WO1998004318A1

WO1998004318A1 - Photodynamic therapy with light emitting particles in bloodstream

Info

Publication number: WO1998004318A1
Application number: PCT/US1997/013303
Authority: WO
Inventors: David Mager; Melvin Tecotzky
Original assignee: Light Medicine, Inc.
Priority date: 1996-07-25
Filing date: 1997-07-25
Publication date: 1998-02-05
Also published as: AU3898897A

Abstract

Light for photodynamic therapy is applied by passing light emitting particles, preferably smaller than about 5 ν in diameter, into the bloodstream of a mammalian subject so that the particles are distributed through the tissue to be treated. Because the particles are widely distributed, the light need not penetrate through substantial thicknesses of tissue to reach the cells to be treated. Therefore, photosensitizers which are sensitive to light at essentially any wavelength can be utilized.

Description

PHOTODYNAMIC THERAPY WITH LIGHT EMΠTING PARTICLES IN BLOODSTREAM

TECHNICAL FIELD The present invention relates to the field of photodynamic therapy. BACKGROUND ART

Photodynamic therapy involves the application of light to abnormal tissues, referred to herein as "lesions" in or on the body of a human or other mammalian subject. A drug which increases die sensitivity of bodily tissues to light, referred to herein as a "photosensitizing agent" is administered to the subject before exposure to the treating light. When the treating light is applied to the tissues, chemical reactions which disrupt die function of the cells in the abnormal tissues occur. Typically, the chemical reactions include generation of reactive species such as singlet oxygen. This process is applied, for example, in treatment of skin cancers, cancers of the internal organs. Preferred photosensitizing agents such as porphyrins tend to concentrate in cancerous tissues and increase the sensitivity of d e cancerous lesion to light to a far greater degree than the increased sensitivity of die surrounding normal tissues. Thus, die cancerous lesion can be killed witiiout destroying all of die surrounding normal tissues. The practice of photodynamic therapy is described, for example, in die article "Photodynamic Therapy in Oncology: Methods and Clinical Use", J. National Cancer Institute, Vol. 85, No. 6, pp. 443-456, March, 1993. The treating light used to perform die photodynamic dierapy typically is applied from outside of d e organs to be treated. For example, where die organ to be treated is die skin, die treating light is applied from outside of the body to the surface of the skin. Where the lesion is present on or in internal organs of die body, die treating light may be applied by aiming a fiberoptic probe connected to a laser onto die surface of the organ so tiiat die light impinges on die surface of die lesion. As described, for example in Tockner et al., Intratiioracic Photodynamic Therapy: A Canine Normal Tissue Tolerance Study and Early Clinical Experience, Lasers In Surgery and Medicine, 14:118-123 (1994) and in Pass et al., Use of Photodynamic Therapy for the Management of Pleural Malignancies, Seminars in Surgical Oncology 11:360-367 (1995), the treating light may be applied tiiroughout the surface of a complex internal body cavity such as die pleural cavity by filling the cavity witii a light-diffusing medium and directing die light into die medium. This assures that die light will impinge on die surfaces of lesions distributed tiiroughout die cavity. These approaches are limited in tiiat tiiey apply die light only at die surfaces of die lesions. This requires tiiat die light penetrate into d e lesions and, in some cases, tiirough die surrounding tissues, to reach the deeper portions of die lesions. Light at wavelengtiis of about 630 to about l,000nm wavelengtii will penetrate into typical tissues. Even with light at these wavelengths, however, it is difficult to deliver the required dose of light to tissues more than 1-2 cm from die exposed surface. Moreover, die requirement to use treating light in die 630-l,000nm wavelengtii band in order to achieve tissue penetration necessarily limits the choice of photosensitizing agents to only those agents which are sensitive to light in this band of wavelengths, encompassing deep red and infrared light. Aldiough useful compounds such as porphyrins and related compounds known as texaphryns and derivatives thereof can be used with treating light in this wavelengtii band, it would be desirable if photodynamic therapy could be performed using otiier photosensitizers.

