US20030109813A1 - Energy-activated targeted cancer therapy - Google Patents

Energy-activated targeted cancer therapy Download PDF

Info

Publication number
US20030109813A1
US20030109813A1 US10317269 US31726902A US2003109813A1 US 20030109813 A1 US20030109813 A1 US 20030109813A1 US 10317269 US10317269 US 10317269 US 31726902 A US31726902 A US 31726902A US 2003109813 A1 US2003109813 A1 US 2003109813A1
Authority
US
Grant status
Application
Patent type
Prior art keywords
target
tissue
tumor
activated
ultrasonic energy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US10317269
Inventor
James Chen
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Light Sciences Corp
Original Assignee
Light Sciences Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date

Links

Images

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K41/00Medicinal preparations obtained by treating materials with wave energy or particle radiation; Therapies using these preparations
    • A61K41/0057Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K41/00Medicinal preparations obtained by treating materials with wave energy or particle radiation; Therapies using these preparations
    • A61K41/0057Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
    • A61K41/00615-aminolevulinic acid-based PDT: 5-ALA-PDT involving porphyrins or precursors of protoporphyrins generated in vivo from 5-ALA
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K41/00Medicinal preparations obtained by treating materials with wave energy or particle radiation; Therapies using these preparations
    • A61K41/0057Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
    • A61K41/0071PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/6811Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin
    • A61K47/6817Toxins
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6849Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A61K47/6867Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from a cell of a blood cancer
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61NELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00Radiation therapy
    • A61N5/06Radiation therapy using light
    • A61N5/0613Apparatus adapted for a specific treatment
    • A61N5/062Photodynamic therapy, i.e. excitation of an agent

Abstract

The present invention is drawn to methods and systems for administering a therapy to a target tissue or target composition in a mammalian subject, using an ultrasonic energy source that preferably transmits energy to a treatment site transcutaneously. The method provides for administering to the subject a therapeutically effective amount of a targeted substance, which preferably selectively binds to the target tissue. Energy at a wavelength or waveband corresponding to that which is absorbed by the targeted substance is then administered. The energy intensity is relatively low, but a high total fluence is employed to ensure the activation of the targeted energy-activated agent or targeted prodrug product. The claimed energy-activated targeted therapy is useful in the treatment of specifically selected target tissues, such as vascular endothelial tissue, the abnormal vascular walls of tumors, solid tumors of the head and neck, tumors of the gastrointestinal tract, tumors of the liver, tumors of the breast, tumors of the prostate, tumors of the lung, nonsolid tumors, malignant cells of the hematopoietic and lymphoid tissue and other lesions in the vascular system or bone marrow, and tissue or cells related to autoimmune and inflammatory disease.

