent.

26. The method according to claim 25, characterized in that the excitation of two photons is simultaneous excitation of two photons.

27. The method according to claim 22, characterized in that the step of treating with light promotes excitation of a single photon.

28. The method according to claim 22, characterized in that the light is a laser.

29. A method for imaging and treating diseased tissue comprising the steps of: imaging a patient to identify diseased tissue; administering a photoactive agent to a patient, a portion of the photoactive agent is retained in the diseased tissue; and treating the diseased tissue formed in light images to photodynamically photoactivate the photoactive agent retained in the diseased tissue formed in images, wherein the photoactive agent is a halogenated xanthene.

30. The method according to claim 29, characterized in that the halogenated xanthene is bengal rose.

The method according to claim 29, characterized in that the halogenated xanthene includes as a functional derivative a selector portion selected from the group comprising DNA, RNA, amino acids, proteins, antibodies, ligands, haptens, carbohydrate receptors or complexing agents, Lipid receptors or complexing agents, protein receptors or complexing agents, chelators, and encapsulation vehicles.

32. The method according to claim 29, characterized in that the imaging is achieved by a method selected from the group comprising computerized axial tomography, fluorography and magnetic resonance imaging.

33. The method according to claim 29, characterized in that the halogenated xanthene is selected from the group comprising halogenated iodinated and brominated xanthenes.

34. The method according to claim 29, characterized in that the halogenated xanthene is selected from the group comprising Rose Bengal, Floxin B, Erythrosin B and Eosin Y.

35. The method in accordance with the claim 29, characterized in that the step of treating with light promotes excitation of two photons of the photoactive agent.

36. The method of compliance with the claim 35, characterized in that the excitation of two photons is simultaneous excitation of two photons.

37. The method according to the claim 29, characterized in that the step of dealing with light promotes excitation of a single photon.

38. The method according to claim 29, characterized in that the imaging and treatment steps use an integrated imaging and treatment device.

39. An integrated imaging and treatment device comprising: an imaging unit; and an integrated activation unit for selectively photoactivating a photodynamic therapy agent (PDT), wherein the imaging unit is connected to the integrated activation unit and wherein the PDT agent is a halogenated xanthene.

40. The device according to claim 39, characterized in that the imaging unit is a CAT scanning system.

41. The device according to claim 39, characterized in that the imaging unit is an MRI device.

42. The device according to claim 39, characterized in that the integrated activation unit includes a lighting source for photoactivating the PDT agent.

43. The device according to claim 42, characterized in that the illumination source is a laser.

44. The device according to claim 5, characterized in that the illumination source is selected from the group comprising titanium YLF lasers: sapphire or neodymium with mode lock, continuous and pulsating wave lamps, diode illumination sources, semiconductor lasers; Other types of gas lasers, from? dye, and solid-state lasers, pulsating or with safe mode, including: argon ion lasers; krypton ion lasers; helium neon lasers; helium-cadmium lasers; ruby lasers; Nd: YAG, Nd: YLF. Nd: YAP, Nd: YV04, Nd: glass, and Nd lasers: CrGsGG; 5 Cr lasers: LiSF; Er: YAG lasers; center lasers F; Ho: YAF and lasers from Ho: YLF; copper vapor lasers; nitrogen lasers; parametric optical oscillators, amplifiers and generators; regeneratively amplified lasers; and amplified pulse lasers in screeching.

45. The device according to claim 39, characterized in that it further comprises a pointing system for guiding the application of light from the activation unit to the PDT agent.

46. The device according to claim 45, characterized in that the pointing system is an optical scanning system.

47. The device according to claim 45, characterized in that the pointer system is a mirror-based galvanometer system.

48. The device according to claim 39, characterized in that the halogenated xanthene is bengal rose.

49. The device according to claim 39, characterized in that the halogenated xanthene includes as functional derivative a selector portion selected from the group comprising DNA, RNA, amino acids, proteins, antibodies, ligands, haptens, carbohydrate receptors or complexing agents, receptors of lipids or complexing agents, protein receptors or complexing agents, chelators, and encapsulation vehicles.

50. The device according to claim 39, characterized in that the halogenated xanthene is selected from the group comprising halogenated iodinated and brominated xanthenes.