Various proposals have been advanced for conducting photodynamic tiierapy using otiier light applying devices. As described in U.S. Patent 5,441,497, light can be administered through a guidewire in an angioplasty balloon catiieter so as to administer light on die intraluminal surfaces of blood vessels. Also, as described in U.S. Patents 5,269,777 and 5,196,005, light can be applied by means of a fiber optic which is inserted into die tissue. As described in U.S. Patent 5,445,608, a fiber optic or a needlelike probe having numerous light emitting diodes tiiereon can be advanced into die center of a tumor or otiier lesion to illuminate the surrounding zone of die lesion. U.S. Patent 5,571,152 suggests die use of microminiature illuminators on die order of 5mm diameter or smaller which are implanted in die lesion. Each microminiature illuminator includes an element such as a light emitting diode and small coil antennas. These microminiature illuminators are implanted in the lesion and driven by RF power administered from outside of die patient. Even with these approaches, however, light is applied only at a few discrete locations within die lesion and die light must penetrate into die surrounding tissue of die lesion. Thus, tiiese approaches still require die use of light at die 630- l,000nm wavelengtii band to penetrate into the tissues. Even with light at tiiese wavelengths, tiiese approaches are still less than optimum for treatment of bulky lesions. DISCLOSURE OF THE INVENTION

One aspect of die present invention provides a method of administering photodynamic tiierapy to a mammalian subject. Preferred mediods according to tiiis aspect of d e present invention include die step of delivering light emitting particles in die bloodstream of die subject. Most preferably, die light emitting particles are less than about five microns in diameter. Therefore, die light emitting particles will be carried by die blood tiiroughout die entire extent of the organ or tissue to be treated and will pass tiirough the capillaries witii die blood. The light emitting particles, dierefore, are intimately dispersed throughout the tissue being treated and the light from the particles will reach all portions of the target organ even if d e light is only transmitted tiirough the tissue for a few microns. Therefore, essentially any wavelength of light can be utilized, including light in regions of die visible spectrum otiier than red and also including ultraviolet light at less tiian about 400nm wavelengtii.

The particles may include a radioactive material and a luminescent material which is responsive to the radiation emitted by die radioactive material to emit light. The radioactive material may emit beta radiation and most preferably emit beta radiation at relatively low electron energy such as below about 35 KeV. Tritium constitutes a preferred radioactive material. Otiier radioactive materials which emit beta radiation at higher electron energies, such as S can also be employed. Alternatively or additionally, the luminescent material may be a chemiluminescent substance. The chemiluminescent material may be activated by exposure to a catalyst or reactant immediately prior to administration of die particles or, preferably, may be maintained in an inactive state by storage at temperatures below body temperature and activated by warming to about body temperature immediately prior to administration, so that die chemiluminescent substance emits light while die particles are disposed in the body.

According to a further embodiment of die invention, die particles may include a phosphorescent material which has a persistent, relatively long-lived emission after exposure to exciting radiation. The metiiod may further include die step of energizing die phosphorescent material of die particles while die particles are isolated from die tissues of die subject. For example, the energizing step may be performed while d e particles are disposed outside die body of die subject and die particles may be delivered into die bloodstream from outside of die body so that persistent emission of die particles continues after introduction of the particles into die bloodstream. For example, die particles may be exposed to exciting radiation while tiiey are disposed outside of die body and subsequently introduced into die body. The particles may be recovered by witiidrawing blood containing particles from die body. The particles may be separated from die blood and die recovered particles may be returned to the energizing step and tiien reintroduced into die bloodstream after die energizing step. Alternatively, die particles may be discarded after one passage tiirough die subject. Because the particles can be exposed to die exciting radiation in die absence of die tissues to be treated and, preferably, in the absence of d e blood, the exciting radiation can be of essentially any form including strong ultraviolet, beta, X-ray or otiier radiation harmful to normal tissue. The separating step may include metiiods such as filtration or centrifiigation of die particles from the blood.