Description

    RELATED APPLICATIONS
  • This application is a divisional application of copending U.S. patent application Ser. No. 09/271,575, filed Mar. 18, 1999, to James Chen entitled “TARGETED TRANSCUTANEOUS CANCER THERAPY.”[0001]
  • Benefit of priority under 35 U.S.C. §119(e) to the following provisional applications is claimed herein: U.S. provisional application Serial No. 60/116,234 to James Chen, filed Jan. 15, 1999, entitled “TARGETED TRANSCUTANEOUS CANCER THERAPY.”[0002]
  • The above-noted applications and provisional applications are incorporated by reference in their entirety.[0003]
  • FIELD OF THE INVENTION
  • This invention generally relates to the delivery to a tumor target site of a therapeutically effective amount of a photosensitizing agent that is activated by a relatively low fluence rate or level of intensity of light administered over a prolonged period of time, and more specifically, to the delivery of a photosensitizing agent that is targeted to bind with cancerous cells at the target site. [0004]
  • BACKGROUND OF THE INVENTION
  • One form of energy activated therapy for destroying abnormal or diseased tissue is photodynamic therapy (PDT). PDT is a two-step treatment process, which has received increasing interest as a mode of treatment for a wide variety of different cancers and diseased tissue. The first step in this therapy is carried out by administering a photosensitive compound systemically by ingestion or injection, or topically applying the compound to a specific treatment site on a patient's body, followed by illumination of the treatment site with light having a wavelength or waveband corresponding to a characteristic absorption waveband of the photosensitizer. The light activates the photosensitizing compound, causing singlet oxygen radicals and other reactive species to be generated, leading to a number of biological effects that destroy the abnormal or diseased tissue, which has absorbed the photosensitizing compound. The depth and volume of the cytotoxic effect on the abnormal tissue, such as a cancerous tumor, depend in part on the depth of the light penetration into the tissue; the photosensitizer concentration and its cellular distribution, and the availability of molecular oxygen which will depend upon the vasculature system supplying the abnormal tissue or tumor. [0005]
  • Various types of PDT light sources and their methods of use have been described in the prior art literature. However, publications describing appropriate light sources and the effects of transcutaneous light delivery to internal treatment sites within a patient's body, for PDT purposes, are relatively limited in number. It has generally been accepted that the ability of a light source external to the body to cause clinically useful cytotoxicity during PDT is limited in depth to a range of 1-2 cm or less, depending on the photosensitizer. [0006]
  • Treatment of superficial tumors in this manner has been associated with inadvertent skin damage due to accumulation of the photosensitizer in normal skin tissue, which is a property of all systemically administered photosensitizers in clinical use. For example, clinically useful porphyrins such as PHOTOPHRIN™ (a QLT, Ltd. brand of sodium porfimer) are associated with general dermal photosensitivity lasting up to six weeks. PURLYTIN™ which is a brand of purpurin, and FOSCAN™, which is brand of chlorin, sensitize the skin to light for at least several weeks, so that patients to whom these drugs are administered must avoid exposure to sunlight or other bright light sources during this time to avoid unintended phototoxic effects on the normal dermal tissue. Indeed, efforts have been made to develop photoprotectants to reduced skin photosensitivity (see, for example: Dillon et al,, “Photochemistry and Photobiology,” 48(2): 235-238 (1988);—and Sigdestad et al., [0007] British J. of Cancer, 74:S89-S92, (1996)).
  • Recently,it has been reported that a relatively intense external laser light source might be employed transcutaneously to cause two-photon absorption by a photosensitizer at a greater depth within a patient's body, so that it is theoretically possible to cause a very limited volume of cytotoxicity in diseased tissue at greater depths than previously believed possible. However, no clinical studies exist to support this contention. One would expect that the passage of an intense beam of light through the skin would lead to the same risk of phototoxic injury to non-target normal tissues, such as skin and subcutaneous normal tissue, if this light is applied in conjunction with a systemically administered photosensitizer. [0008]
  • For example, one PDT modality discloses the use of an intense laser source to activate a photosensitizer drug within a precisely defined boundary (see U.S. Pat. No. 5,829,448, Fisher et al., “Method for improved selectivity in photo-activation of molecular agents”). The two-photon methodology requires a high power, high intensity laser for drug activation using a highly collimated beam, with a high degree of spatial control. For a large tumor, this treatment is not practical, since the beam would have to be swept across the skin surface in some sort of set, repeating pattern, so that the beam encompasses the entire volume of the tumor. Patient or organ movement would be a problem, because the beam could become misaligned. Exposure of normal tissue or skin in the path of the beam and subcutaneous tissue photosensitivity is not addressed in the prior art literature. [0009]
  • Any photosensitizer absorbed by normal tissue in the path of the beam will likely be activated and cause unwanted collateral normal tissue damage. Clearly, it would be preferable to employ a technique that minimizes the risk of damage to normal tissue and which does not depend upon a high intensity laser light source to produce two photon effects. Further, it would be preferable to provide a prolonged exposure of an internal treatment site with light at a lower fluence rate or lower intensity, which tends to reduce the risk of harm to non-target tissue or skin and subcutaneous normal tissue and reduces any collateral tissue damage due to phototoxicity. [0010]
  • Other PDT modalities have employed the use of a light source producing a low total fluence delivered over a short time period to avoid harm to skin caused by activation of a photosensitizer and have timed the administration of such drugs to better facilitate destruction of small tumors in animals (see, for example, U.S. Pat. No. 5,705,518, Richter et al.). However, although not taught or suggested by the prior art, it would be preferable to employ a light source that enables a relatively large total fluence PDT, but at a lower intensity so that larger tumor volumes can more readily be treated. [0011]
  • If, as is often the case, a target tumor tissue lies below an intact cutaneous layer of normal tissue, the main drawbacks of all transcutaneous illumination methods, whether they be external laser or external non-laser light sources, are: (1) the risk of damage to non-target tissues, such as the more superficial cutaneous and subcutaneous tissues overlying the target tumor mass; (2) the limited volume of a tumor that can be treated; and (3) the limitation of treatment depth. Damage to normal tissue lying between the light source and the target tissue in a tumor occurs due to the uptake of photosensitizer by the skin and other tissues overlying the tumor mass, and the resulting undesired photoactivation of the photosensitizer absorbed by these tissues. The consequences of inadvertent skin damage caused by transcutaneous light delivery to a subcutaneous tumor may include severe pain, serious infection, and fistula formation. The limited volume of tumor that can be clinically treated and the limitations of the light penetration below the skin surface in turn have led those skilled in this art to conclude that clinical transcutaneous PDT is only suitable for treatment of superficial, thin lesions. [0012]
  • U.S. Pat. No. 5,445,608, Chen et al., discloses the use of implanted light sources for internally administering PDT. Typically, the treatment of any internal cancerous lesions with PDT requires at least a minimally invasive procedure such as an endoscopic technique, for positioning the light source proximate to the tumor, or open surgery to expose the tumor site. There is some risk associated with any internal procedure performed on the body. Clearly, there would be significant advantage to a completely noninvasive form, of PDT directed to subcutaneous and deep tumors, which avoids the inadvertent activation of any photosensitizer in skin and intervening tissues. To date, this capability has not been clinically demonstrated nor realized. Only in animal studies utilizing mice or other rodents with very thin cutaneous tissue layers, have very small superficial subcutaneous tumors been treated with transcutaneously transmitted light. These minimal in vivo studies do not provide an enabling disclosure or even suggest how transcutaneous light sources might safely be used to treat large tumors in humans with PDT, however. [0013]
  • Another PDT modality in the prior art teaches the destruction of abnormal cells that are circulating in the blood using light therapy, while leaving the blood vessels intact (see, for example: U.S. Pat. No. 5,736,563, Richter et al.; WO 94/06424, Richter; WO 93/00005, Champan et al.; U.S. Pat. No. 5,484,803, Richter et al., and WO 93/24127, North et al. Instead, it might be preferable to deliberately damage and occlude blood vessels that form the vasculature supplying nutrients and oxygen to a tumor mass, thus rendering a given volume of abnormal tissue in the tumor (not circulating cells) ischemic and anoxic and thus promoting the death of the tumor tissue serviced by these blood vessels. [0014]
  • To facilitate the selective destruction of the blood vessels that service a tumor, it would be desirable to selectively bind a photosensitizing agent to specific target tissue antigens, such as those found on the epithelial cells comprising tumor blood vessels. This targeting scheme should decrease the amount of photosensitizing drug required for effective PDT, which in turn should reduce the total light energy, and the light intensity needed for effective photoactivation of the drug. Even if only a portion of a blood vessel is occluded as a result of the PDT, downstream thrombosis is likely to occur, leading to a much greater volume of tumor necrosis compared to a direct cytotoxic method of destroying the tumor cells, in which the photosensitizer drug must be delivered to all abnormal cells that are to be destroyed. [0015]
  • One method of ensuring highly specific uptake of a photosensitizer by epithelial cells in tumor vessels would be to use the avidin-biotin targeting system. Highly specific binding of a targeted agent such as a PDT drug to tumor blood vessels (but not to the cells in normal blood vessels) is enabled by this two step system. While there are reports in the scientific literature describing the binding between biotin and streptavidin to target tumor cells, there are no reports of using this ligand-receptor binding pair to bind with cells in tumor vessels nor in conjunction with carrying out prolonged PDT light exposure (see, for example: Savitsky et al., [0016] SPIE, 3191:343-353, (1997); and Ruebner et al., SPIE, 2625:328-332, (1996)). In a non-PDT modality, the biotin-streptavidin ligand-receptor binding pair has also been reported as useful in binding tumor targeting conjugates with radionuclides (see U.S. Pat. No. 5,630,996, Reno et al.) and with monoclonal antibodies (see Casalini et al.; J Nuclear Med, 38(9):1378-1381, (1997)) and U.S. Pat. No. 5,482,698, Griffiths).
  • Other ligand-receptor binding pairs have been used in PDT for targeting tumor antigens, but the prior art fails to teach their use in conjunction with targeting cells in blood vessels or treatment of large, established tumors (see, for example, Mew et al., [0017] J. of Immunol., 130(3): 1473-1477, (1983)).
  • High powered lasers are usually employed as a light source in administering PDT to shorten the time required for the treatment (see W.G. Fisher, et al., [0018] Photochemistry and Photobiology, 66(2):141-155, (1997)). However, it would likely be safer to use a low power, non-coherent light source that remains energized for two or more hours to increase the depth of the photoactivation. This approach is contrary to the prior art that recommends PDT be carried out with a brief exposure from a high powered, collimated light source.
  • Recently, there has been much interest in the use of anti-angiogenesis drugs for treating cancerous tumors by minimizing the blood supply that feeds a tumor's growth. However, targeting of tumor vessels using anti-angiogenesis drugs may lead to reduction in size of small tumors and may prevent new tumor growth, but will likely be ineffective in causing reliable regression of large, established tumors in humans. However, by using a combination of anti-angiogenesis and a photosensitizer in the targeting conjugate, it is likely that a large volume tumor can be destroyed by administering PDT. [0019]
  • In treating large tumors, a staged procedure may be preferable in order to control tumor swelling and the amount of necrotic tissue produced as the PDT causes destruction of the tumor mass. For example, by activating a photosensitizer bound to tumor vessels in the center of a large tumor and then sequentially expanding the treatment zone outward in a stepwise manner, a large volume tumor can be gradually ablated in a controlled fashion in order to prevent swelling due to edema and inflammation, which is problematic in organs such as the brain. [0020]
  • Delivered in vivo, PDT has been demonstrated to cause vessel thrombosis and vascular constriction, occlusion, and collapse. And though the treatment of very superficial, thin tumors has been reported using transcutaneous light, there are no clinical reports of transcutaneous light activation being used to destroy deeper, thick tumors that are disposed more than 2 cm below the skin surface. Clearly, there is a need for a PDT paradigm that enables large volume tumors that are disposed well below the surface of the skin to be destroyed with transcutaneous light activation. [0021]
  • It is apparent that the usual method of administering PDT to treat bulky tumors, which relies on invasive introduction of optical fibers, is not the best approach. It would be highly advantageous to apply light transcutaneously in a completely noninvasive method to treat such large tumors (as well as small and even microscopic tumors), without risking damage to non-target tissues, such as skin and normal subcutaneous tissue. Instead of the conventional technique, a method of photoactivation and a series of photosensitizer constructs is needed that enable PDT induced cytotoxicity, on both a macro and microscopic scale, without risk to the cutaneous layer, or any surrounding normal tissues. Also, the therapeutic index should be enhanced if a specific photosensitizer drug targeting scheme is employed. [0022]
  • Citation of the above documents is not intended as an admission that any of the foregoing is pertinent prior art. All statements as to the date or representation as to the contents of these documents is based on the information available to the applicants and does not constitute any admission as to the correctness of the dates or contents of these documents. Further, all documents referred to throughout this specification are hereby incorporated by reference herein, in their entirety. [0023]
  • SUMMARY OF THE INVENTION
  • In accord with the present invention, a method is defined for transcutaneously administering a photodynamic therapy to a target tissue in a mammalian subject. The method includes the step of administering to the subject a therapeutically effective amount of either a photosensitizing agent having a characteristic light absorption waveband, a photosensitizing agent delivery system that delivers the photosensitizing agent, or a prodrug that produces a prodrug product having a characteristic light absorption waveband. The photosensitizing agent, photosensitizing agent delivery system, or prodrug selectively binds to the target tissue. Light having a waveband corresponding at least in part with the characteristic light absorption waveband of said photosensitizing agent or of the prodrug is used for transcutaneously irradiating at least a portion of the mammalian subject. An intensity of the light used for irradiating is substantially less than 500 mw/cm[0024] 2, and a total fluence of the light is sufficiently high to activate the photosensitizing agent or the prodrug product, as applicable.
  • Preferably, sufficient time is allowed for any of the photosensitizing agent, the photosensitizing agent delivery system, or the prodrug (depending upon which one of these was administered) that is not bound to the target tissue to clear from non-target tissues of the mammalian subject prior to the step of irradiating with the light. [0025]
  • In one application of the invention, the target tissue is vascular endothelial tissue. In another application, the target tissue is an abnormal vascular wall of a tumor. As further defined, the target tissue is selected from the group consisting of: a vascular endothelial tissue, an abnormal vascular wall of a tumor, a solid tumor, a tumor of a head, a tumor of a neck, a tumor of a gastrointestinal tract, a tumor of a liver, a tumor of a breast, a tumor of a prostate, a tumor of a lung, a nonsolid tumor, malignant cells of one of a hematopoietic tissue and a lymphoid tissue, lesions in a vascular system, a diseased bone marrow, and diseased cells in which the disease is one of an autoimmune and an inflammatory disease. In yet a further application of the present invention, the target tissue is a lesion in a vascular system. It is contemplated that the target tissue is a lesion of a type selected from the group consisting of atherosclerotic lesions, arteriovenous malformations, aneurysms, and venous lesions. [0026]
  • The step of irradiating generally comprises the step of providing a light source that is activated to produce the light. In one preferred embodiment of the invention, the light source is disposed external to an intact skin layer of the mammalian subject during the step of irradiating. In another preferred embodiment, the method includes the step of inserting the light source underneath an intact skin layer, but external to an intact surface of an organ of the mammalian subject, and the organ comprises the target tissue. [0027]
  • Preferably, the photosensitizing agent is conjugated to a ligand. The ligand may be either an antibody or an antibody fragment that is specific in binding with the target tissue. Alternatively, the ligand is a peptide, or a polymer, either of which is specific in binding with the target tissue. [0028]
  • The photo sensitizing agent is preferably selected from the group consisting of indocyanine green (ICG), methylene blue, toluidine blue, aminolevulinic acid (ALA), chlorins, phthalocyanines, porphyrins, purpurins, texaphyrins, and other photosensitizer agents that have characteristic light absorption peak in a range of from about 500 nm to about 1100 nm. [0029]
  • The step of irradiating is preferably carried out for a time interval of from about 30 minutes to about 72 hours, or more preferably, from about 60 minutes to about 48 hours, or most preferably, from about 3 hours to about 24 hours. [0030]
  • In yet another application of the invention, the target tissue is bone marrow, or comprises cells afflicted with either an autoimmune disease or an inflammatory disease. [0031]
  • An additional application of the invention contemplates a method for administering photodynamic therapy to a target composition in a mammalian subject by transillumination. The target composition may include one or more pathogenic agents, including: bacteria, viruses, fungi, protozoa, and toxins as well as tissues infected or infiltrated therewith. [0032]
  • Preferably, the total fluence of the light used for irradiating is between about 30 Joules and about 25,000 Joules, more preferably, between about 100 Joules and about 20,000 Joules, and most preferably, between about 500 Joules and about 10,000 Joules. [0033]
  • Another application of the present invention uses an energy activated compound that has a characteristic energy absorption waveband. The energy activated compound selectively binds to the target tissue. Energy having a waveband corresponding at least in part with the characteristic energy absorption waveband of said energy activated compound is used for transcutaneously irradiating at least a portion of the mammalian subject. Preferably the waveband is in the ultrasonic range of energy. Said compound is activated by said irradiating step, wherein the intensity of said ultrasonic energy is substantially less than that level which would result in damage to normal tissue, but at a sufficiently high total fluence of ultrasonic energy that is absorbed by said compound which in turn destroys the target tissue to which it is bound. Preferably, the total fluence of the ultrasonic energy used for irradiating is between about 5 kHz and more than about 300 MHz, more preferably, between about 10 kHz and more than about 200 MHz, and most preferably, between about 20 kHz and more than about 100 MHz.[0034]
  • BRIEF DESCRIPTION OF THE DRAWING FIGURES
  • The foregoing aspects and many of the attendant advantages of this invention will become more readily appreciated as the same becomes better understood by reference to the following detailed description, when taken in conjunction with the accompanying drawings, wherein: [0035]
  • FIG. 1 is a schematic diagram illustrating an external light source being used to administer transcutaneous cancer-therapy to a relatively large, singular tumor, and to multiple, small tumors; [0036]
  • FIG. 2 is a schematic cross-sectional view of a section of a tumor blood vessel, illustrating binding of an antibody/photosensitive drug to endothelial tissue; [0037]
  • FIGS. 3A and 3B are schematic diagrams illustrating biotin-avidin targeting of endothelial antigens for use in rendering PDT; [0038]
  • FIGS. [0039] 4A-4C schematically illustrate tissue amplified infarction downstream of photodynamic transcutaneous therapy applied to endothelium tissue;
  • FIG. 5 is a schematic diagram illustrating the use of an external ultrasound source for transcutaneous application of PDT to a deep tumor; [0040]
  • FIG. 6 is a schematic diagram showing the use of an external light source for transcutaneous treatment of intraosseous disease; [0041]
  • FIG. 7 is a schematic diagram showing both an external light source transcutaneously administering light and an intraluminal light source position within either the terminal ileum or colon to treat Crohn's disease with targeted PDT; [0042]
  • FIG. 8 is a schematic diagram illustrating an intraluminal light source in the form of a capsule or pill for administering light to destroy [0043] H. pylori on the gastric lining with targeted PDT; and
  • FIG. 9 is a schematic diagram showing how an internal light source administers transillumination of a deep tumor through an organ wall to provide targeted PDT that destroys the tumor.[0044]
  • DESCRIPTION OF THE PREFERRED EMBODIMENT Introduction and General Description of the Invention
  • This invention is directed to methods and compositions for therapeutically treating a target tissue or destroying or impairing a target cell or a biological component in a mammalian subject by the specific and selective binding of a photosensitizer agent to the target tissue, cell, or biological component. At least a portion of the subject is irradiated with light at a wavelength or waveband within a characteristic absorption waveband of the photosensitizing agent. The light is administered at a relatively low fluence rate or intensity, but at an overall high total fluence dose, resulting in minimal collateral normal tissue damage. It is contemplated that an optimal total fluence for the light administered to a patient will be determined clinically, using a light dose escalation trial. It is further contemplated that the total fluence administered during a treatment will preferably be in the range of 30 Joules to 25,000 Joules, more preferably, in the range from 100 Joules to 20,000 Joules, and most preferably, in the range from 500 Joules to 10,000 Joules. [0045]
  • The terminology used herein is generally intended to have the art recognized meaning and any differences therefrom as used in the present disclosure, will be apparent to the ordinary skilled artisan. For the sake of clarity, terms may also have a particular meaning, as will be clear from their use in context. For example, “transcutaneous” as used in regard to light in this specification and in the claims that follow, more specifically herein refers to the passage of light through unbroken tissue. Where the tissue layer is skin or dermis, transcutaneous includes “transdermal” and it will be understood that the light source is external to the outer skin layer. However, the term “transillumination” as used herein refers to the passage of light through a tissue layer, such as the outer surface layer of an organ, e.g., the liver, and it will be apparent that the light source is external to the organ, but internal or implanted within the subject or patient. [0046]
  • One aspect of the present invention provides for the precise targeting of photosensitive agents or drugs and compounds to specific target antigens of a subject or patient and to the method for activating the targeted photosensitizer agents by subsequently administering to the subject light at a relatively low fluence rate or intensity, over a prolonged period of time, from a light source that is external to the target tissue in order to achieve maximal cytotoxicity of the abnormal tissue, with minimal adverse side effects or collateral normal tissue damage. [0047]
  • FIG. 1 illustrates transcutaneous delivery of light [0048] 12 from an external source 10 to a relatively deep tumor 14, or to a plurality of small, but relatively deep tumors 16. The light emitted by external source 10 is preferably of a longer waveband, but still within an absorption waveband of the photosensitive agent (not shown in this Figure) that has been selectively bound to tumor 14 and smaller tumors 16. The longer wavelength of light 12 enables it to pass through a dermal layer 18 and penetrate into the patient's body beyond the depth of tumor(s) being treated with targeted PDT. In these two examples, the PDT is directed specifically at target cells in tumor 14 or in tumors 16.
  • As used in this specification and the following claims, the terms “target cells” or “target tissues” refer to those cells or tissues, respectively that are intended to be impaired or destroyed by PDT delivered in accord with the present invention. Target cells or target tissues take up or bind with the photosensitizing agent, and, when sufficient light radiation of the waveband corresponding to the characteristic waveband of the photosensitizing agent is applied, these cells or tissues are impaired or destroyed. Target cells are cells in target tissue, and the target tissue includes, but is not limited to, vascular endothelial tissue, abnormal vascular walls of tumors, solid tumors such as (but not limited to) tumors of the head and neck, tumors of the gastrointestinal tract, tumors of the liver, tumors of the breast, tumors of the prostate, tumors of the lung, nonsolid tumors and malignant cells of the hematopoietic and lymphoid tissue, other lesions in the vascular system, bone marrow, and tissue or cells related to autoimmune disease. [0049]
  • Further, target cells include virus-containing cells, and parasite-containing cells. Also included among target cells are cells undergoing substantially more rapid division as compared to non-target cells. The term “target cells” also includes, but is not limited to, microorganisms such as bacteria, viruses, fungi, parasites, and infectious agents. Thus, the term “target cell” is not limited to living cells but also includes infectious organic particles such as viruses. “Target compositions” or “target biological components” include, but are not be limited to: toxins, peptides, polymers, and other compounds that may be selectively and specifically identified as an organic target that is intended to be impaired or destroyed by this treatment method. [0050]
  • FIG. 2 includes a section of a tumor blood vessel [0051] 20 having a wall 22, with an endothelial lining 24. A plurality of endothelial antigens 26 are disposed along the endothelial lining. In this example, antibodies 28 that are specific to endothelial antigens 26 have been administered and are shown binding with the endothelial antigens. Coupled to antibodies 28 are PDT photosensitive drug molecules 30. Thus, the PDT photosensitive drug molecules are bound to the endothelial antigens via antibodies 28, but are not bound to non-target cells, since the antibodies are selective only to the endothelial antigens.
  • “Non-target cells” are all the cells of a mammal that are not intended to be impaired, damaged, or destroyed by the treatment method rendered in accord with the present invention. These non-target cells include but are not limited to healthy blood cells, and other normal tissue, not otherwise identified to be targeted. [0052]
  • “Destroy” means to kill the desired target cell. “Impair” means to change the target cell in such a way as to interfere with its function. For example, in North et al., it is observed that after virus-infected T cells treated with benzoporphyrin derivatives (“BPD”) were exposed to light, holes developed in the T cell membrane and increased in size until the membrane completely decomposed ([0053] Blood Cells 18:129-40, (1992)). Target cells are understood to be impaired or destroyed even if the target cells are ultimately disposed of by macrophages.
  • “Energy activated agent” is a chemical compound that binds to one or more types of selected target cells and, when exposed to energy of an appropriate waveband, absorbs the energy, causing substances to be produced that impair or destroy the target cells. [0054]
  • “Photosensitizing agent” is a chemical compound that binds to one or more types of selected target cells and, when exposed to light of an appropriate waveband, absorbs the light, causing substances to be produced that impair or destroy the target cells. Virtually any chemical compound that preferentially is absorbed or bound to a selected target and absorbs light causing the desired therapy to be effected may be used in this invention. Preferably, the photosensitizing agent or compound is nontoxic to the animal to which it is administered or is capable of being formulated in a nontoxic composition that can be administered to the animal. In addition, following exposure to light, the photosensitizing agent in any resulting photodegraded form is also preferably nontoxic. A comprehensive listing of photosensitive chemicals may be found in Kreimer-Bimbaum, Sem. Hematol, 26:157-73, (1989). Photosensitive agents or compounds include, but are not limited to, chlorins, bacteriochlorins, phthalocyanines, porphyrins, purpurins, merocyanines, psoralens, benzoporphyrin derivatives (BPD), and porfimer sodium and pro-drugs such as delta-aminolevulinic acid, which can produce photosensitive agents such as protoporphyrin IX. Other suitable photosensitive compounds include ICG, methylene blue, toluidine blue, texaphyrins, and any other agent that absorbs light in a range of 500 nm-1100 nm. [0055]
  • The term “prodrug” is used herein to mean any of a class of substances that are not themselves photosensitive agents, but when introduced into the body, through metabolic, chemical, or physical processes, are converted into a photosensitive agent. In the following disclosure, an aminolevulinic acid (ALA) is the only exemplary prodrug. After being administered to a patient, ALA is metabolically converted into a porphyrin compound that is an effective photosensitive agent. [0056]
  • “Radiation” as used herein includes all wavelengths and wavebands. Preferably, the radiation wavelength or waveband is selected to correspond with or at least overlap the wavelength(s) or wavebands that excite the photosensitive compound. Photosensitive agents or compound typically have one or more absorption wavebands that excite them to produce the substances, which damage or destroy target tissue, target cells, or target compositions. Even more preferably, the radiation wavelength or waveband matches the excitation wavelength or waveband of the photosensitive compound and has low absorption by the non-target cells and the rest of the intact animal, including blood proteins. For example, a preferred wave length of light for ICG is in the range 750-850 nm. [0057]
  • The radiation used to activate the photosensitive compound is further defined in this invention by its intensity, duration, and timing with respect to dosing a target site. The intensity or fluence rate must be sufficient for the radiation to penetrate skin and reach the target cells, target tissues, or target compositions. The duration or total fluence dose must be sufficient to photoactivate enough photosensitive agent to achieve the desired effect on the target site. Both intensity and duration are preferably limited to avoid over treating the subject or animal. Timing with respect to the dosage of the photosensitive agent employed is important, because (1) the administered photosensitive agent requires some time to home in on target cells, tissue, or compositions at the treatment site, and (2) the blood level of many photosensitive agents decreases with time. [0058]
  • The present invention provides a method for providing a medical therapy to an animal, and the term “animal” includes, but is not limited to, humans and other mammals. The term “mammals” or “mammalian subject” includes farm animals, such as cows, hogs and sheep, as well as pet or sport animals such as horses, dogs, and cats. [0059]
  • Reference herein to “intact animal” means that the whole, undivided animal is available to be exposed to radiation. No part of the animal is removed for exposure to the radiation, in contrast with photophoresis, in which an animal's blood is circulated outside its body for exposure to radiation. However, in the present invention, the entire animal need not be exposed to radiation. Only a portion of the intact animal subject may or need be exposed to radiation, sufficient to ensure that the radiation is administered to the treatment site where the target tissue, cells, or compositions are disposed. [0060]
  • In the present invention, a photosensitizing agent is generally administered to the animal before the animal is subjected to radiation. Preferred photosensitizing agents include, but are not limited to, chlorins, bacteriochlorins, phthalocyanines, porphyrins, purpurins, merocyanines, psoralens and pro-drugs such as delta.-aminolevulinic acid, which can produce drugs such as protoporphyrin. More preferred photosensitizing agents are: methylene blue, toluidine blue, texaphyrins, and any other agent that absorbs light having a wavelength or waveband in the range from 600 nm-1100 nm. Most preferred of the photosensitizing agents is ICG. The photosensitizing agent is preferably administered locally or systemically, by oral ingestion, or by injection, which may be intravascular, subcutaneous, intramuscular, intraperitoneal or directly into a treatment site, such as intratumoral. The photosensitizing agent also can be administered enterally or topically via patches or implants. [0061]
  • The photosensitizing agent also can be conjugated to specific ligands known to be reactive with a target tissue, cell, or composition, such as receptor-specific ligands or immunoglobulins or immunospecific portions of immunoglobulins, permitting them to be more concentrated in a desired target cell or microorganism than in non-target tissue or cells. The photosensitizing agent may be further conjugated to a ligand-receptor binding pair. Examples of a suitable binding pair include but are not limited to: biotin-streptavidin, chemokine-chemokine receptor, growth factor-growth factor receptor, and antigen-antibody. As used herein, the term “photosensitizing agent delivery system” refers to a photosensitizing agent conjugate, which because of its conjugation, has increased selectivity in binding to a target tissue, target cells, or target composition. The use of a photosensitizing agent delivery system is expected to reduce the required dose level of the conjugated photosensitizing agent, since the conjugate material is more selectively targeted at the desired tissue, cell, or composition, and less of it is wasted by distribution into other tissues whose destruction should be avoided. [0062]
  • In FIGS. 3A and 3B, an example of a photosensitizing agent delivery system [0063] 40 is illustrated in which the target tissue is endothelial layer 24, which is disposed along blood vessel wall 22 of tumor blood vessel 20. As shown in FIG. 3A, antibodies 28 are coupled with biotin molecules 42 and thus selectively bound to endothelial antigens 26 along the endothelial layer. FIG. 3B illustrates avidin molecules 44 coupled to PDT photosensitive drug molecules 30, where the avidin molecules bind with biotin molecules 42. This system thus ensures that the PDT photosensitive drug molecules 30 only bind with the selectively targeted endothelial tissue. When light of the appropriate waveband is administered, it activates the PDT photosensitive drug molecules, causing the endothelial tissue to be destroyed.