51. The device according to claim 39, characterized in that the halogenated xanthene is selected from the group comprising Rose Bengal, Floxin B, Erythrosin B and Eosin Y.

52. The device according to claim 39, characterized in that the integrated activation unit promotes activation of two photons for photoactivating the PDT agent

53. The device according to claim 52, characterized in that the excitation of two photons is simultaneous excitation of two. photons.

54. The device according to claim 39, characterized in that the integrated activation unit promotes excitation of a single photon to photoactivate the PDT agent.

55. A method for imaging diseased tissue comprising the steps of: administering a halogenated xanthene to a patient prior to imaging, retaining a portion of the halogenated xanthene in diseased tissue; and forming in images the patient using a signal detected from the halogenated xanthene for contrast and identification of the diseased tissue.

56. The method of compliance with the claim 55, characterized in that the halogenated xanthene is rose Bengal.

57. The method of compliance with the claim 55, characterized in that the halogenated xanthene includes as a functional derivative a selection portion selected from the group comprising DNA, RNA, amino acids, proteins, antibodies, ligands, haptens, carbohydrate receptors or complexing agents, lipid receptors or complexing agents, receptors of proteins or complexing agents, chelators, and encapsulation vehicles.

58. The method according to claim 55, characterized in that the imaging is achieved by a method that is selected from the group comprising computerized axial tomography, fluorography and magnetic resonance imaging.

59. The method according to claim 55, characterized in that the halogenated xanthene is mixed with a conventional imaging contrast agent before the step of administering, and the step of administering the resulting mixture to the patient.

60. The method according to claim 59, characterized in that the conventional imaging contrast agent is selected from the group comprising Omnipaque® (Iohexol), Omniscan® (Gadodiamide) and one of several paramagnetic MRI contrast agents including gadolinium DPTA (Gd-DPTA).

61. The method according to claim 59, characterized in that the conventional imaging contrast agent is an X-ray contrast agent.

62. The method according to claim 59, characterized in that the conventional imaging contrast agent is an MRI contrast agent.

63. The method according to claim 5 55, characterized in that the halogenated xanthene is selected from the group comprising halogenated iodinated and brominated xanthenes. 6 The method according to claim 55, characterized in that the halogenated xanthene is selected P_ > of the group comprising Rose Bengal, Floxin B, Erythrosin B and Eosin Y. 65. The method according to claim 55, characterized in that the detection of halogenated xanthene is based on resonance of aromatic protons in xanthene 15 halogenated. 66. The method according to claim 55, characterized in that the detection of the halogenated xanthene is based on resonance of aromatic halides in the halogenated xanthene. 67. A method for locating and treating diseased tissue comprising the steps of: administering a contrast agent including a halogenated xanthene to a patient; image the diseased tissue in the patient using an imaging contrast agent; Y • after that select and photoactivate the halogenated xanthene 5 as a PDT agent at determined locations in the imaging step. 68. The method according to claim 67, characterized in that the contrast agent includes an X-ray contrast agent combined with halogenated xanthene m. 69. The method according to claim 67, characterized in that the contrast agent includes an MRI contrast agent combined with the halogenated xanthene. 15 70. The method according to the claim 67, characterized in that the contrast agent is selected from the group comprising Omnipaque® (Iohexol), Omniscan® (Gadodiamide) and one of several paramagnetic MRI contrast agents including gadolinium DPTA (Gd-DPTA). 20 71. The method according to the claim 67, characterized in that the halogenated xanthene is rose Bengal. 72. The method according to claim 67, characterized in that the halogenated xanthene includes as A functional derivative is a selection portion selected from the group comprising DNA, RNA, amino acids, proteins, antibodies, ligands, haptens, carbohydrate receptors or adjuvants before, lipid receptors or accompanying agents, protein receptors or coupling agents, chelators , and packaging vehicles. 73. The method of conformid-id with claim 67, characterized in that the imaging is carried out by a method selected from the group comprising computerized axial tomography, fluorography and magnetic resonance imaging. 74. The method according to claim 11, characterized in that the halogenated halogen with a functional derivative is a selection portion selected from the group comprising DNA, RNA, amino acids, proteins, antibodies, ligands, haptens, carbohydrate receptors or complexing agents, receptors-lipids or complexing agents, protein receptors or agents accmplejanr.es, chelators, and encapsulation vehicles.