In a further variant, each particle may include an electrical storage element such as a capacitor and an electrically powered light emitting element such as a light emitting diode. The particles may be energized by charging the storage element in each such particle while the particle is outside of the patient's body. The energy stored in the storage elements is converted to light by die light emitting elements and at least part of such conversion occurs while die particles are disposed in die body. The charging step may be performed by exposing the particles to electromagnetic radiation or by engaging contacts on the particles witii a source of electrical potential. The method may further include the step of controlling die conversion of electrical energy to light by die light emitting elements so that ti is conversion occurs principally while die particles are within the body of die subject. For example, each particle may have a control element responsive to an electromagnetic field and die step of controlling may include the step of applying an electromagnetic field within die body of die subject so that the field impinges on die particles only in a selected region of die body as, for example, the region immediately surrounding a lesion to be treated. This promotes efficient use of the stored light and further tends to minimize exposure of normal tissues to the treating light emitted by die particles.

Preferably, the step of delivering die particles into die patient's bloodstream is performed so tiiat die particles are delivered by die bloodstream to less tiian all of die subject's body. Thus, the delivering step may include die step of perfusing only a selected portion of the subject's body, such as a particular target organ in need of treatment, with blood containing the particles. For example, blood containing die particles may be passed into an artery serving the selected portion of the subject's body and this blood may be recovered from a vein serving said portion of the body, thereby diverting the particles away from one or more other organs of the body. Where organs other tiian die liver are being treated, it is normally desirable to exclude die particles from die liver, as many photosensitizers tend to concentrate in die liver. By excluding die particles from die liver, die adverse effects of exciting photosensitizers in normal liver tissue are substantially avoided.

In die preferred methods, a photosensitizer is administered to die subject so tiiat the photosensitizer is present in the subject when the light is emitted by die particles. Preferably, the photosensitizer is administered selectively so that the photosensitizer is emitted only to a target portion of the subject's body. Where the particles are administered by perfusing a target organ, die blood used for such perfusion may include die photosensitizer.

The blood used to deliver die particles may be die subject's own blood; donated blood of die same species or a known artificial bloodlike substance capable of carrying oxygen to die tissue.

A further aspect of die present invention provides compositions of matter for use in administering photodynamic tiierapy. Compositions according to this aspect of die invention include biocompatible particles less tiian about five microns in diameter, die particles containing a luminescent material. The composition may further include a diluent pharmaceutically acceptable for infusion into the blood or blood or a blood substitute. The particles may be in suspension in the diluent, die blood or die blood substitute. As discussed above in conjunction with die metiiod, the particles desirably include a radioactive material and a luminescent material responsive to die radiation from such material to emit light; or a phosphorescent material having persistent emission or a chemiluminescent material. The particles desirably include a biocompatible coating such as a crosslinked hydrocarbon polymer, a halogenated hydrocarbon polymer, a silicon polymer, or glass. Although particles up to about five microns in diameter may be employed, still smaller particles are more preferred. Most preferably, die particles have diameters of about one micron or less. The luminescent material may be adapted to emit light at the conventional red or infrared wavelengths used for photodynamic therapy or, alternatively, may be adapted to emit light at wavelengtiis less than about 600nm.

Yet anodier aspect of die present invention provides apparatus for administering photodynamic tiierapy to a mammalian subject. Apparatus according to this aspect of the invention includes means for delivering light emitting particles into the blood circulation of die subject so tiiat the particles pass through at least some portion of the subject's body in the bloodstream. Preferred apparatus in accordance with this aspect of die invention further includes means for separating the light emitting particles from the blood of die subject after passage through the body of die subject as, for example, by centrifugation or filtration. These and otiier object, features and advantages of die present invention will be more readily apparent from die detailed description of the preferred embodiments set forth below, taken in conjunction witii d e accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a diagrammatic view depicting a particle in accordance witii one embodiment of the invention.

Fig. 2 is a diagrammatic view depicting a particle in accordance witii another embodiment of the invention. Fig. 3 is a diagrammatic view depicting a subject and apparatus in a process according to one embodiment of the invention.