  • FIGS. [0064] 4A-4C illustrate a mechanism for amplifying the effect on a tumor of PDT administered to destroy the endothelial tissue in a tumor blood vessel 50. Tumor blood vessel 50 distally branches into two smaller blood vessels 52. In FIG. 4A, the PDT administered to activate the PDT photosensitive drug molecules has produced substantial damage to the endothelium, creating an intravascular thrombosis (or clot) 54. As shown in FIG. 4B, the intravascular thrombosis is carried distally through tumor blood vessel 50 until it reaches the bifurcation point where smaller diameter blood vessels 52 branch. Due to the flow through smaller internal diameter of blood vessels 52, intravascular thrombosis 54 can not advance any further, and is stopped, creating a plug that virtually stops blood flow through tumor blood vessel 50. The interruption of blood flow also interrupts the provision of nutrients and oxygen to the surrounding tumor cells, causing the tumor cells to die. In FIG. 4C, the dying tumor cells 56 are within a zone of tumor cell death or necrosis 58 surrounding the vessel and which zone increases in volume over time, thereby amplifying the effects of the PDT on the endothelium tissue of the tumor blood vessels.
  • A photosensitizing agent can be administered in a dry formulation, such as pills, capsules, suppositories or patches. The photosensitizing agent also may be administered in a liquid formulation, either alone, with water, or with pharmaceutically acceptable excipients, such as are disclosed in Remington's Pharmaceutical Sciences. The liquid formulation also can be a suspension or an emulsion. In particular, liposomal or lipophilic formulations are desirable. If suspensions or emulsions are utilized, suitable excipients include water, saline, dextrose, glycerol, and the like. These compositions may contain minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, antioxidants, pH buffering agents, and the like. [0065]
  • The dose of photosensitizing agent will vary with the target tissue, cells, or composition, the optimal blood level (see Example 1), the animal's weight, and the timing and duration of the radiation administered. Depending on the photosensitizing agent used, an equivalent optimal therapeutic level will have to be empirically established. Preferably, the dose will be calculated to obtain a desired blood level of the photosensitizing agent, which will likely be between about 0.01 μg/ml and 100 μg/ml. More preferably, the dose will produce a blood level of the photosensitizing agent between about 0.01 μg/ml and 10 μg/ml. [0066]
  • The intensity of radiation used to treat the target cell or target tissue is preferably between about 5 mW/cm[0067] 2 and about 100 mW/cm2. More preferably, the intensity of radiation employed should be between about 10 mW/cm2 and about 75 mW/cm2. Most preferably, the intensity of radiation is between about 15 mW/cm2 and about 50 mW/cm2.
  • The duration of radiation exposure administered to a subject is preferably between about 30 minutes and about 72 hours. More preferably, the duration of radiation exposure is between about 60 minutes and about 48 hours. Most preferably, the duration of radiation exposure is between about 2 hours and about 24 hours. [0068]
  • It is contemplated that a targeted photosensitizer agent can be substantially and selectively photoactivated in the target cells and target tissues within a therapeutically reasonable period of time and without excess toxicity or collateral damage to non-target normal tissues. Thus, there appears to be a therapeutic window bounded by the targeted photosensitizer agent dosage and the radiation dosage. In view of problems in the prior art related to either extracorporeal treatment of target tissues or use of high intensity laser light irradiation intra-operatively, the present invention offers substantial advantages. In accord with the present invention, targeted transcutaneous PDT will be employed to treat patients injected with a photosensitizer agent and will subject the patients to a relatively low fluence rate, but high total fluence dose of radiation. This approach is an attractive method for treating target tissues that include neoplastic diseased tissue, infectious agents, and other pathological tissues, cells, and compositions. [0069]
  • One aspect of the present invention is drawn to a method for transcutaneous energy activation therapy applied to destroy tumors in a mammalian subject or patient by first administering to the subject a therapeutically effective amount of a first conjugate comprising a first member of a ligand-receptor binding pair conjugated to an antibody or antibody fragment. The antibody or antibody fragment selectively binds to a target tissue antigen. Simultaneously or subsequently, a therapeutically effective amount of a second conjugate comprising a second member of the ligand-receptor binding pair conjugated to an energy-sensitive agent or energy-sensitive agent delivery system or prodrug is administered to the patient, wherein the first member binds to the second member of the ligand-receptor binding pair. These steps are followed by irradiating at least a portion of the subject with energy having a wavelength or waveband absorbed by the energy-sensitive agent, or energy-sensitive agent delivery system, or by the product thereof. This radiation energy is preferably provided by an energy source that is external to the subject and is preferably administered at a relatively low fluence rate that results in the activation of the energy-sensitive agent, or energy-sensitive delivery system, or prodrug product. [0070]
  • While one preferred embodiment of the present invention is drawn to the use of light energy for administering PDT to destroy tumors, other forms of energy are within the scope of this invention, as will be understood by those of ordinary skill in the art. Such forms of energy include, but are not limited to: thermal, sonic, ultrasonic, chemical, light, microwave, ionizing (such as x-ray and gamma ray), mechanical, and electrical. For example, sonodynamically induced or activated agents include, but are not limited to: gallium-porphyrin complex (see Yumita et al., [0071] Cancer Letters, 112: 79-86, (1997)), other porphyrin complexes, such as protoporphyrin and hematoporphyrin (see Umemura et al., Ultrasonics Sonochemistry 3:S187-S191, (1996)); other cancer drugs, such as daunorubicin and adriamycin, used in the presence of ultrasound therapy (see Yumita et al., Japan J. Hyperthermic Oncology, 3(2):175-182, (1987)).
  • FIG. 5 illustrates the use of an external ultrasound transducer head [0072] 60 for generating an ultrasonic beam 62 that penetrates through a dermal layer 64 and into a subcutaneous layer 66. The external ultrasound transducer head is brought into contact with dermal layer 64 so that ultrasonic beam 62 is directed toward a relatively deep tumor 68. The ultrasonic beam activates a PDT photosensitive drug that has been administered to the patient and selectively targeted at tumor 68, causing the drug to destroy the tumor.
  • This invention further preferably employs an energy source, e.g., a light source, that is external to the target tissue. The target tissues may include and may relate to the vasculature or blood vessels that supply blood to tumor tissue or the target tissues may include the tumor tissue antigens, per se. These target tissue antigens will be readily understood by one of ordinary skill in the art to include but to not be limited to: tumor surface antigen, tumor endothelial antigen, non-tumor endothelial antigen, and tumor vessel wall antigen, or other antigens of blood vessels that supply blood to the tumor. [0073]
  • Where the target tissue includes endothelial or vascular tissue, a preferable ligand-receptor binding pair includes biotin-streptavidin. In this preferred embodiment, the activation of photosensitizer agents by a relatively low fluence rate of a light source over a prolonged period of time results in the direct or indirect destruction, impairment or occlusion of blood supply to the tumor resulting in hypoxia or anoxia to the tumor tissues. Where the target tissue includes tumor tissue other than endothelial or vascular, the activation of photosensitizer agents by a relatively low fluence rate of a light source over a prolonged period of time results in the direct destruction of the tumor tissue due to deprivation of oxygen and nutrients from the tumor cells. [0074]
  • The ordinary skilled artisan would be familiar with various ligand-receptor binding pairs, including those known and those currently yet to be discovered. Those known include, but are not limited to: biotin-streptavidin, chemokine-chemokine receptor, growth factor-growth factor receptor, and antigen-antibody. The present invention contemplates at least one preferred embodiment that uses biotin-streptavidin as, the ligand-receptor binding pair. However, the ordinary skilled artisan will readily understand from the present disclosure that any ligand-receptor binding pair may be useful in practicing this invention, provided that the ligand-receptor binding pair demonstrates a specificity for the binding by the ligand to the receptor and further provided that the ligand-receptor binding pair permits the creation of a first conjugate comprising a first member of the ligand-receptor binding pair conjugated to an antibody or antibody fragment. In this case, the antibody or antibody fragment selectively binds to a target tissue antigen and permits the creation of a second conjugate comprising a second member of the ligand-receptor binding pair conjugated to an energy-sensitive or photosensitizing agent, or energy-sensitive or photosensitizing agent delivery system, or prodrug. The first member then binds to the second member of the ligand-receptor binding pair. [0075]
  • Another preferred embodiment of the present invention includes a photosensitizing agent delivery system that utilizes both a liposome delivery system and a photosensitizing agent, where each is separately conjugated to a second member of the ligand-receptor binding pair, and where the first member binds to the second member of the ligand-receptor binding pair. More preferably, the ligand-receptor binding pair is biotin-streptavidin. In this embodiment, the photosensitizing agent as well as the photosensitizing agent delivery system may both be specifically targeted through selective binding to a target tissue antigen by the antibody or antibody fragment of the first member binding pair. Such dual targeting is expected to enhance the specificity of uptake and to increase the quantity of uptake of the photosensitizing agent by the target tissue, cell, or compositions. [0076]
  • EXAMPLES
  • Having now generally described the invention, it will be more readily understood through reference to the following examples, which are provided by way of illustration and are not intended to be limiting in regard to the scope of the invention, unless specified. [0077]
  • Example 1
  • Transcutaneous Photodynamic Therapy of a Solid Type Tumor [0078]
  • A patient in the terminal phase of recurrent malignant colon cancer presented with a protruding colon carcinoma tumor mass of approximately 500 grams and approximately 13 cm in diameter, which extended through the patient's dermis. Due to the advanced state of the patient's disease and due to the highly vascularized nature of this tumor mass, resection was not feasible. Further, this large tumor mass presented a significant amount of pain and discomfort to the patient, as well as greatly impairing the patient's ability to lie flat. [0079]
  • Six separate light source probes, each including a linear array of LEDs, were surgically implanted in this large human tumor using standard surgical procedures. An intensity of about 25-30 mW of light from each light source probe (650 nm peak wavelength) was delivered to the tumor for 40 hours following oral administration to the patient of a single dose of an (ALA) photosensitizer agent (60 mg/kg). However, after 18 hours, two of the light source probes became unseated from the tumor mass and were disconnected from the electrical power supply used to energize the LEDs on each probe. The total fluence delivered to the tumor bed during this single extended duration treatment was in excess of 20,000 Joules. Extensive tumor necrosis in a radius of up to 5 cm around each of the light source probes was observed after 40 hours of PDT, with no collateral damage to surrounding normal tissue. The extent of this PDT induced necrotic effect in a large volume of tumor tissue was totally unexpected and has not been described before in any PDT studies in subjects in vivo or clinically. Over the course of four weeks following PDT, the necrotic tumor tissue was debrided from the patient resulting in a reduction of approximately 500 grams of tumor tissue. The patient noted a significant improvement in his quality of life, with a resurgent level of energy and improved well being. [0080]
  • The average thickness of human skin is approximately 1 cm. Therefore, if this same method of prolonged, relatively low fluence rate, but overall high total fluence of light delivery is utilized to deliver the light transcutaneously, a therapeutic effect well below the skin surface, to a depth of is contemplated. [0081]
  • The fluence rate employed in this Example represented about 150-180 mW/cm[0082] 2, with a total fluence more than 20,000 Joules. The preferable fluence rate contemplated more broadly by the present invention is between about 5 mW/cm2 and about 100 mW/cm2, more preferably, between about 10 mW/cm2 and about 75 mW/cm2, and most preferably, between about 15 mW/cm2 and about 50 mW/cm2.
  • It is further contemplated that the optimal total fluence be empirically determined, using,a light dose escalation trial, and will likely and preferably be in the range of about 30 Joules to about 25,000 Joules, and more preferably be in the range from about 100 Joules to about 20,000 Joules, and most preferably be in the range from about 500 Joules to about 10,000 Joules. [0083]
  • Example 2
  • Transcutaneous Photodynamic Therapy of Intraosseous Disease [0084]
  • The current accepted therapy for treating leukemia and other malignant bone marrow diseases employs a systemic treatment utilizing chemotherapy and/or radiotherapy, sometimes followed by a bone marrow transplant. There are significant risks associated with non-discriminative ablative therapies that destroy all marrow elements, including the risks of infections, bleeding diathesis, and other hematological problems. [0085]
  • There is a definite need for alternative therapies that do not subject patients to procedures which may be risky and which inherently cause pain and suffering. This example is directed to a method of treating intraosseous malignancy that has major advantages over the prior art techniques for treating this disease. [0086]
  • A targeted antibody-photosensitizer conjugate (APC) is constructed, which binds selectively to antigens present on leukemic cells. This ligand-receptor binding pair or APC is infused intravenously and is taken up in the marrow by circulating leukemic cells, and by stationary deposits that may reside in other organs. When unbound to leukemic cells, APC is eliminated from the body. Internal or external light sources may be used to activate the targeted drug. For example, light bar probes disclosed in U.S. Pat. No. 5,445,608 may be inserted into bone marrow to treat the intraosseous disease. The devices disclosed in U.S. Pat. No. 5,702,432 may be used to treat disease cells circulating in the patient's lymphatic or vascular system. An external device transcutaneously activating the targeted drug, for example, a light source that emits light that is transmitted through the dermal layer may also be used in treating the marrow compartment in accord with the present invention. [0087]
  • PDT targeting has been described for leukemic cells (see U.S. Pat. No. 5,736,563). but not with capability of treating marrow in situ. Without this capability, simply lowering the leukemic cell count would have little clinical benefit, since the marrow is a major source of new leukemic clones, and the marrow must. be protected from failure, which will lead to the death of the patient regardless of how well the pathologic cell load in the circulation is treated. Specific APC promotes the selective damage of leukemic cells in marrow, while reducing collateral and non-target tissue damage. Further, the use of a relatively low fluence rate, but overall high total fluence dose is particularly effective in this therapy. Optimal fluence rates and dosing times are readily empirically determined using dose escalation for both drug and light dose as is often done in a clinical trial. Any of a number of different types of leukemia cell antigens may be selected, provided that the antigen chosen is as specific as possible for the leukemia cell. Such antigens will be known to those of ordinary skill in this art. The selection of a specific photosensitizer agent may be made, provided that the photosensitizer agent chosen is activated by light having a waveband of from about 500 nm to about 1100 nm, and more preferably, a waveband from about 630 nm to about 1000 nm, and most preferably, a waveband from about 800 nm to about 950 nm or greater. The photosensitizer agents noted above are suitable for use in this Example. [0088]
  • With reference to FIG. 6, external light source [0089] 10 is administering light 12 transcutaneously through dermal layer 18. Light 12 has a sufficiently long wavelength to pass through a subcutaneous layer 70 and through a cortical bone surface 74, into a bone marrow compartment 76. Leukemia cells 78 have penetrated bone marrow compartment 76 and are distributed about within it. To provide targeted PDT treatment that will destroy the leukemia cells, antibodies 82 bound with PDT photosensitive drug molecules 84 have been administered to the patient and have coupled with leukemia antigens 80 on the leukemia cells 78. The light provided by external light source 10 thus activates the PDT photosensitive drug, causing it to destroy the leukemia cells. This targeted PDT process is carried out with minimal invasive or adverse impact on the patient, in contrast to the more conventional treatment paradigms currently used.
  • Example 3
  • Transcutaneous Photodynamic Therapy of Crohn's Disease [0090]
  • Crohn's disease is a chronic inflammation of the gastrointestinal tract thought to be mediated in large part by dysfunction of CD4[0091] + T cells lining the gut mucosa, especially in terminal ileum. The current accepted therapy for Crohn's disease provides for surgical removal of the inflamed bowel segment and the use of anti-inflammatory agents, steroids and other immunosuppressive drugs. None of these measures is entirely satisfactory due to surgical risk, recurrence of disease, medication side effects, and refractoriness of the disease. There is a clear need for alternative therapies useful in treating this immune dysfunction that offer greater efficacy and reduced side effects and risk. This Example, details of which are illustrated in FIG. 7, indicates the drug compositions and methodologies useful in accord with the present invention to selectively destroy the dysfunctional cells or inhibit their function. In the illustrated example, external light source 10 is administering light 12 that has a sufficiently long wavelength to penetrate dermal tissue 18, which is disposed over a patient's abdomen, and pass through a subcutaneous layer 90, into a terminal ileum or colon 92. The light passes through wall 94 of the terminal ileum or colon. Alternatively (or in addition), light 12′ can be administered from an intraluminal probe 96, from sources (not separately shown) that are energized with an electrical current supplied through a lead 98.
  • Ligand-receptor binding pairs [0092] 100, or more specifically, APCs, are created that bind selectively to CD4+ T cell antigens 102 of T cells 104, which are disposed along the interior, intraluminal surface of the terminal ileum or colon. For example, the CD4+ antigen itself may be targeted by those antibodies 106 that bind specifically to the CD4+ antigen. Many of the photosensitizer agents noted above may be used for photosensitizing drug molecules 108, in the therapy of this Example. The APC is preferably formulated into a pharmaceutically acceptable compound that can be released in the terminal ileum and colon in a manner similar to that known to be used for the orally delivered form of Budesonide™ also known as Entocort™. The APC, compound is ingested and releases the conjugate into the terminal ileum and colon. At the time of therapy, the bowel should have been prepped in much the same manner as done in preparing for a colonoscopy, so that it is cleared of fecal material. The targeted photosensitizer will bind to the pathologic T cells and any unbound APC is removed via peristaltic action. The sensitizer bound to the T cells is activated by intraluminally positioned light source probe 96, details of which are disclosed in any one of U.S. Pat. Nos. 5,766,234; 5,782,896; 5,800,478; and 5,827,186, each of which is hereby incorporated by reference herein in its entirety; or by a flexible intraluminal optical fiber (not shown) that is passed via the nasopharynx; or, by the transcutaneous light illumination provided by external light source 10. Transcutaneous light illumination is preferred because it is entirely noninvasive.
  • In this exemplary treatment, the following protocol may be utilized: [0093]
  • Step 1 Patient is NPO (“non per os” or nothing by mouth) and the bowel has been prepped or cleansed by administering an enema to clear it of fecal material; [0094]
  • Step 2 Specially formulated APC conjugate compound [0095] 100 is ingested;
  • Step 3 The APC conjugate is released to the terminal ileum and colon; [0096]
  • Step 4 If transcutaneous illumination is not used, one or more light source probes [0097] 96 are ingested or passed into the GI tract and advanced to the terminal ileum or colon.
  • Step 5 the APC conjugate is bound to target T cells [0098] 104 and any unbound conjugate fraction passes distally via peristalsis (and is subsequently eliminated from the body).
  • Step 6 If an internal light source is used, the light source should preferably be imaged using ultrasound or computer assisted topography (i.e., a CT scan—not shown) to confirm—its location and the I light source can then be activated while positioned in the ileum. Once activated, the light source will deliver light at the appropriate waveband for the photosensitizing agent selected, at a relatively low fluence rate, but at a high total fluence dose, as noted above. The optimal drug dose and fluence parameters will be determined clinically in a drug and light dose escalation trial. The light dose and drug dose are such that T cell inactivation occurs, leading to decreased regulation of the immune process and a reduction of any pathologic inflammation—both of which are factors—characteristic of this disease. [0099]
  • Step 7 The light source is deactivated. It is particularly important to deactivate an internal light source before withdrawing it from the treatment site to prevent nonspecific APC activation. [0100]
  • The present invention can also be employed to target other types of immunologic cells, such as other T cells, macrophages, neutrophils, B cells, and monocytes. A tiered approach can thus be employed, starting with CD4[0101] + T cells, then moving to CD8+ T cells, and then monocytes, and neutrophils. By inhibiting or preventing interaction and/or secretion of inflammatory cell products, the pathologic process is controlled at the lumenal site, completely avoiding systemic side effects and major surgery. The same process can be applied to treat ulcerative colitis with the same benefits. As indicated above, the APC can be activated with light administered transcutaneously, using any number of different types of external light sources such as LEDs, laser diodes, and lamps that emit light with a wavelength or waveband sufficiently long to penetrate through the overlying dermal and internal tissue, and into the intestine. The, optimal wavelength or waveband of this light is determined by both the light absorption properties of the photosensitizer and the need to use light with as long a wavelength as possible to ensure adequate penetration into the patient's body. A desirable photosensitizer is preferably one that absorbs in the range from about 700 nm to about 900 rim, which optimizes tissue penetration. The appropriate fluence rate and total fluence delivered is readily determined by a light dose escalation clinical trial. The light dose and drug dose are such that T cell inactivation occurs, leading to reduced regulation of the immune process and a reduction in pathologic inflammation.
  • Example 4
  • Intraluminal Transcutaneous PDT Targeted at [0102] Helicobacterpylori
  • Targeting of photosensitizers to bind with bacterial cells is known in the prior art. Many antigens that can serve as targets for ligand-receptor binding pairs, and more specifically, APC have been identified, and the techniques to construct such conjugates are well known to those of ordinary skill in this art. What is not apparent from the prior art are the steps necessary to for apply such conjugates in the treatment of a clinical disease. This Example describes the clinical application of APC to the treatment of an infection using PDT. FIG. 8 illustrates details of the example, as described below. [0103]
  • [0104] Helicobacter pylori is reportedly associated with tumors of the stomach in mice and as a putative agent of ulcerative pathology in humans. However, it appears that the use of PDT for destroying an H. pylori infection in human patients has not been carried out, although proposals to use laser light for PDT destruction of bacteria have been set forth (Millson et al., J. of Photochemistry and Photobiology, 32: 59-65 (1996)).
  • In this Example, a capsular or pill-shaped and sized light source [0105] 120 is administered orally to a patient, so that it passes into the stomach 118 of the patient, where it administers light 122. Alternatively, an optical fiber (not shown) may be passed into the stomach via the nasopharynx to administer light 122 to the treatment site. In order to implement targeted PDT for treating ulcers in humans, an APC 124, which antibody 131 is targeted against a suitable Helicobacter pylori antigen 126 is formulated into an ingestible compound that releases the APC to a gastric mucus/epithelial layer 128 where the bacterium is found. The APC is ingested at a time when the stomach and duodenum is substantially empty in order to promote binding of the APC to bacterium 130. Any unbound APC is diluted by gastric juice and carried distally by peristalsis to be eliminated from the body in fecal matter. Light sources suitable for intraluminal passage are disclosed in any one of U.S. Pat. Nos. 5,766,234; 5,782,896; 5,800,478; and 5,827,186, the disclosure of each being specifically hereby incorporated herein in its entirety. Alternatively, light source 120 in capsule or pill form, e.g., as disclosed in copending commonly assigned U.S. patent application, Ser. No. 09/260,923, entitled, “Polymer Battery for Internal Light Device.”—filed on Mar. 2, 1999 is used for activating the APC. The light source is preferably energized just prior to its ingestion or remotely after ingestion, when in the stomach or in a desired intraluminal passage. If necessary, multiple light sources are ingested to insure that adequate photoactivation of the localized APC occurs sufficient to kill the bacterium. Light is delivered at a relatively low fluence rate but at a high total fluence dose, as discussed above. The light source(s) may be deactivated after passage beyond the duodenum to avoid unwanted distal photoactivation. In this manner, a photosensitizing agent 132 comprising the APC is activated topically without the need for a procedure such as endoscopy with fiberoptic gastric illumination in order to provide the activating light. Since the APC is targeted, nonspecific uptake by normal tissue and other normal compositions of the body is minimized in order to prevent injury to normal gastric tissue and problems with the gastric system.
  • In this exemplary treatment, the following protocol may be utilized: [0106]
  • Step 1 Patient is NPO for six hours to insure that the stomach is empty. [0107]
  • Step 2 The APC is ingested. [0108]
  • Step 3 One hour elapses to allow for bacterial binding and distal passage of unbound APC. The optimal period can be longer or shorter and is readily determined by measuring the clinical response; for example, response can be determined endoscopically by observation and biopsy. [0109]
  • Step 4 One or more light sources are ingested sequentially and activated in the stomach. The length of time that light is administered by these sources and the number of sources that are ingested will be determined clinically in a light dose escalation study. The churning action of the stomach serves to translocate the light source(s) so that the light is distributed more evenly prior to passage of the source(s) into the duodenum. Since each light source is small (the size of a pill or tablet), it passes easily out through the GI system via peristalsis. [0110]
  • Step 5 The light sources are deactivated after distal passage beyond the gastroduodenal area and excreted in fecal matter. [0111]
  • Note that it is also contemplated that an external light source located over the gastric area can be used to transcutaneously administer light to the treatment site, and that an ultrasonic transducer (not shown here, but generally like that shown in FIG. 5) can alternatively be employed to activate the APC, provided that photosensitizer agent [0112] 132 comprising the APC is activated by the frequency of ultrasonic energy transmitted by the transducer. The use of an external light source requires that the APC and the light source absorb and emit in the near infrared to infrared range, respectively, so that the light will efficiently penetrate the patient's skin and reach the treatment site. Examples of long waveband photosensitizers are ICG, toluidine blue, and methylene blue, as disclosed herein.
  • Example 5
  • Transcutaneous PDT for Targeting Pulmonary Tuberculosis [0113]
  • An APC is formulated to bind with great affinity to [0114] Mycobacterium tuberculosis in a selective and specific manner. Preferably, the APC is formulated as an aerosol, which can be easily inhaled, enabling distribution into all lung segments. Steam is then inhaled to solubilize any unbound APC and facilitate its removal from the lung by exhalation. Alternatively, the APC is formulated as an injectable compound and administered intravenously. Either way, the bound APC is photoactivated by an external light source disposed on the chest and/or back.
  • Step 1 The APC is inhaled or injected. [0115]
  • Step 2 Time is allowed to elapse to allow binding of the APC with the [0116] Mycobacterium tuberculosis, followed by steam inhalation to remove any unbound APC (if inhaled). The time required to ensure a therapeutically effective dose of bound APC may be routinely determined clinically using standard clinical practices and procedures.
  • Step 3 The light source is disposed adjacent to the thorax and activated for a sufficient time to ensure that therapeutic irradiation has occurred, which may be routinely determined clinically using conventional clinical practices and procedures. The fluence rate and total fluence dose may be determined as noted above. [0117]
  • Note that alternatively, an internal light source disposed within the thoracic area can be used to administer the light. A further alternative would be the use of an external ultrasonic transducer to produce ultrasonic sound waves that activate the APC. The use of an external light source requires that the APC and the light source respectively absorb and emit light in the near infrared to infrared range to ensure efficient skin penetration of the light. Examples of long waveband photosensitizers are ICG, toluidine blue, methylene blue. [0118]
  • Example 6
  • Transcutaneous PDT for Targeting Otitis Media [0119]
  • A photosensitizer conjugate is formulated which binds with great affinity to [0120] Streptococcus pneumoniae and Hemophilus influenzae in a selective manner. The APC is formulated into an injectable compound, which can be administered intravenously or instilled topically into the middle ear via a previously placed tympanostomy tube. The drug is activated using light emitted by a small light source about the size, shape, and weight of a hearing aid, which is disposed behind the ear and aimed at the middle ear, so that the light passes into the middle ear transcutaneously.
  • Step 1 The APC fluid formulation is instilled into the middle ear. [0121]
  • Step 2 Sufficient time is allowed to elapse to allow binding of the APC with the disease organisms, and then, any excess fluid is drained away by gravity or actively aspirated using a needle and syringe. [0122]
  • Step 3 The light source is positioned behind the ear and activated. The light source need not be very intense since the middle ear cavity is small. Further, the fluence rate and total fluence dose may be followed as discussed above. [0123]
  • Example 7
  • Transcutaneous PDT for Targeting Antibiotic Associated Pseudo Membranous Colitis [0124]
  • In cases where [0125] Clostridium difficile causes pseudomembranous colitis, the same scheme disclosed above for the treatment of H. pylori may be applied. The difference is that the APC is targeted toward C. difficile and the ingested light source is activated in the colon rather than in the stomach. Alternatively, the photosensitive agent can be activated with transcutaneously transmitted light from an external light source, or by ultrasonic energy produced by an ultrasonic transmitter.
  • Example 8
  • Transcutaneous PDT for Targeting Septic Shock Disease [0126]
  • A number of anti-endotoxin antibodies and peptides have been developed and synthesized that can be bound to photosensitizers to form anti-endotoxin APCs. These APCs are injected, allowed to bind and then activated transcutaneously with light, or by using the intracorporeal light emitting devices disclosed in U.S. Pat. No. 5,702,432. For transcutaneous activation, an external light source is placed over a major vessel, preferably an artery, but most preferably a vein where the blood flow is slower, to allow more time for APC activation. [0127]
  • Example 9
  • Liver Cancer Photodynamic Therapy by Transillumination [0128]
  • This Example uses the present invention for the treatment of an organ infiltrated with tumor tissue. Reference is made to FIG. 9. Specifically, light [0129] 140 is administered by transillumination through liver tissue 148 from an implanted light source 144 that is disposed external to the surface of liver 142, but within the patient's body underneath the skin layer 18. In this embodiment, a patient is injected intravenously with a photosensitizer agent ICG, conjugated to an antibody that is specific to vascular endothelial antigen (not separately shown) on a tumor 146, so that the antibody binds with the antigen, but not to other tissue in the liver. The optimal dose of ICG will be empirically determined, for example, via a dose escalation clinical trial as is so often performed to evaluate chemotherapeutic agents. One or more light source probes 144 are surgically implanted (e.g., endoscopically) adjacent to, but not invading parenchymal tissue 148 of liver 142. After delaying a time sufficient to permit clearing of the photosensitizer conjugate from the non-target tissues, the light source(s) is(are) activated, irradiating the target tissue with light 140 at a relatively low fluence rate, but administering a high total fluence dose of light in the waveband from about 750 nm to about 850 nm.
  • The specific dose of photosensitizer conjugate administered to the patient is that which will result in a concentration of active ICG in the blood of between about 0.01 μg/ml and about 100 μg/ml and more preferably, between about 0.01 μg/ml and about 10 [μg/ml. It is well within the skill of the ordinary skilled artisan to determine the specific therapeutically effective dose using standard clinical practices and procedures. Similarly, a specific acceptable fluence rate and a total fluence dose may be empirically determined based upon the information provided in this disclosure. [0130]
  • Although the present invention has been described in connection with the preferred form of practicing it, those of ordinary skill in the art will understand that many modifications can be made thereto within the scope of the claims that follow. Accordingly, it is not intended that the scope of the invention in any way be limited by the above description, but instead be determined entirely by reference to the claims that follow. [0131]