Fig. 4 is an electrical circuit diagram depicting a circuit incorporated in a particle according to a further embodiment of die invention. MODES FOR CARRYING OUT THE INVENTION

A particle according to one embodiment of the invention is depicted in Fig. 1. The particle includes a core of a radioactive material 20; a layer of a radio-responsive phosphor 22 on die core and an outer coating of a biocompatible material 24. In an alternate embodiment, die phosphor may constitute die core 20, whereas layer 22 may include the radioactive material. In a further alternative embodiment, die radioactive material 20 and phosphor 22 may be combined with one anodier as a unitary body. Thus, the phosphor and radioactive material may be interspersed witii one another, or the radioactive material may be a constituent of die phosphor itself. Preferred radioactive materials for use in particles according to this aspect of the present invention include beta-emitting radioactive materials. Among the radioactive materials which can be utilized are tiiose listed in Table 1 below

TABLE I

MAX DECAY

ATOMIC HALF LIFE ENERGY

ISOTOPE WEIGHT (days) (Mev) β POWER

H3 3 4,475 0.01861 0.328 w/gm

P32 32 14 1.71 1,667.0 w/gm

Rul06 106 367 0.0394

Where the particles are intended to apply light witiiout also applying X-rays to the surrounding tissues, the more preferred radioactive materials are those which emit electrons at less than about 35keV, and preferably at about 30keV or less, and which have decay energies less than these values. For this purpose, tritium (³H) is die most preferred isotope. Tritium desirably is present as a chemically stable tritium based compound which has a high density of tritium per unit volume, such as tritium- substituted water (tritium density of 0.27 gram/cm³ ), lithium hydride (.246), Decaborane - (.2632), ammonium bromide - (0.275) , and titanium hydride (0.43). If isotopes having greater decay energies are employed, die resulting particles will emit X-rays along with light. Such X-rays can be utilized as part of the treatment regime. In this case, die particles desirably are administered primarily to die organ or organs requiring treatment as described below so as to limit the X-ray exposure of the other organs. The most preferred high-energy β isotope is ³⁵S. Also, the radioisotope and its decay products should have reasonably low toxicity. The phosphors used witii β isotopes are cathodoluminescent, i.e., adapted to emit light in response to energetic electrons. Any of the phosphors set forth in Table II below as electron-responsive may be employed.

TABLE II-PHOSPHORS

The particle further includes a biocompatible outer surface 24. Outer surface 24 may be in the form of a distinct coating such as a crosslinked hydrocarbon polymer; a halogenated hydrocarbon polymer; a silicone polymer; glass , or any otiier suitable biocompatible material which, at the thickness employed, is transparent or translucent to the light at die treatment wavelengtii which will be emitted from die luminescent material. Polymeric and inorganic coatings can be applied to particles by known processes such as chemical vapor deposition and plasma enhanced chemical vapor deposition, as well as by known liquid-phase processes. For example, suitable coatings can be prepared by plasma polymerization of materials set forth in Table III, below, to a tiiickness of about 5 nm to about 1000 nm (1 micron), most preferably to about 50 nm.

TABLE III - PLASMA POLYMERIZED COATINGS

MONOMER POLYMER

Acetylene (gas) Crosslinked hydrocarbon with many -C=C-bonds

Ethylene (gas) Crosslinked hydrocarbon with some -C=C-bonds

Methane, Ethane (gases) Crosslinked hydrocarbon with low unsaturation

Butadiene (gas) Crosslinked hydrocarbon with conjugated double bonds

Hexamethyldisiloxsane Ranges from soluble linear polymer to highly (HMDS; liquid) crosslinked, insoluble; high temperature resistance

Trimethylsilane (gas) Similar to HMDS

Dimethylsilane (gas) Similar to HMDS

Hexamethyldisilazane (liquid) Highly crosslinked

Hexamethyldisilane Oiquid)

Fluorocarbons (i.e. C7F16) Crosslinked Teflon-like polymers Oiquids)