Claims (20)

    What is claimed:
  1. 1. A method for transcutaneously administering a therapy to a target tissue in a mammalian subject, comprising the steps of:
    (a) administering to the subject a therapeutically effective amount of a targeted compound that is activated by ultrasonic energy to render the therapy, where the targeted compound selectively binds to the target tissue, but not to a non-target tissue; and
    (b) irradiating at least a portion of the subject with ultrasonic energy at a wavelength that activates the targeted compound, causing the target tissue to be destroyed.
  2. 2. The method of claim 1, wherein the step of irradiating is delayed for a period of time sufficient for any of the compound that has not bound to the target tissue to clear from adjacent non-target tissue of the mammalian subject, prior to the step of irradiating.
  3. 3. The method of claim 1, wherein the target tissue is selected from the group consisting of a vascular endothelial tissue, an abnormal vascular wall of a tumor, a solid tumor in one of the head, the neck, the gastrointestinal tract, the liver, the breast, the prostate, and the lung, a nonsolid tumor, malignant cells in hematopoietic tissue, malignant cells in lymphoid tissue, lesions in a vascular system, diseased bone marrow, cells afflicted by an autoimmune disease and cells afflicted with an inflammatory disease.
  4. 4. The method of claim 1, further comprising the step of providing an ultrasonic emitting source for emitting the ultrasonic energy used for the step of irradiating.
  5. 5. The method claim 4, wherein the ultrasonic energy emitting source is disposed external to an intact skin layer.
  6. 6. The method of claim 1, wherein said compound includes an energy-activated agent that is conjugated to a ligand.
  7. 7. The method of claim 6, wherein the ligand is selected from the group consisting of a target-specific antibody, a target-specific peptide and a target-specific polymer.
  8. 8. The method of claim 1, wherein the compound is selected from the group consisting of indocyanine green, methylene blue, toluidine blue, aminolevulinic acid, phthalocyanines, porphyrins, purpurins and texaphyrins.
  9. 9. The method of claim 1, wherein the compound is selected from the group consisting of gallium-porphyrin complexes, protoporphyrin, hematoporphyrin, daunorubicin and adriamycin.
  10. 10. The method of claim 1, wherein the step of irradiating is carried out for a time interval of from about 30 minutes to about 72 hours.
  11. 11. The method of claim 1, wherein the ultrasonic energy used for the step of irradiating is at a frequency between about 5 kHz and more than about 300 MHz.
  12. 12. The method of claim 1, wherein the ultrasonic energy used for the step of irradiating is at a frequency between about 20 kHz and more than about 100 MHz.
  13. 13. The method of claim 1, wherein the targeted compound activated by ultrasonic energy comprises one of:
    (a) a targeted compound activated by ultrasonic energy;
    (b) a delivery system that delivers the targeted compound activated by ultrasonic energy to bind with the target tissue; or
    (c) a prodrug that produces a prodrug product activated by ultrasonic energy, wherein the prodrug product selectively binds to the target tissue.
  14. 14. An ultrasonic energy-activated targeted delivery system that is selectively targeted at a target tissue, comprising:
    (a) an ultrasonic energy-activated agent that absorbs energy and destroys a target tissue to which it is bound; and
    (b) a ligand conjugated to the ultrasonic energy-activated agent, said ligand binding to a receptor on the target tissue with specificity, so that binding of the ligand to a non-target tissue is minimized.
  15. 15. The ultrasonic energy-activated targeted delivery system of claim 14, wherein the energy-activated agent comprises a prodrug.
  16. 16. The ultrasonic energy-activated targeted delivery system of claim 14, wherein the ligand comprises an antibody that binds to the receptor.
  17. 17. The ultrasonic energy-activated targeted delivery system of claim 14, wherein said receptor is selected from the group consisting of a vascular endothelium antigen, an antigen that is specific for an abnormal vascular wall of a tumor and an antigen that is specific for a non-vascular tumor tissue.
  18. 18. The ultrasonic energy-activated targeted delivery system of claim 14, wherein the ligand is selected from the group consisting of a target-specific antibody, a target-specific antibody fragment, a target-specific peptide and a target-specific polymer.
  19. 19. The ultrasonic energy-activated targeted delivery system of claim 14, wherein the ligand and the receptor comprise a binding pair selected from the group consisting of a biotin-streptavidin, a chemokine-chemokine receptor, a growth factor-growth factor receptor and an antigen-antibody.
  20. 20. The ultrasonic energy-activated targeted delivery system of claim 14, wherein the ligand is a target-specific antibody specific to an antigen selected from the group consisting of tumor surface antigen, tumor endothelial antigen, non-tumor endothelial antigen and tumor vessel wall antigen.
US10317269 1999-01-15 2002-12-10 Energy-activated targeted cancer therapy Abandoned US20030109813A1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
US11623499 true 1999-01-15 1999-01-15
US09271575 US6602274B1 (en) 1999-01-15 1999-03-18 Targeted transcutaneous cancer therapy
US10317269 US20030109813A1 (en) 1999-01-15 2002-12-10 Energy-activated targeted cancer therapy