Thiophene Oiquid) Conductive polymer like electropolymerized material

Aniline Oiquid) Conductive polymer like electropolymerized material

Other biocompatible exterior surfaces include biologically- derived materials such as proteinaceous and lipid-like materials and synthetic analogs of such materials. For example, the radioisotope and phosphor may be enclosed in a shell of a lipid material, commonly referred to as a liposome. In a further variant, the radioisotope and the phosphor may be contained within a dead or living cell compatible with the subject to be treated. As used in this disclosure with reference to die surface of a particle, the term "biocompatible" means that the particle surfaces can remain in contact with the blood for a period of time long enough to perform the required treatment witiiout provoking such a severe reaction as to permanentiy injure or kill the subject. Manifestly, higher degrees of biocompatability are more desirable. Particles in accordance with further embodiments of the invention utilize a persistent phosphor, i.e., a phosphor having a decay time of more than about one second, and preferably more than about 10 seconds, instead of die radioisotope and phosphor combination discussed above. The decay times of various phosphors are set forth in table II, above. As described below, particles incorporating a persistent phosphor can be excited before introduction into the tissues to be treated and will continue to emit light as they pass through the tissues. Particles incorporating persistent phosphors desirably also include biocompatible coatings as discussed above. Particles in accordance witii other embodiments of the invention include a chemiluminescent material or combination of materials. One such combination includes luminol (5-amino, 2,3 dihydro-1,4- phthalazine-dione) and hydrogen peroxide. Chemiluminescent systems such as those based on luciferin derived from fireflies and synthetic versions of the same emit in the yellow-green range, whereas other luciferin-based systems emit in the blue-green range. Particles incorporating chemiluminescent systems may have biocompatible coatings similar to those discussed above. Chemiluminescent particles may be maintained in an inactive state by chilling them to temperatures well below room temperature, typically to about 0°C or below, and may be restored to an active, emitting condition by reheating them to approximately body temperature, i.e., to about 35-40°C. Alternatively, where the chemiluminescent reaction requires oxygen, the particles may be maintained in an inactive state by maintaining them in an anaerobic condition, and tiien exposing them to oxygen just prior to administration to the subject. Where this approach is employed, the biocompatible coating should have substantial permeability to oxygen. Similarly, other low molecular weight reactants can be omitted from the particles when initially prepared and supplied just prior to administration of the particles to a subject.

As shown in Fig. 2, particles in accordance with further embodiments of die invention may include one or more voids 26 within d e particle to minimize the specific gravity of the particle and bring its specific gravity closer to that of the blood plasma. Thus, the particle may include a hollow microsphere 28 defining the void, and the active ingredients—the radioisotope, phosphor, and/or chemiluminescent material ~ may be present as one or more layers on the exterior surface of the microsphere. Alternatively, the voids may be present in die mass or masses of active ingredients. For example, the active ingredients may be compounded as microscopic agglomerates with void spaces therein. The specific gravity of die particles also can be adjusted by adjusting the thickness of the coating. For most species, the specific gravity of blood is slightly more than 1. The particles may have specific gravity greater or less than the specific gravity of the blood.

A composition for use in administering photodynamic therapy may include particles as described above alone or in admixture with a suitable diluent suitable for administration in the bloodstream of die subject. A preferred diluent is an isotonic aqueous solution such as saline or Ringer's solution. Other suitable diluents include the subject's blood or blood plasma, and artificial liquids capable of carrying oxygen and capable of acting as a temporary substitute for the subjects blood. The composition can be sterilized and packaged in any known type of sterile packaging. Apparatus for administering photodynamic therapy in accordance with one embodiment of the invention includes die conventional elements commonly used for isolation and selective perfiision of a target organ 40 in the body of a subject 42. Thus, d e apparatus may include an arterial catheter 44, a venous catheter 46 and clamps 48 for temporarily blocking the arteries and veins serving the target organ. The perfusion apparatus further includes conduits defining an extracorporeal circulation patii from venous catheter 46, through a conventional blood pump 50 and back to arterial catheter 44, so that blood may be continually circulated tiirough the target organ without contacting the other organs in the body of the subject. The extracorporeal circulation path may include conventional devices 53 for treating the blood, as by oxygenating it, and controlling its temperature, before it is passed through the target organ. Other conventional control and safety devices may also be employed. The apparatus further includes a separation centrifuge 52 and filter 54 interposed in the extracorporeal circulation path for recovering particles from the circulating blood. These elements are arranged to direct die recovered particles to a storage tank 56. Storage tank 56 is equipped witii temperature control devices (not shown) for maintaining the stored material at or slightly above the normal body temperature of subject 42. The storage tank is connected to a pump 58, which in turn is connected to a particle treatment cell 60. Cell 60 is an elongated conduit transparent to radiation which is used to excite die particles. For example, where the particles include a persistent phosphor be excited by ultraviolet radiation, cell 60 is formed in whole or in part from a material transparent to ultraviolet radiation. Where X-rays are employed to excite a phosphor, the cell desirably includes a polymeric wall transparent to the X-rays. If electron beam radiation is employed, the cell may include any known electron beam window material, such as a tiiin sheet of a metal foil or a ceramic foil such as boron nitride hydride.

An excitation irradiation source 62 is arranged to apply exciting radiation to particles in cell 60. Source 62 may be any conventional source of light, electron beam, X-ray or other radiation suitable for exciting a phosphor carried by the particles. For example, conventional X-ray tubes; electron beam guns and lamps may be employed.

Where the particles to be employed include luminescent materials which do not require external radiation, such as chemiluminescent materials or luminescent materials powered by internal radioactive sources, the excitation irradiation source 62 and cell 60 may be omitted. In a metiiod according to one embodiment of the invention, the bloodstream serving the target organ 40 is isolated from the remainder of die circulatory system in the conventional manner, as by clamps 48. The extracorporeal circulation is established through pump 50 and treatment device 53. A photosensitizer is administered to the subject so that the photosensitizer reaches the target organ 40. The photosensitizer may be administered systemically prior to isolation of the target organ, or by addition through the extracorporeal circulation after isolation of the target organ. Storage unit 56 holds the particles and diluent at a temperature at or above the normal body temperature of the subject. In the illustrated method, the particles incorporate a persistent phosphor which must be excited by externally applied radiation. Pump 58 is actuated to draw the diluent and suspended particles from the storage unit and pass them tiirough into the target orcell 60, where they are exposed to the exciting radiation. After passage through excitation cell 60, the particles and diluent mix with die blood in die extracorporeal circulation and pass into the target organ through the artery serving the organ. The bloodstream passing tiirough the organ carries the particles through the target organ, so that the particles reach all regions of the organ and are intimately distributed in the tissues of the organ, including the tissue constituting a lesion 41 on the organ. The particles emit treating light which excites the photosensitizer and causes it to react and kill die target cells. Because the particles are intimately distributed tiiroughout the tissues in the small blood vessels and capillaries, the treating light emitted by die particles will reach all of the tissue. Preferably, the photosensitizer tends to concentrate in the lesion, or d e tissues of the lesion are more sensitive to the effects of the photosensitizer than the other tissues of organ 41. After passing through the target organ, the particles pass into the veins serving the target organ and out of the subject's body through the venous catheter 46. The particles are recovered from die blood in the extracorporeal circulation by centrifuge 52 and filter 54, and are returned to storage tank 56. The diluent may be recovered from the blood in the extracorporeal circulation and may be returned to tank 56 along witii die particles. Additional particles and/or diluent may be added to die storage tank as needed. The particles and diluent are continually recycled and returned to the subject. The process continues until the desired dose of treating light has been administered to the target organ. The desired dose will vary with the photosensitizer and with the purpose of the treatment. However, for treatment of malignant tumors a dose of about 1 to about 50 joules/cm , and more preferably about 2 to about 35 joules/cm³ is commonly employed. The lower doses are used with the more efficient photosensitizers as discussed below.