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US10317269 US20030109813A1 (en) 1999-01-15 2002-12-10 Energy-activated targeted cancer therapy
US11115740 US20050196401A1 (en) 1999-01-15 2005-04-26 Energy-activated targeted cancer therapy
US11906110 US20080114285A1 (en) 1999-01-15 2007-09-27 Energy-activated targeted cancer therapy

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US09271575 Division US6602274B1 (en) 1999-01-15 1999-03-18 Targeted transcutaneous cancer therapy

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US11115740 Division US20050196401A1 (en) 1999-01-15 2005-04-26 Energy-activated targeted cancer therapy

Publications (1)

Publication Number Publication Date
US20030109813A1 true true US20030109813A1 (en) 2003-06-12

Family

ID=40418902

Family Applications (7)

Application Number Title Priority Date Filing Date
US09271575 Active US6602274B1 (en) 1999-01-15 1999-03-18 Targeted transcutaneous cancer therapy
US09905501 Expired - Fee Related US6899723B2 (en) 1999-01-15 2001-07-13 Transcutaneous photodynamic treatment of targeted cells
US10317269 Abandoned US20030109813A1 (en) 1999-01-15 2002-12-10 Energy-activated targeted cancer therapy
US10410700 Abandoned US20030208249A1 (en) 1999-01-15 2003-04-08 Energy-activated targeted cancer therapy
US10802284 Active 2021-12-15 US7018395B2 (en) 1999-01-15 2004-03-16 Photodynamic treatment of targeted cells
US11115740 Abandoned US20050196401A1 (en) 1999-01-15 2005-04-26 Energy-activated targeted cancer therapy
US11906110 Abandoned US20080114285A1 (en) 1999-01-15 2007-09-27 Energy-activated targeted cancer therapy

Family Applications Before (2)

Application Number Title Priority Date Filing Date
US09271575 Active US6602274B1 (en) 1999-01-15 1999-03-18 Targeted transcutaneous cancer therapy
US09905501 Expired - Fee Related US6899723B2 (en) 1999-01-15 2001-07-13 Transcutaneous photodynamic treatment of targeted cells

Family Applications After (4)

Application Number Title Priority Date Filing Date
US10410700 Abandoned US20030208249A1 (en) 1999-01-15 2003-04-08 Energy-activated targeted cancer therapy
US10802284 Active 2021-12-15 US7018395B2 (en) 1999-01-15 2004-03-16 Photodynamic treatment of targeted cells
US11115740 Abandoned US20050196401A1 (en) 1999-01-15 2005-04-26 Energy-activated targeted cancer therapy
US11906110 Abandoned US20080114285A1 (en) 1999-01-15 2007-09-27 Energy-activated targeted cancer therapy

Country Status (5)

Country Link
US (7) US6602274B1 (en)
EP (1) EP1140176A1 (en)
JP (1) JP2002534219A (en)
CA (1) CA2356776A1 (en)
WO (1) WO2000041727A1 (en)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020049247A1 (en) * 2000-01-12 2002-04-25 Chen James C. Novel treatment for eye disease
US20030060719A1 (en) * 1998-06-19 2003-03-27 Irion Klaus M. Use of 5-aminolevulinic acid or a derivate thereof for photodynamic diagnosis and /or photodynamic therapy
US20040215292A1 (en) * 1999-01-15 2004-10-28 James Chen Photodynamic treatment of targeted cells
US20050004510A1 (en) * 1999-01-15 2005-01-06 James Chen Noninvasive vascular therapy
US20060240096A1 (en) * 2005-04-22 2006-10-26 Kugler Chad J Devices and methods for treating the gastrointestinal system
US20080033519A1 (en) * 2003-03-14 2008-02-07 Light Sciences Oncology, Inc. Light generating device for intravascular use
US7820143B2 (en) 2002-06-27 2010-10-26 Health Research, Inc. Water soluble tetrapyrollic photosensitizers for photodynamic therapy
US20100274330A1 (en) * 2003-03-14 2010-10-28 Light Sciences Oncology, Inc. Device for treatment of blood vessels using light
US7897140B2 (en) 1999-12-23 2011-03-01 Health Research, Inc. Multi DTPA conjugated tetrapyrollic compounds for phototherapeutic contrast agents
US20110218474A1 (en) * 2008-08-19 2011-09-08 Oncowave Medical Gmbh Apparatus for the destruction of tumor cells or pathogens in the blood stream

Families Citing this family (137)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2302044C (en) * 1997-08-25 2011-07-05 Advanced Photodynamic Technologies, Inc. Treatment device for topical photodynamic therapy and method of making same
US6183773B1 (en) * 1999-01-04 2001-02-06 The General Hospital Corporation Targeting of sebaceous follicles as a treatment of sebaceous gland disorders
US6454789B1 (en) * 1999-01-15 2002-09-24 Light Science Corporation Patient portable device for photodynamic therapy
US6217848B1 (en) * 1999-05-20 2001-04-17 Mallinckrodt Inc. Cyanine and indocyanine dye bioconjugates for biomedical applications
US20030114434A1 (en) * 1999-08-31 2003-06-19 James Chen Extended duration light activated cancer therapy
US7351807B2 (en) 2000-01-18 2008-04-01 Mallinckrodt Inc. Cyanine-sulfenates for dual phototherapy
JP2003530146A (en) * 2000-02-10 2003-10-14 マサチューセッツ・アイ・アンド・イア・インファーマリー Photodynamic therapy for treating conditions of the eye
WO2002082988A2 (en) * 2001-04-16 2002-10-24 The Johns Hopkins University Method for imaging and spectroscopy of tumors and determination of the efficacy of anti-tumor drug therapies
US20030031627A1 (en) 2001-07-31 2003-02-13 Mallinckrodt Inc. Internal image antibodies for optical imaging and therapy
US7223282B1 (en) * 2001-09-27 2007-05-29 Advanced Cardiovascular Systems, Inc. Remote activation of an implantable device
US9993659B2 (en) * 2001-11-01 2018-06-12 Pthera, Llc Low level light therapy for enhancement of neurologic function by altering axonal transport rate
US20030144712A1 (en) * 2001-12-20 2003-07-31 Jackson Streeter, M.D. Methods for overcoming organ transplant rejection
US20040153130A1 (en) * 2002-05-29 2004-08-05 Amir Oron Methods for treating muscular dystrophy
US20030109906A1 (en) * 2001-11-01 2003-06-12 Jackson Streeter Low level light therapy for the treatment of stroke
US20110060266A1 (en) * 2001-11-01 2011-03-10 Photothera, Inc. Enhanced stem cell therapy and stem cell production through the administration of low level light energy
US20040132002A1 (en) * 2002-09-17 2004-07-08 Jackson Streeter Methods for preserving blood
US7303578B2 (en) * 2001-11-01 2007-12-04 Photothera, Inc. Device and method for providing phototherapy to the brain
EP1312353A1 (en) * 2001-11-16 2003-05-21 Ecole Polytechnique Federale De Lausanne (Epfl) Method for hair removal
US20030118657A1 (en) * 2001-12-04 2003-06-26 West Jennifer L. Treatment of disease states characterized by excessive or inappropriate angiogenesis
US7316922B2 (en) * 2002-01-09 2008-01-08 Photothera Inc. Method for preserving organs for transplant
EP1467760A2 (en) * 2002-01-23 2004-10-20 Light Sciences Corporation Systems and methods for photodynamic therapy
US7041121B1 (en) * 2002-01-31 2006-05-09 Medtronicvidamed, Inc. Apparatus for treating prostate cancer and method for same
US20040039242A1 (en) * 2002-04-02 2004-02-26 Seedling Enterprises, Llc Apparatus and methods using visible light for debilitating and/or killing microorganisms within the body
WO2003089063A1 (en) * 2002-04-16 2003-10-30 Lumerx, Inc Chemiluminescent light source using visible light for biotherapy
US20040156743A1 (en) * 2002-08-28 2004-08-12 Eric Bornstein Near infrared microbial elimination laser system
US20080131968A1 (en) * 2002-08-28 2008-06-05 Nomir Medical Technologies, Inc. Near-infrared electromagnetic modification of cellular steady-state membrane potentials
US8506979B2 (en) 2002-08-28 2013-08-13 Nomir Medical Technologies, Inc. Near-infrared electromagnetic modification of cellular steady-state membrane potentials
US7713294B2 (en) 2002-08-28 2010-05-11 Nomir Medical Technologies, Inc. Near infrared microbial elimination laser systems (NIMEL)
US20040126272A1 (en) * 2002-08-28 2004-07-01 Eric Bornstein Near infrared microbial elimination laser system
EP1417974A1 (en) * 2002-11-08 2004-05-12 Boehringer Ingelheim International GmbH Compositions and methods for treating cancer using cytotoxic CD44 antibody immunoconjugates and radiotherapy
US7255560B2 (en) * 2002-12-02 2007-08-14 Nomir Medical Technologies, Inc. Laser augmented periodontal scaling instruments
US7534255B1 (en) 2003-01-24 2009-05-19 Photothera, Inc Low level light therapy for enhancement of neurologic function
US20040220513A1 (en) * 2003-03-04 2004-11-04 Jackson Streeter Low level light therapy for the enhancement of hepatic functioning
WO2004080284A9 (en) * 2003-03-07 2005-07-28 Univ Texas Antibody-targeted photodynamic therapy
US7344555B2 (en) 2003-04-07 2008-03-18 The United States Of America As Represented By The Department Of Health And Human Services Light promotes regeneration and functional recovery after spinal cord injury
EP1470837A3 (en) * 2003-04-23 2005-08-10 Dwayne J. Dickey Switched photodynamic therapy apparatus and method
WO2004099375A3 (en) * 2003-04-30 2007-04-19 Gen Hospital Corp Indirectly linked photosensitizer immunoconjugates, processes for the production thereof and methods of use therof
US7470124B2 (en) * 2003-05-08 2008-12-30 Nomir Medical Technologies, Inc. Instrument for delivery of optical energy to the dental root canal system for hidden bacterial and live biofilm thermolysis
CA2446663A1 (en) * 2003-10-24 2005-04-24 Shane Burch Bone-treatment instrument and method
US7553326B2 (en) 2003-11-24 2009-06-30 Sweet Richard M Method and apparatus for preventing dialysis graft intimal hyperplasia
US7744555B2 (en) * 2004-02-06 2010-06-29 Depuy Spine, Inc. Implant having a photocatalytic unit
US8267883B2 (en) * 2004-02-06 2012-09-18 Depuy Spine, Inc. Photocatalytic implant having a sensor
US20060004317A1 (en) * 2004-06-30 2006-01-05 Christophe Mauge Hydrocephalus shunt
US20070065420A1 (en) * 2005-08-23 2007-03-22 Johnson Lanny L Ultrasound Therapy Resulting in Bone Marrow Rejuvenation
US20060079947A1 (en) * 2004-09-28 2006-04-13 Tankovich Nikolai I Methods and apparatus for modulation of the immune response using light-based fractional treatment
US20060173514A1 (en) * 2005-02-02 2006-08-03 Advanced Photodynamic Technologies, Inc. Wound treatment device for photodynamic therapy and method of using same
US20060200212A1 (en) * 2005-02-17 2006-09-07 Brawn Peter R Light therapy device for treatment of bone disorders and biostimulation of bone and soft tissue
US20070248930A1 (en) 2005-02-17 2007-10-25 Biolux Research Ltd. Light therapy apparatus and methods
US8529560B2 (en) 2005-03-04 2013-09-10 The Invention Science Fund I, Llc Hair treatment system
US8540701B2 (en) * 2005-03-04 2013-09-24 The Invention Science Fund I, Llc Hair treatment system
US20060200114A1 (en) * 2005-03-04 2006-09-07 Searete Llc, A Limited Liability Corporation Of State Of Delaware Hair removal system with light source array
US8679101B2 (en) * 2005-03-04 2014-03-25 The Invention Science Fund I, Llc Method and system for temporary hair removal
US7963287B2 (en) * 2005-04-28 2011-06-21 Boston Scientific Scimed, Inc. Tissue-treatment methods
US8157807B2 (en) * 2005-06-02 2012-04-17 The Invention Science Fund I, Llc Skin treatment including patterned light
US20060276859A1 (en) * 2005-06-02 2006-12-07 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Photopatterning of skin
US9055958B2 (en) * 2005-06-29 2015-06-16 The Invention Science Fund I, Llc Hair modification using converging light
US20100087534A1 (en) * 2005-07-05 2010-04-08 Maria-Anna Ortner Use of a Photosensitizing Agent in the Treatment or Prevention of an Inflammation-Associated Disorder in the Gastrointestinal Tract of a Mammal
US20070038270A1 (en) * 2005-07-05 2007-02-15 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Multi step photopatterning of skin
US8346484B2 (en) 2005-07-21 2013-01-01 The Invention Science Fund I, Llc Selective resonance of chemical structures
US20090118721A1 (en) * 2005-07-21 2009-05-07 Eric Bornstein Near Infrared Microbial Elimination Laser System (NIMELS)
US8386183B2 (en) * 2005-07-21 2013-02-26 The Invention Science Fund I, Llc Selective resonant reconfiguration of chemical structures
US9211332B2 (en) 2005-07-21 2015-12-15 The Invention Science Fund I, Llc Selective resonance of bodily agents
US9427465B2 (en) 2005-07-21 2016-08-30 Deep Science, Llc Selective resonance of chemical structures
US7979213B2 (en) * 2005-07-21 2011-07-12 The Invention Science Fund I, Llc Selective resonance of chemical structures
US20070021924A1 (en) * 2005-07-21 2007-01-25 Ishikawa Muriel Y Selective resonance of chemical structures
US8386186B2 (en) * 2005-07-21 2013-02-26 The Invention Science Fund I, Llc Selective resonance of chemical structures
US8364412B2 (en) * 2005-07-21 2013-01-29 The Invention Science Fund I, Llc Selective resonance of chemical structures
US8195403B2 (en) * 2005-07-21 2012-06-05 The Invention Science Fund I, Llc Selective resonance of bodily agents
US7976571B2 (en) * 2005-08-02 2011-07-12 Wolfgang Neuberger Photodynamic therapy irradiation system for the treatment of superficial hyperproliferative tissue growth
US20070032846A1 (en) * 2005-08-05 2007-02-08 Bran Ferren Holographic tattoo
US20070048340A1 (en) * 2005-08-31 2007-03-01 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Multi step patterning of a skin surface
WO2007030478A3 (en) * 2005-09-06 2008-02-14 Light Sciences Oncology Inc Implantable device for therapeutic treatment within a body lumen
WO2007056498A3 (en) * 2005-11-07 2007-10-11 William Louis Barnard Light delivery apparatus
WO2007084981A3 (en) * 2006-01-19 2007-11-29 David Chamberland System and method for photoacoustic imaging and monitoring of laser therapy
CA2642741A1 (en) * 2006-01-24 2007-08-02 Nomir Medical Technologies, Inc. Optical method and device for modulation of biochemical processes in adipose tissue
US7575589B2 (en) * 2006-01-30 2009-08-18 Photothera, Inc. Light-emitting device and method for providing phototherapy to the brain
WO2007103721A3 (en) * 2006-03-01 2007-11-08 Richard Rox Anderson System and method for providing cell specific laser therapy of atherosclerotic plaques by targeting light absorbers in macrophages
US20070208331A1 (en) * 2006-03-02 2007-09-06 Chu Michael S Systems and methods of treatment within a gastrointestinal lumen
CA2644694C (en) * 2006-03-10 2014-05-13 Sangeeta N. Bhatia Triggered self-assembly conjugates and nanosystems
US20070255356A1 (en) * 2006-04-28 2007-11-01 Ondine International, Ltd. Photodisinfection delivery devices and methods
WO2007130465A3 (en) * 2006-05-02 2008-12-04 Alan A Creamer Systems and methods for treating superficial venous malformations like spider veins
US7465312B2 (en) 2006-05-02 2008-12-16 Green Medical, Inc. Systems and methods for treating superficial venous malformations like spider veins
US8057464B2 (en) * 2006-05-03 2011-11-15 Light Sciences Oncology, Inc. Light transmission system for photoreactive therapy
US8585707B2 (en) * 2006-06-07 2013-11-19 Gary S. Rogers Continuous low irradiance photodynamic therapy method
US20080033412A1 (en) * 2006-08-01 2008-02-07 Harry Thomas Whelan System and method for convergent light therapy having controllable dosimetry
US8308784B2 (en) 2006-08-24 2012-11-13 Jackson Streeter Low level light therapy for enhancement of neurologic function of a patient affected by Parkinson's disease
US20090035576A1 (en) * 2006-09-08 2009-02-05 Prasad Paras N Nanoparticles for two-photon activated photodynamic therapy and imaging
US20080233051A1 (en) * 2006-09-08 2008-09-25 Prasad Paras N Nanoparticles for two-photon activated photodynamic therapy and imaging
US20080123083A1 (en) * 2006-11-29 2008-05-29 The Regents Of The University Of Michigan System and Method for Photoacoustic Guided Diffuse Optical Imaging
WO2008067455A3 (en) * 2006-11-30 2008-10-09 Jerry S Culp System and method for targeted activation of a pharmaceutical agent within the body cavity that is activated by the application of energy
US20080173093A1 (en) * 2007-01-18 2008-07-24 The Regents Of The University Of Michigan System and method for photoacoustic tomography of joints
US20080221211A1 (en) * 2007-02-02 2008-09-11 Jackson Streeter Method of treatment of neurological injury or cancer by administration of dichloroacetate
US20080221647A1 (en) * 2007-02-23 2008-09-11 The Regents Of The University Of Michigan System and method for monitoring photodynamic therapy
EP2164418B1 (en) 2007-06-27 2014-01-08 The General Hospital Corporation Apparatus for optical inhibition of photodynamic therapy
US20090104212A1 (en) * 2007-08-06 2009-04-23 Immunolight Methods and systems for treating cell proliferation disorders using two-photon simultaneous absorption
US20100305436A1 (en) * 2007-09-14 2010-12-02 Light Sciences Oncology , Inc. Systems, devices, and methods for photoactive assisted resection
WO2009052187A3 (en) * 2007-10-15 2010-07-01 Stokes John P Convergent well irradiating plaque for choroidal melanoma
EP2222636B1 (en) 2007-12-21 2013-04-10 Ligand Pharmaceuticals Inc. Selective androgen receptor modulators (sarms) and uses thereof
CA2715813C (en) * 2008-02-13 2017-03-21 Erich Zurfluh Light delivery device that provides a radial light output pattern
US8376013B2 (en) 2008-03-11 2013-02-19 Duke University Plasmonic assisted systems and methods for interior energy-activation from an exterior source
US20090254154A1 (en) * 2008-03-18 2009-10-08 Luis De Taboada Method and apparatus for irradiating a surface with pulsed light
US8770203B2 (en) * 2008-07-14 2014-07-08 Immunolight, Llc. Advanced methods and systems for treating cell proliferation disorders
US7993640B2 (en) 2008-08-06 2011-08-09 Light Sciences Oncology, Inc. Enhancement of light activated therapy by immune augmentation using anti-CTLA-4 antibody
US7848035B2 (en) 2008-09-18 2010-12-07 Photothera, Inc. Single-use lens assembly
CA2775660A1 (en) * 2008-09-29 2010-04-01 Tom Kerber Device for photodynamical therapy of cancer
WO2010056732A1 (en) 2008-11-12 2010-05-20 Marv Enterprises Llc Utilization of stents for the treatment of blood borne carcinomas
US20100211136A1 (en) * 2009-02-19 2010-08-19 Photothera, Inc. Apparatus and method for irradiating a surface with light
US9216386B2 (en) * 2009-03-17 2015-12-22 Marv Enterprises, LLC Sequential extracorporeal treatment of bodily fluids
US20100241038A1 (en) * 2009-03-20 2010-09-23 Bwt Property, Inc. Phototherapy Method for Assisting Transvenous Lead Placement
WO2010114901A1 (en) 2009-03-31 2010-10-07 The Board Of Trustees Of The University Of Arkansas Method of controlled drug release from a liposome carrier
US20100256125A1 (en) * 2009-04-06 2010-10-07 Zila Pharmaceuticals, Inc. Use of improved toluidine blue in photodynamic therapy
US20120101427A1 (en) * 2009-04-28 2012-04-26 Gerard Farmer Novel photosensitizer formulations for oral administration
US9345902B2 (en) 2009-05-19 2016-05-24 Ramot At Tel Aviv University Ltd. Low-level energy laser therapy
US20110008372A1 (en) * 2009-07-08 2011-01-13 Light Sciences Oncology, Inc. Enhancement of light activated drug therapy through combination with other therapeutic agents
US8348929B2 (en) 2009-08-05 2013-01-08 Rocin Laboratories, Inc. Endoscopically-guided tissue aspiration system for safely removing fat tissue from a patient
US8465471B2 (en) 2009-08-05 2013-06-18 Rocin Laboratories, Inc. Endoscopically-guided electro-cauterizing power-assisted fat aspiration system for aspirating visceral fat tissue within the abdomen of a patient
US20110213336A1 (en) 2009-08-05 2011-09-01 Cucin Robert L Method of and apparatus for sampling, processing and collecting tissue and reinjecting the same into human patients
WO2011020064A3 (en) 2009-08-14 2011-07-07 Light Sciences Oncology, Inc. Low-profile intraluminal light delivery system and methods of using the same
US20110206737A1 (en) * 2010-02-24 2011-08-25 Empire Technology Development Llc Photosensitizer-containing composition
RU2455921C2 (en) * 2010-03-04 2012-07-20 Сергей Дмитриевич Фокеев Method of treating lung cancer complicated by hemorrhage
JP5719159B2 (en) * 2010-03-15 2015-05-13 ソニー株式会社 Evaluation device
DE102010013307A1 (en) * 2010-03-29 2011-09-29 Karl Storz Gmbh & Co. Kg Light source means for endoscopic or exoscopic applications
US20110309267A1 (en) * 2010-06-16 2011-12-22 California Institute Of Technology Iterative time-reversal enhanced transmission solving approach
EP2648651B1 (en) 2010-12-08 2016-11-23 Biolux Research Limited Apparatuses useful for regulating bone remodeling or tooth movement using light therapy and a functional appliance
WO2012128326A1 (en) * 2011-03-23 2012-09-27 国立大学法人筑波大学 Nanoparticles for photo dynamic therapy
EP2691152B1 (en) 2011-03-27 2017-06-21 Ramot at Tel Aviv University, Ltd. Low level laser therapy for alzheimer's disease
US9694075B2 (en) 2011-04-08 2017-07-04 Sanovas, Inc. Treatment of hypoxic tumors with localized oxygenation
US10029115B2 (en) 2011-04-08 2018-07-24 Sanovas Intellectual Property, Llc Photodynamic therapy for tumors with localized delivery
WO2013005379A1 (en) * 2011-07-01 2013-01-10 Sbiファーマ株式会社 Photodynamic therapy using photosensitizing agent or 5-aminolevulinic acid
US9849087B2 (en) 2011-11-08 2017-12-26 The Board Of Trustees Of The University Of Arkansas Methods and compositions for X-ray induced release from pH sensitive liposomes
US9662509B2 (en) 2013-05-23 2017-05-30 Cook Medical Technologies Llc Intraluminal activation system and method of activating an inactive agent
CN105682603A (en) 2013-10-22 2016-06-15 碧奥鲁克斯研究有限公司 Intra-oral light-therapy apparatuses and methods for their use
US9516995B2 (en) 2013-12-17 2016-12-13 Biovision Technologies, Llc Surgical device for performing a sphenopalatine ganglion block procedure
US10016580B2 (en) 2013-12-17 2018-07-10 Biovision Technologies, Llc Methods for treating sinus diseases
US9694163B2 (en) 2013-12-17 2017-07-04 Biovision Technologies, Llc Surgical device for performing a sphenopalatine ganglion block procedure
US9510743B2 (en) 2013-12-17 2016-12-06 Biovision Technologies, Llc Stabilized surgical device for performing a sphenopalatine ganglion block procedure
KR101686145B1 (en) * 2015-05-18 2016-12-13 한국과학기술원 Composition for Phototherapy of Cancer Comprising Complex of Liposome And Indocyanine Green

Citations (93)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10500A (en) * 1854-02-07 Tool-holder
US46983A (en) * 1865-03-28 Improvement in treating ores
US49247A (en) * 1865-08-08 Improvement in the manufacture of pyroligneous acid
US49502A (en) * 1865-08-22 Improved process for purifying coal-oil
US87205A (en) * 1869-02-23 Improved velocipede
US114434A (en) * 1871-05-02 Improvement in dry-earth closets
US127224A (en) * 1872-05-28 Improvement in cotton-seed cleaners
US127230A (en) * 1872-05-28 Improvement in lamp-chimney cleaners
US3046118A (en) * 1949-07-23 1962-07-24 Azoplate Corp Process of making printing plates and light sensitive material suitable for use therein
US3046120A (en) * 1950-10-31 1962-07-24 Azoplate Corp Light-sensitive layers for photomechanical reproduction
US4337759A (en) * 1979-10-10 1982-07-06 John M. Popovich Radiant energy concentration by optical total internal reflection
US4675338A (en) * 1984-07-18 1987-06-23 Nippon Petrochemicals Co., Ltd. Tetrapyrrole therapeutic agents
US4753958A (en) * 1985-02-07 1988-06-28 University Of Cal Photochemotherapy of epithelial diseases with derivatives of hematoporphyrins
US4823244A (en) * 1988-01-29 1989-04-18 Niagara Medical Innovations Inc. Light source assembly
US4849207A (en) * 1985-10-23 1989-07-18 Nihon Medi-Physics Co., Ltd. Porphyrin derivatives
US4932934A (en) * 1982-09-27 1990-06-12 Health Research, Inc. Methods for treatment of tumors
US4998930A (en) * 1988-08-03 1991-03-12 Phototherapeutic Systems Intracavity laser phototherapy method
US5002962A (en) * 1988-07-20 1991-03-26 Health Research, Inc. Photosensitizing agents
US5026367A (en) * 1988-03-18 1991-06-25 Cardiovascular Laser Systems, Inc. Laser angioplasty catheter and a method for use thereof
US5190536A (en) * 1988-11-08 1993-03-02 Health Research, Inc. Submersible lens fiberoptic assembly for use in PDT treatment
US5283255A (en) * 1987-01-20 1994-02-01 The University Of British Columbia Wavelength-specific cytotoxic agents
US5404869A (en) * 1992-04-16 1995-04-11 Tir Technologies, Inc. Faceted totally internally reflecting lens with individually curved faces on facets
US5445608A (en) * 1993-08-16 1995-08-29 James C. Chen Method and apparatus for providing light-activated therapy
US5482698A (en) * 1993-04-22 1996-01-09 Immunomedics, Inc. Detection and therapy of lesions with biotin/avidin polymer conjugates
US5484778A (en) * 1990-07-17 1996-01-16 University Hospitals Of Cleveland Phthalocyanine photosensitizers for photodynamic therapy and methods for their use
US5484803A (en) * 1992-09-21 1996-01-16 Quadra Logic Technologies Inc. Transcutaneous in vivo activation of photosensitive agents in blood
US5494793A (en) * 1986-12-15 1996-02-27 British Technology Group Usa Inc. Monomeric phthalocyanine reagents
US5514669A (en) * 1993-09-29 1996-05-07 Medical College Of Ohio Use of photodynamic therapy to treat prostatic tissue
US5519534A (en) * 1994-05-25 1996-05-21 The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Irradiance attachment for an optical fiber to provide a uniform level of illumination across a plane
US5543514A (en) * 1989-12-21 1996-08-06 Board Of Regents, The University Of Texas System Water-soluble sapphyrins
US5591855A (en) * 1994-10-14 1997-01-07 Cephalon, Inc. Fused pyrrolocarbazoles
US5613769A (en) * 1992-04-16 1997-03-25 Tir Technologies, Inc. Tir lens apparatus having non-circular configuration about an optical axis
US5616140A (en) * 1994-03-21 1997-04-01 Prescott; Marvin Method and apparatus for therapeutic laser treatment
US5630996A (en) * 1992-06-09 1997-05-20 Neorx Corporation Two-step pretargeting methods using improved biotin-active agent conjugates
US5634711A (en) * 1993-09-13 1997-06-03 Kennedy; John Portable light emitting apparatus with a semiconductor emitter array
US5643334A (en) * 1995-02-07 1997-07-01 Esc Medical Systems Ltd. Method and apparatus for the diagnostic and composite pulsed heating and photodynamic therapy treatment
US5645562A (en) * 1995-03-13 1997-07-08 Cordis Corporation Balloon catheter with light conductor
US5655832A (en) * 1992-04-16 1997-08-12 Tir Technologies, Inc. Multiple wavelength light processor
US5705518A (en) * 1992-11-20 1998-01-06 University Of British Columbia Method of activating photosensitive agents
US5707401A (en) * 1994-03-10 1998-01-13 Esc Medical Systems, Ltd. Apparatus for an efficient photodynamic treatment
US5709653A (en) * 1996-07-25 1998-01-20 Cordis Corporation Photodynamic therapy balloon catheter with microporous membrane
US5715837A (en) * 1996-08-29 1998-02-10 Light Sciences Limited Partnership Transcutaneous electromagnetic energy transfer
US5735817A (en) * 1995-05-19 1998-04-07 Shantha; T. R. Apparatus for transsphenoidal stimulation of the pituitary gland and adjoining brain structures
US5741316A (en) * 1996-12-02 1998-04-21 Light Sciences Limited Partnership Electromagnetic coil configurations for power transmission through tissue
US5746494A (en) * 1994-11-22 1998-05-05 Asahi Kogaku Kogyo Kabushiki Kaisha Illuminating apparatus of endoscope
US5746495A (en) * 1997-02-05 1998-05-05 Klamm; Thomas L. Portable work light with optical fiber adapter
US5757557A (en) * 1997-06-09 1998-05-26 Tir Technologies, Inc. Beam-forming lens with internal cavity that prevents front losses
US5766234A (en) * 1996-03-07 1998-06-16 Light Sciences Limited Partnership Implanting and fixing a flexible probe for administering a medical therapy at a treatment site within a patient'body
US5766222A (en) * 1997-07-07 1998-06-16 Petit; Michael G. Nipple illuminator for photodynamic therapy
US5770730A (en) * 1996-03-08 1998-06-23 Health Research, Inc. Synthesis of carbodimide analogs of chlorins and bacteriochlorins and their use for diagnosis and treatment of cancer
US5769844A (en) * 1991-06-26 1998-06-23 Ghaffari; Shahriar Conventional light-pumped high power system for medical applications
US5776427A (en) * 1992-03-05 1998-07-07 Board Of Regents, The University Of Texas System Methods for targeting the vasculature of solid tumors
US5775339A (en) * 1996-03-26 1998-07-07 Pharmacyclics, Inc. Photodynamic therapy of pigment-related lesions
US5776175A (en) * 1995-09-29 1998-07-07 Esc Medical Systems Ltd. Method and apparatus for treatment of cancer using pulsed electromagnetic radiation
US5782896A (en) * 1997-01-29 1998-07-21 Light Sciences Limited Partnership Use of a shape memory alloy to modify the disposition of a device within an implantable medical probe
US5798349A (en) * 1994-03-14 1998-08-25 The General Hospital Corporation Use of green porphyrins to treat neovasculature in the eye
US5797868A (en) * 1996-07-25 1998-08-25 Cordis Corporation Photodynamic therapy balloon catheter
US5855866A (en) * 1992-03-05 1999-01-05 Board Of Regenis, The University Of Texas System Methods for treating the vasculature of solid tumors
US5863538A (en) * 1992-03-05 1999-01-26 Board Of Regents, The University Of Texas System Compositions for targeting the vasculature of solid tumors
US5865840A (en) * 1997-10-22 1999-02-02 Light Sciences Limited Partnership Enhancement of light activation effect by immune augmentation
US5876427A (en) * 1997-01-29 1999-03-02 Light Sciences Limited Partnership Compact flexible circuit configuration
US5881200A (en) * 1994-09-29 1999-03-09 British Telecommunications Public Limited Company Optical fibre with quantum dots
US5882328A (en) * 1995-01-13 1999-03-16 Qlt Phototherapeutics, Inc. Method to prevent transplant rejection
US5882779A (en) * 1994-11-08 1999-03-16 Spectra Science Corporation Semiconductor nanocrystal display materials and display apparatus employing same
US5906579A (en) * 1996-08-16 1999-05-25 Smith & Nephew Endoscopy, Inc. Through-wall catheter steering and positioning
US5909670A (en) * 1995-01-09 1999-06-01 U S West, Inc. Method and system for playback of advertisements in an electronic classified advertising system
US5912257A (en) * 1995-09-06 1999-06-15 The Research Foundation Of State University Of New York Two-photon upconverting dyes and applications
US5913884A (en) * 1996-09-19 1999-06-22 The General Hospital Corporation Inhibition of fibrosis by photodynamic therapy
US5913834A (en) * 1993-11-04 1999-06-22 Francais; Caramia System for imparting sensory effects across a mother's abdomen to a fetus and monitoring effects on the fetus
US5919217A (en) * 1987-12-08 1999-07-06 Medic-Light, Inc. Portable phototherapy unit
US5921244A (en) * 1997-06-11 1999-07-13 Light Sciences Limited Partnership Internal magnetic device to enhance drug therapy
US5924788A (en) * 1997-09-23 1999-07-20 Teledyne Lighting And Display Products Illuminating lens designed by extrinsic differential geometry
US5926320A (en) * 1997-05-29 1999-07-20 Teldedyne Lighting And Display Products, Inc. Ring-lens system for efficient beam formation
US5929105A (en) * 1997-05-07 1999-07-27 Qltphoto Therapeutics, Inc. Ethylene glycol esters as photoactive agents
US5943354A (en) * 1994-03-18 1999-08-24 Brown University Research Foundation Optical sources having a strongly scattering gain medium providing laser-like action
US5942534A (en) * 1996-10-10 1999-08-24 The General Hospital Corporation Photodynamic therapy for the treatment of osteoarthritis
US6013053A (en) * 1996-05-17 2000-01-11 Qlt Photo Therapeutics Inc. Balloon catheter for photodynamic therapy
US6015897A (en) * 1993-12-07 2000-01-18 Neorx Corporation Biotinamido-n-methylglycyl-seryl-o-succinamido-benzyl dota
US6021347A (en) * 1996-12-05 2000-02-01 Herbst; Ewa Electrochemical treatment of malignant tumors
US6058937A (en) * 1997-07-18 2000-05-09 Miravant Systems, Inc. Photodynamic Therapy of highly vascularized tissue
US6071944A (en) * 1997-11-12 2000-06-06 Bowling Green State University Method of treatment of pigmented cancer cells utilizing photodynamic therapy
US6080160A (en) * 1996-12-04 2000-06-27 Light Sciences Limited Partnership Use of shape memory alloy for internally fixing light emitting device at treatment site
US6083485A (en) * 1994-12-07 2000-07-04 Institut Fur Diagnostikforschung Gmbh Near infrared radiation in-vivo diagnostic methods and dyes
US6092531A (en) * 1998-02-10 2000-07-25 Light Sciences Limited Partnership Movable magnet transmitter for inducing electrical current in an implanted coil
US6183444B1 (en) * 1998-05-16 2001-02-06 Microheart, Inc. Drug delivery module
US6210425B1 (en) * 1999-07-08 2001-04-03 Light Sciences Corporation Combined imaging and PDT delivery system
US6217869B1 (en) * 1992-06-09 2001-04-17 Neorx Corporation Pretargeting methods and compounds
US6238426B1 (en) * 1999-07-19 2001-05-29 Light Sciences Corporation Real-time monitoring of photodynamic therapy over an extended time
US6344050B1 (en) * 1998-12-21 2002-02-05 Light Sciences Corporation Use of pegylated photosensitizer conjugated with an antibody for treating abnormal tissue
US6416531B2 (en) * 1998-06-24 2002-07-09 Light Sciences Corporation Application of light at plural treatment sites within a tumor to increase the efficacy of light therapy
US6520669B1 (en) * 2000-06-19 2003-02-18 Light Sciences Corporation Flexible substrate mounted solid-state light sources for exterior vehicular lighting
US6534040B2 (en) * 1999-12-23 2003-03-18 Health Research, Inc. Chlorin and bacteriochlorin-based aminophenyl DTPA and N2S2 conjugates for MR contrast media and radiopharmaceuticals
US6580228B1 (en) * 2000-08-22 2003-06-17 Light Sciences Corporation Flexible substrate mounted solid-state light sources for use in line current lamp sockets

Family Cites Families (90)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US1272224A (en) * 1916-05-04 1918-07-09 James R Combs Change-making machine.
NL95406C (en) 1954-08-20
JPS634805B2 (en) 1981-05-07 1988-02-01 Yakult Honsha Kk
US4521762A (en) * 1981-08-27 1985-06-04 Gte Automatic Electric Laboratories, Incorporated Integratable D/A converter
US4577636A (en) * 1982-11-23 1986-03-25 The Beth Israel Hospital Association Method for diagnosis of atherosclerosis
US4693885A (en) 1984-07-18 1987-09-15 Nippon Petrochemicals Co., Ltd. Tetrapyrrole therapeutic agents
WO1986001720A1 (en) 1984-09-13 1986-03-27 Cytogen Corporation Antibody therapeutic agent conjugates
US4693556A (en) 1985-06-04 1987-09-15 Laser Therapeutics, Inc. Apparatus for producing a spherical pattern of light and method of manufacture
US5534506A (en) * 1986-01-02 1996-07-09 University Of Toledo Use of purpurins, chlorins and purpurin- and chlorin-containing compositions
US5811248A (en) 1986-03-31 1998-09-22 Charter Ventures Atherosclerotic plaque specific antigens, antibodies thereto, and uses thereof
US4861876A (en) 1986-11-26 1989-08-29 Wayne State University Hematoporphyrin derivative and method of preparation and purification
US5171749A (en) * 1987-01-20 1992-12-15 University Of British Columbia Wavelength-specific cytotoxic agents
US4878891A (en) 1987-06-25 1989-11-07 Baylor Research Foundation Method for eradicating infectious biological contaminants in body tissues
US4957481A (en) 1987-10-01 1990-09-18 U.S. Bioscience Photodynamic therapeutic technique
US5549660A (en) 1990-11-15 1996-08-27 Amron, Ltd. Method of treating acne
US5500009A (en) * 1990-11-15 1996-03-19 Amron, Ltd. Method of treating herpes
JPH0629196B2 (en) * 1987-12-01 1994-04-20 甲子郎 梅村 For treating tumor physiological effect enhancer by ultrasound
US5053006A (en) * 1988-04-19 1991-10-01 Watson Brant D Method for the permanent occlusion of arteries
US5055446A (en) 1988-10-21 1991-10-08 University Of Cincinnati Method to improve survival of patients during sepsis by diet composition
US5028594A (en) * 1988-12-27 1991-07-02 Naxcor Use of photodynamic compositions for cytotoxic effects
US5041078A (en) 1989-03-06 1991-08-20 Baylor Research Foundation, A Nonprofit Corporation Of The State Of Texas Photodynamic viral deactivation with sapphyrins
US5565552A (en) 1992-01-21 1996-10-15 Pharmacyclics, Inc. Method of expanded porphyrin-oligonucleotide conjugate synthesis
US4997639A (en) * 1989-11-27 1991-03-05 Nippon Petrochemicals Company, Limited Method for detecting cholesterol deposited in bodies of mammals
US5594136A (en) * 1989-12-21 1997-01-14 Pharmacyclics, Inc. Texaphyrin solid supports and devices
JP3154742B2 (en) * 1991-04-30 2001-04-09 日本石油化学株式会社 Mammals of arteriosclerosis treatment agent
DE69221828D1 (en) 1991-06-21 1997-10-02 Baxter Int A method for inactivating pathogens in a body fluid
US5263925A (en) 1991-07-22 1993-11-23 Gilmore Jr Thomas F Photopheresis blood treatment
US5209235A (en) * 1991-09-13 1993-05-11 Cardiovascular Imaging Systems, Inc. Ultrasonic imaging catheter assembly and method for identification of the same
US5770592A (en) 1991-11-22 1998-06-23 Alcon Laboratories, Inc. Prevention and treatment of ocular neovascularization using angiostatic steroids
US5284869A (en) 1991-12-17 1994-02-08 Emil Bisaccia Photophoresis methods for treating atherosclerosis and for preventing restenosis following angioplasty
US6890555B1 (en) * 1992-02-05 2005-05-10 Qlt, Inc. Liposome compositions of porphyrin photosensitizers
US5330741A (en) * 1992-02-24 1994-07-19 The Regents Of The University Of California Long-wavelength water soluble chlorin photosensitizers useful for photodynamic therapy and diagnosis of tumors
US5474765A (en) * 1992-03-23 1995-12-12 Ut Sw Medical Ctr At Dallas Preparation and use of steroid-polyanionic polymer-based conjugates targeted to vascular endothelial cells
US5806955A (en) 1992-04-16 1998-09-15 Tir Technologies, Inc. TIR lens for waveguide injection
US5676453A (en) 1992-04-16 1997-10-14 Tir Technologies, Inc. Collimating TIR lens devices employing fluorescent light sources
US5776966A (en) 1992-05-27 1998-07-07 University Of British Columbia Selective cell inactivation in blood
US5807881A (en) 1992-05-27 1998-09-15 Quadra Logic Technologies, Inc. Method for selectively reducing activated leukocyte cell population
US5298018A (en) * 1992-08-14 1994-03-29 Pdt Cardiovascular, Inc. Method for treating cardiovascular disease through adjunctive photodynamic therapy
GB2272278B (en) 1992-10-23 1997-04-09 Cancer Res Campaign Tech Light source
US5700243A (en) 1992-10-30 1997-12-23 Pdt Systems, Inc. Balloon perfusion catheter
US5368841A (en) 1993-02-11 1994-11-29 The General Hospital Corporation Photodynamic therapy for the destruction of the synovium in the treatment of rheumatoid arthritis and the inflammatory arthritides
JP3565442B2 (en) 1993-04-22 2004-09-15 新日本石油化学株式会社 Diagnostic and / or therapeutic agents of the mammalian arthritis
US5441531A (en) 1993-10-18 1995-08-15 Dusa Pharmaceuticals Inc. Illuminator and methods for photodynamic therapy
US5556612A (en) 1994-03-15 1996-09-17 The General Hospital Corporation Methods for phototherapeutic treatment of proliferative skin diseases
US5851225A (en) 1994-03-18 1998-12-22 Spectra Science Corporation Photoemitting catheters and other structures suitable for use in photo-dynamic therapy and other applications
US5474528A (en) 1994-03-21 1995-12-12 Dusa Pharmaceuticals, Inc. Combination controller and patch for the photodynamic therapy of dermal lesion
US5456661A (en) 1994-03-31 1995-10-10 Pdt Cardiovascular Catheter with thermally stable balloon
US5498710A (en) * 1994-04-22 1996-03-12 Health Research, Inc. Alkyl ether analogues of benzoporphyrin derivatives
US5591847A (en) * 1994-05-23 1997-01-07 Health Research, Inc. Long wavelength absorbing photosensitizers related to purpurin-18, bacteriopurpurin-18 and related compounds with imide linkages
US5698866A (en) 1994-09-19 1997-12-16 Pdt Systems, Inc. Uniform illuminator for phototherapy
WO1996010585A1 (en) * 1994-09-30 1996-04-11 Inex Pharmaceuticals Corp. Glycosylated protein-liposome conjugates and methods for their preparation
WO1997040679A1 (en) 1996-05-01 1997-11-06 Imarx Pharmaceutical Corp. Methods for delivering compounds into a cell
US6107325A (en) 1995-01-17 2000-08-22 Qlt Phototherapeutics, Inc. Green porphyrins as immunomodulators
US6176842B1 (en) * 1995-03-08 2001-01-23 Ekos Corporation Ultrasound assembly for use with light activated drugs
US5576013A (en) 1995-03-21 1996-11-19 Eastern Virginia Medical School Treating vascular and neoplastic tissues
US5686113A (en) 1995-03-21 1997-11-11 Temple University Of The Commonwealth System Of Higher Education Microcapsules of predetermined peptide(s) specificity (ies), their preparation and uses
FR2732094A1 (en) 1995-03-22 1996-09-27 Philips Eclairage Light generator for optical fibers
US5571152A (en) 1995-05-26 1996-11-05 Light Sciences Limited Partnership Microminiature illuminator for administering photodynamic therapy
US6032070A (en) * 1995-06-07 2000-02-29 University Of Arkansas Method and apparatus for detecting electro-magnetic reflection from biological tissue
US5703896A (en) 1995-06-07 1997-12-30 The Regents Of The University Of Colorado Silicon quantum dot laser
JP2961074B2 (en) * 1995-09-06 1999-10-12 明治製菓株式会社 Shinsei vascular occlusion agent for photodynamic therapy
US5835648A (en) 1996-03-07 1998-11-10 Miravant Systems, Inc. Surface illuminator for photodynamic therapy
US5814008A (en) 1996-07-29 1998-09-29 Light Sciences Limited Partnership Method and device for applying hyperthermia to enhance drug perfusion and efficacy of subsequent light therapy
US5849027A (en) 1996-09-04 1998-12-15 Mbg Technologies, Inc. Photodynamic therapy method and apparatus
US5702432A (en) 1996-10-03 1997-12-30 Light Sciences Limited Partnership Intracorporeal light treatment of blood
US5829448A (en) 1996-10-30 1998-11-03 Photogen, Inc. Method for improved selectivity in photo-activation of molecular agents
US5997569A (en) 1997-01-29 1999-12-07 Light Sciences Limited Partnership Flexible and adjustable grid for medical therapy
US5824657A (en) 1997-03-18 1998-10-20 Cubist Pharmaceuticals, Inc. Aminoacyl sulfamides for the treatment of hyperproliferative disorders
US5817048A (en) 1997-03-20 1998-10-06 Brown University Research Foundation Ultrasonic alternative to laser-based photodynamic therapy
US5827186A (en) 1997-04-11 1998-10-27 Light Sciences Limited Partnership Method and PDT probe for minimizing CT and MRI image artifacts
US5957960A (en) 1997-05-05 1999-09-28 Light Sciences Limited Partnership Internal two photon excitation device for delivery of PDT to diffuse abnormal cells
US6048359A (en) * 1997-08-25 2000-04-11 Advanced Photodynamic Technologies, Inc. Spatial orientation and light sources and method of using same for medical diagnosis and photodynamic therapy
US6138681A (en) 1997-10-13 2000-10-31 Light Sciences Limited Partnership Alignment of external medical device relative to implanted medical device
US20030030342A1 (en) * 1998-02-10 2003-02-13 Chen James C. Contactless energy transfer apparatus
US6331744B1 (en) 1998-02-10 2001-12-18 Light Sciences Corporation Contactless energy transfer apparatus
US5997842A (en) 1998-04-13 1999-12-07 Light Sciences Limited Partnership Radionuclide excited phosphorescent material for administering PDT
WO1999058149B1 (en) 1998-05-13 2000-02-03 Light Sciences Lp Controlled activation of targeted radionuclides
US6096066A (en) 1998-09-11 2000-08-01 Light Sciences Limited Partnership Conformal patch for administering light therapy to subcutaneous tumors
US20010049502A1 (en) 1998-11-25 2001-12-06 Light Sciences Corporation Guide sheath for repeated placement of a device
US6602274B1 (en) 1999-01-15 2003-08-05 Light Sciences Corporation Targeted transcutaneous cancer therapy
US6454789B1 (en) 1999-01-15 2002-09-24 Light Science Corporation Patient portable device for photodynamic therapy
US6162242A (en) * 1999-01-21 2000-12-19 Peyman; Gholam A. Selective photodynamic treatment
US6273904B1 (en) 1999-03-02 2001-08-14 Light Sciences Corporation Polymer battery for internal light device
US20030114434A1 (en) * 1999-08-31 2003-06-19 James Chen Extended duration light activated cancer therapy
US6319273B1 (en) 1999-12-16 2001-11-20 Light Sciences Corporation Illuminating device for treating eye disease
JP2003519670A (en) 2000-01-12 2003-06-24 ライト サイエンシーズ コーポレイション A new treatment of eye disease
US6559374B2 (en) * 2000-07-21 2003-05-06 North Carolina State University Trans beta substituted chlorins and methods of making and using the same
CA2490692A1 (en) * 2002-06-27 2004-01-08 Health Research, Inc. Fluorinated chlorin and bacteriochlorin photosensitizers for photodynamic therapy
EP1606291A2 (en) * 2002-07-02 2005-12-21 Health Research, Inc. Efficient synthesis of pyropheophorbide a and its dervatives
US20050085455A1 (en) * 2003-10-16 2005-04-21 Light Sciences Corporation Photodynamic therapy for local adipocyte reduction

Patent Citations (100)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10500A (en) * 1854-02-07 Tool-holder
US46983A (en) * 1865-03-28 Improvement in treating ores
US49247A (en) * 1865-08-08 Improvement in the manufacture of pyroligneous acid
US49502A (en) * 1865-08-22 Improved process for purifying coal-oil
US87205A (en) * 1869-02-23 Improved velocipede
US114434A (en) * 1871-05-02 Improvement in dry-earth closets
US127224A (en) * 1872-05-28 Improvement in cotton-seed cleaners
US127230A (en) * 1872-05-28 Improvement in lamp-chimney cleaners
US3046118A (en) * 1949-07-23 1962-07-24 Azoplate Corp Process of making printing plates and light sensitive material suitable for use therein
US3046120A (en) * 1950-10-31 1962-07-24 Azoplate Corp Light-sensitive layers for photomechanical reproduction
US4337759A (en) * 1979-10-10 1982-07-06 John M. Popovich Radiant energy concentration by optical total internal reflection
US4932934A (en) * 1982-09-27 1990-06-12 Health Research, Inc. Methods for treatment of tumors
US4675338A (en) * 1984-07-18 1987-06-23 Nippon Petrochemicals Co., Ltd. Tetrapyrrole therapeutic agents
US4753958A (en) * 1985-02-07 1988-06-28 University Of Cal Photochemotherapy of epithelial diseases with derivatives of hematoporphyrins
US4849207A (en) * 1985-10-23 1989-07-18 Nihon Medi-Physics Co., Ltd. Porphyrin derivatives
US5494793A (en) * 1986-12-15 1996-02-27 British Technology Group Usa Inc. Monomeric phthalocyanine reagents
US5399583A (en) * 1987-01-20 1995-03-21 The University Of British Columbia Method of treating skin diseases
US5283255A (en) * 1987-01-20 1994-02-01 The University Of British Columbia Wavelength-specific cytotoxic agents
US5919217A (en) * 1987-12-08 1999-07-06 Medic-Light, Inc. Portable phototherapy unit
US4823244A (en) * 1988-01-29 1989-04-18 Niagara Medical Innovations Inc. Light source assembly
US5026367A (en) * 1988-03-18 1991-06-25 Cardiovascular Laser Systems, Inc. Laser angioplasty catheter and a method for use thereof
US5314905A (en) * 1988-07-20 1994-05-24 Health Research, Inc. Pyropheophorbides conjugates and their use in photodynamic therapy
US5002962A (en) * 1988-07-20 1991-03-26 Health Research, Inc. Photosensitizing agents
US4998930A (en) * 1988-08-03 1991-03-12 Phototherapeutic Systems Intracavity laser phototherapy method
US5190536A (en) * 1988-11-08 1993-03-02 Health Research, Inc. Submersible lens fiberoptic assembly for use in PDT treatment
US5543514A (en) * 1989-12-21 1996-08-06 Board Of Regents, The University Of Texas System Water-soluble sapphyrins
US5484778C1 (en) * 1990-07-17 2001-05-08 Univ Cleveland Hospitals Phthalocynine photosensitizers for photodynamic therapy and methods for their use
US5484778A (en) * 1990-07-17 1996-01-16 University Hospitals Of Cleveland Phthalocyanine photosensitizers for photodynamic therapy and methods for their use
US5769844A (en) * 1991-06-26 1998-06-23 Ghaffari; Shahriar Conventional light-pumped high power system for medical applications
US5776427A (en) * 1992-03-05 1998-07-07 Board Of Regents, The University Of Texas System Methods for targeting the vasculature of solid tumors
US6051230A (en) * 1992-03-05 2000-04-18 Board Of Regents, The University Of Texas System Compositions for targeting the vasculature of solid tumors
US5855866A (en) * 1992-03-05 1999-01-05 Board Of Regenis, The University Of Texas System Methods for treating the vasculature of solid tumors
US5863538A (en) * 1992-03-05 1999-01-26 Board Of Regents, The University Of Texas System Compositions for targeting the vasculature of solid tumors
US5655832A (en) * 1992-04-16 1997-08-12 Tir Technologies, Inc. Multiple wavelength light processor
US5404869A (en) * 1992-04-16 1995-04-11 Tir Technologies, Inc. Faceted totally internally reflecting lens with individually curved faces on facets
US5613769A (en) * 1992-04-16 1997-03-25 Tir Technologies, Inc. Tir lens apparatus having non-circular configuration about an optical axis
US5630996A (en) * 1992-06-09 1997-05-20 Neorx Corporation Two-step pretargeting methods using improved biotin-active agent conjugates
US6217869B1 (en) * 1992-06-09 2001-04-17 Neorx Corporation Pretargeting methods and compounds
US5484803A (en) * 1992-09-21 1996-01-16 Quadra Logic Technologies Inc. Transcutaneous in vivo activation of photosensitive agents in blood
US5736563A (en) * 1992-09-21 1998-04-07 Quadra Logic Technologies, Inc. Transcutaneous in vivo activation of photosensitive agents in blood
US5705518A (en) * 1992-11-20 1998-01-06 University Of British Columbia Method of activating photosensitive agents
US5482698A (en) * 1993-04-22 1996-01-09 Immunomedics, Inc. Detection and therapy of lesions with biotin/avidin polymer conjugates
US5445608A (en) * 1993-08-16 1995-08-29 James C. Chen Method and apparatus for providing light-activated therapy
US5634711A (en) * 1993-09-13 1997-06-03 Kennedy; John Portable light emitting apparatus with a semiconductor emitter array
US5514669A (en) * 1993-09-29 1996-05-07 Medical College Of Ohio Use of photodynamic therapy to treat prostatic tissue
US5913834A (en) * 1993-11-04 1999-06-22 Francais; Caramia System for imparting sensory effects across a mother's abdomen to a fetus and monitoring effects on the fetus
US6015897A (en) * 1993-12-07 2000-01-18 Neorx Corporation Biotinamido-n-methylglycyl-seryl-o-succinamido-benzyl dota
US5707401A (en) * 1994-03-10 1998-01-13 Esc Medical Systems, Ltd. Apparatus for an efficient photodynamic treatment
US5798349A (en) * 1994-03-14 1998-08-25 The General Hospital Corporation Use of green porphyrins to treat neovasculature in the eye
US5943354A (en) * 1994-03-18 1999-08-24 Brown University Research Foundation Optical sources having a strongly scattering gain medium providing laser-like action
US5616140A (en) * 1994-03-21 1997-04-01 Prescott; Marvin Method and apparatus for therapeutic laser treatment
US5519534A (en) * 1994-05-25 1996-05-21 The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Irradiance attachment for an optical fiber to provide a uniform level of illumination across a plane
US5881200A (en) * 1994-09-29 1999-03-09 British Telecommunications Public Limited Company Optical fibre with quantum dots
US5591855A (en) * 1994-10-14 1997-01-07 Cephalon, Inc. Fused pyrrolocarbazoles
US5882779A (en) * 1994-11-08 1999-03-16 Spectra Science Corporation Semiconductor nanocrystal display materials and display apparatus employing same
US5746494A (en) * 1994-11-22 1998-05-05 Asahi Kogaku Kogyo Kabushiki Kaisha Illuminating apparatus of endoscope
US6083485A (en) * 1994-12-07 2000-07-04 Institut Fur Diagnostikforschung Gmbh Near infrared radiation in-vivo diagnostic methods and dyes
US5909670A (en) * 1995-01-09 1999-06-01 U S West, Inc. Method and system for playback of advertisements in an electronic classified advertising system
US5882328A (en) * 1995-01-13 1999-03-16 Qlt Phototherapeutics, Inc. Method to prevent transplant rejection
US5643334A (en) * 1995-02-07 1997-07-01 Esc Medical Systems Ltd. Method and apparatus for the diagnostic and composite pulsed heating and photodynamic therapy treatment
US5645562A (en) * 1995-03-13 1997-07-08 Cordis Corporation Balloon catheter with light conductor
US5735817A (en) * 1995-05-19 1998-04-07 Shantha; T. R. Apparatus for transsphenoidal stimulation of the pituitary gland and adjoining brain structures
US5912257A (en) * 1995-09-06 1999-06-15 The Research Foundation Of State University Of New York Two-photon upconverting dyes and applications
US5776175A (en) * 1995-09-29 1998-07-07 Esc Medical Systems Ltd. Method and apparatus for treatment of cancer using pulsed electromagnetic radiation
US5766234A (en) * 1996-03-07 1998-06-16 Light Sciences Limited Partnership Implanting and fixing a flexible probe for administering a medical therapy at a treatment site within a patient'body
US5864035A (en) * 1996-03-08 1999-01-26 Health Research, Inc. Synthesis of isoimide of chlorins and bacteriochlorins and their use for diagnosis and treatment of cancer
US5770730A (en) * 1996-03-08 1998-06-23 Health Research, Inc. Synthesis of carbodimide analogs of chlorins and bacteriochlorins and their use for diagnosis and treatment of cancer
US5775339A (en) * 1996-03-26 1998-07-07 Pharmacyclics, Inc. Photodynamic therapy of pigment-related lesions
US6013053A (en) * 1996-05-17 2000-01-11 Qlt Photo Therapeutics Inc. Balloon catheter for photodynamic therapy
US5709653A (en) * 1996-07-25 1998-01-20 Cordis Corporation Photodynamic therapy balloon catheter with microporous membrane
US5797868A (en) * 1996-07-25 1998-08-25 Cordis Corporation Photodynamic therapy balloon catheter
US5906579A (en) * 1996-08-16 1999-05-25 Smith & Nephew Endoscopy, Inc. Through-wall catheter steering and positioning
US5715837A (en) * 1996-08-29 1998-02-10 Light Sciences Limited Partnership Transcutaneous electromagnetic energy transfer
US5913884A (en) * 1996-09-19 1999-06-22 The General Hospital Corporation Inhibition of fibrosis by photodynamic therapy
US5942534A (en) * 1996-10-10 1999-08-24 The General Hospital Corporation Photodynamic therapy for the treatment of osteoarthritis
US5741316A (en) * 1996-12-02 1998-04-21 Light Sciences Limited Partnership Electromagnetic coil configurations for power transmission through tissue
US6080160A (en) * 1996-12-04 2000-06-27 Light Sciences Limited Partnership Use of shape memory alloy for internally fixing light emitting device at treatment site
US6021347A (en) * 1996-12-05 2000-02-01 Herbst; Ewa Electrochemical treatment of malignant tumors
US5782896A (en) * 1997-01-29 1998-07-21 Light Sciences Limited Partnership Use of a shape memory alloy to modify the disposition of a device within an implantable medical probe
US5876427A (en) * 1997-01-29 1999-03-02 Light Sciences Limited Partnership Compact flexible circuit configuration
US5746495A (en) * 1997-02-05 1998-05-05 Klamm; Thomas L. Portable work light with optical fiber adapter
US5929105A (en) * 1997-05-07 1999-07-27 Qltphoto Therapeutics, Inc. Ethylene glycol esters as photoactive agents
US5926320A (en) * 1997-05-29 1999-07-20 Teldedyne Lighting And Display Products, Inc. Ring-lens system for efficient beam formation
US5757557A (en) * 1997-06-09 1998-05-26 Tir Technologies, Inc. Beam-forming lens with internal cavity that prevents front losses
US5921244A (en) * 1997-06-11 1999-07-13 Light Sciences Limited Partnership Internal magnetic device to enhance drug therapy
US5766222A (en) * 1997-07-07 1998-06-16 Petit; Michael G. Nipple illuminator for photodynamic therapy
US6058937A (en) * 1997-07-18 2000-05-09 Miravant Systems, Inc. Photodynamic Therapy of highly vascularized tissue
US5924788A (en) * 1997-09-23 1999-07-20 Teledyne Lighting And Display Products Illuminating lens designed by extrinsic differential geometry
US5865840A (en) * 1997-10-22 1999-02-02 Light Sciences Limited Partnership Enhancement of light activation effect by immune augmentation
US6071944A (en) * 1997-11-12 2000-06-06 Bowling Green State University Method of treatment of pigmented cancer cells utilizing photodynamic therapy
US6092531A (en) * 1998-02-10 2000-07-25 Light Sciences Limited Partnership Movable magnet transmitter for inducing electrical current in an implanted coil
US6183444B1 (en) * 1998-05-16 2001-02-06 Microheart, Inc. Drug delivery module
US6416531B2 (en) * 1998-06-24 2002-07-09 Light Sciences Corporation Application of light at plural treatment sites within a tumor to increase the efficacy of light therapy
US6554853B2 (en) * 1998-12-21 2003-04-29 Light Sciences Corporation Use of pegylated photosensitizer conjugated with an antibody for treating abnormal tissue
US6344050B1 (en) * 1998-12-21 2002-02-05 Light Sciences Corporation Use of pegylated photosensitizer conjugated with an antibody for treating abnormal tissue
US6210425B1 (en) * 1999-07-08 2001-04-03 Light Sciences Corporation Combined imaging and PDT delivery system
US6238426B1 (en) * 1999-07-19 2001-05-29 Light Sciences Corporation Real-time monitoring of photodynamic therapy over an extended time
US6534040B2 (en) * 1999-12-23 2003-03-18 Health Research, Inc. Chlorin and bacteriochlorin-based aminophenyl DTPA and N2S2 conjugates for MR contrast media and radiopharmaceuticals
US6520669B1 (en) * 2000-06-19 2003-02-18 Light Sciences Corporation Flexible substrate mounted solid-state light sources for exterior vehicular lighting
US6580228B1 (en) * 2000-08-22 2003-06-17 Light Sciences Corporation Flexible substrate mounted solid-state light sources for use in line current lamp sockets

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030060719A1 (en) * 1998-06-19 2003-03-27 Irion Klaus M. Use of 5-aminolevulinic acid or a derivate thereof for photodynamic diagnosis and /or photodynamic therapy
US7767208B2 (en) 1999-01-15 2010-08-03 Light Sciences Oncology, Inc. Noninvasive vascular therapy
US20040215292A1 (en) * 1999-01-15 2004-10-28 James Chen Photodynamic treatment of targeted cells
US20050004510A1 (en) * 1999-01-15 2005-01-06 James Chen Noninvasive vascular therapy
US20050196401A1 (en) * 1999-01-15 2005-09-08 James Chen Energy-activated targeted cancer therapy
US7897140B2 (en) 1999-12-23 2011-03-01 Health Research, Inc. Multi DTPA conjugated tetrapyrollic compounds for phototherapeutic contrast agents
US20060088530A1 (en) * 2000-01-12 2006-04-27 Chen James C Photodynamic therapy treatment for eye disease
US20020049247A1 (en) * 2000-01-12 2002-04-25 Chen James C. Novel treatment for eye disease
USRE43274E1 (en) 2002-06-27 2012-03-27 Health Research, Inc. Fluorinated photosensitizers related to chlorins and bacteriochlorins for photodynamic therapy
US7820143B2 (en) 2002-06-27 2010-10-26 Health Research, Inc. Water soluble tetrapyrollic photosensitizers for photodynamic therapy
US20100274330A1 (en) * 2003-03-14 2010-10-28 Light Sciences Oncology, Inc. Device for treatment of blood vessels using light
US20080033519A1 (en) * 2003-03-14 2008-02-07 Light Sciences Oncology, Inc. Light generating device for intravascular use
US20060240096A1 (en) * 2005-04-22 2006-10-26 Kugler Chad J Devices and methods for treating the gastrointestinal system
US20110218474A1 (en) * 2008-08-19 2011-09-08 Oncowave Medical Gmbh Apparatus for the destruction of tumor cells or pathogens in the blood stream

Also Published As

Publication number Publication date Type
US6602274B1 (en) 2003-08-05 grant
US20040215292A1 (en) 2004-10-28 application
US20050196401A1 (en) 2005-09-08 application
JP2002534219A (en) 2002-10-15 application
US20030208249A1 (en) 2003-11-06 application
US7018395B2 (en) 2006-03-28 grant
WO2000041727A1 (en) 2000-07-20 application
EP1140176A1 (en) 2001-10-10 application
CA2356776A1 (en) 2000-07-20 application
US20080114285A1 (en) 2008-05-15 application
US20020087205A1 (en) 2002-07-04 application
US6899723B2 (en) 2005-05-31 grant

Similar Documents

Publication Publication Date Title
Kinsella et al. Photodynamic therapy in oncology
Rockson et al. Photoangioplasty: an emerging clinical cardiovascular role for photodynamic therapy
Schmidt-Erfurth et al. Mechanisms of action of photodynamic therapy with verteporfin for the treatment of age-related macular degeneration
Barr et al. Eradication of high-grade dysplasia in columnar-lined (Barrett's) oesophagus by photodynamic therapy with endogenously generated protoporphyrin IX
Friesen et al. 5-Aminolevulinic acid-based photodynamic detection and therapy of brain tumors
US5514669A (en) Use of photodynamic therapy to treat prostatic tissue
Solban et al. Targeted photodynamic therapy
US5399583A (en) Method of treating skin diseases
EDELL et al. Bronchoscopic phototherapy with hematoporphyrin derivative for treatment of localized bronchogenic carcinoma: a 5-year experience
US5705518A (en) Method of activating photosensitive agents
Chen et al. New technology for deep light distribution in tissue for phototherapy
Hasan et al. Photodynamic therapy of cancer
US5171749A (en) Wavelength-specific cytotoxic agents
McCaughan Photodynamic therapy
Dougherty Photodynamic therapy—new approaches
Bown Phototherapy of tumors
Peterson et al. Combination chemotherapy and photodynamic therapy with N-(2-hydroxypropyl) methacrylamide copolymer-bound anticancer drugs inhibit human ovarian carcinoma heterotransplanted in nude mice
US5257970A (en) In situ photodynamic therapy
Abels Targeting of the vascular system of solid tumours by photodynamic therapy (PDT)
Dougherty Photosensitization of malignant tumors
Hopper Photodynamic therapy: a clinical reality in the treatment of cancer
Popovic et al. Photodynamic therapy of brain tumors
US20020197262A1 (en) Photoimmunotherapies for cancer using photosensitizer immunoconjugates and combination therapies
Chen et al. Liposomal delivery of photosensitising agents
Paszko et al. Nanodrug applications in photodynamic therapy

Legal Events

Date Code Title Description
AS Assignment

Owner name: LIGHT SCIENCES CORPORATION, WASHINGTON

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:CHEN, JAMES;REEL/FRAME:013686/0359

Effective date: 20020114