The process can be varied. In the embodiment of Fig. 3, separation of the particles from die blood prior to exposure to the excitation radiation protects die blood from die effects of the radiation. Where the radiation can be tolerated by die blood, die separation step can be omitted. As mentioned above in connection with the apparatus, the excitation irradiation unit and cell can be omitted where die particles do not require excitation. Also, the particles can be discarded rather than reused after passing through the subject. The light emitted by the particles can be more precisely targeted to die lesion by directing the particles into a smaller artery just upstream of the lesion. Alternatively, the particles can be injected into die systemic circulation and may pass tiiroughout the body if die effect of the treating light can be tolerated by the body. The particles need not be recovered from die subject. Thus, the particles may be allowed to remain in die subject's body. Where the phosphors include metals, a chelating agent may be administered to die subject to minimize the effect of metals leaching from the particles. In a further variant, the particles may be allowed to lodge within the tissues of the target organ. Thus, some or all of die particles may lodge in the capillaries of the target organ, and will continue to emit light in the target organ. This approach is particularly suitable where the particles are chemiluminescent or radioisotope-activated particles capable of emitting light for prolonged periods without external excitation.

Some useful photosensitizers are listed below in Table IV: TABLE IV

Drug Manufacturer WaveExtinction Drug Light lengths coefficient Dosage Dosage

Photofrin QLT 420, 5,000 ©630 2mg/kg 135 hematoporphryn 630 nm joules/cm2 derivative) 50,000@42 Onm

ALA DUSA 420, 5,000 ©630 5.4-120

(aminolevulinic 630 nm acid) 50,000@42 Onm

LuTex Pharmacy clics 450, 90-240

Outetium 732 texaphrin)

SnET2 PDT Inc 440, 0.75mg/ 100-300 (tin ethyl 664 kg etiopuφurin)

SnOEBc PDT Inc 430, 691 mTHPC Scotia 400, 100,000© 0.2mg/k 25 (meta- 670 670 nm g joules/cm2 tetrahydroxyphen ylchlorin)

NP6 Nippon 400, Petrochemical 660

Benzoporphyrn 360, 1 mg/kg 690

Zinc 670 2 mg/kg 150

Phthalocyanine

Disulphonate

Bacteriochlorins 800 100,000© bacteriopurprans 800 nm & ketochlorins

Notably, some of the conventional photosensitizers listed in Table IV such as porphyrins are sensitive both in the red and infrared regions (above 600 nm wavelength) and at wavelengths below 600 nm, such as at about 410 nm. These photosensitizers typically exhibit higher quantum efficiency at shorter wavelengtiis. That is, shorter-wavelength light is more efficiently converted to chemical action in die cell, for example, Photofrin is approximately 15 times more sensitive to blue light of 410 nanometers compared to its activation with red light at 630 nanometers. Thus, 2 joules of blue light from particles perfused in a gram of tissue will liberate at least the same number of singlet oxygens as 30 joules of red light delivered from the surface.

Because the shorter-wavelength light can be administered effectively using the methods according to preferred embodiments of the present invention, particles which emit shorter-wavelength treating light are preferred for use with such photosensitizers.

Compounds which have not been utilized heretofore as photosensitizers can also be employed. One notable example is tetracycline, which is capable of acting as a photosensitizer responsive to light at about 380nm wavelength. Prior to the present invention, tetracycline was not usable as a photosensitizer because there was no effective way to supply the treating light. Tetracycline has been widely utilized as an antibiotic, and is well tolerated by humans and other mammalian species. Moreover, tetracycline does not tend to concentrate in the liver. Because the present invention effectively removes the limitations on the wavelength of light used for photodynamic tiierapy, essentially any substance which can be administered to the subject either systemically or locally and which will cause the tissues to become sensitive to light at any wavelength can be used as a photosensitizer. Preferably, the photosensitizing substance is selectively absorbed by die tissues or lesions to be treated.

EXAMPLE The following non-limiting example illustrates certain principles of the invention: To begin treatment, the patient is administered, for example, 2mg/kg of Photofrin (Hematoporphyrin derivative) or 0.2 mg/kg of mTHPC (meta Tetrahydroxyphenylchlorin) . To treat 50 grams of tumor with Photofrin and , 2 cubic centimeters of 3 micron diameter particles suspended in physiological saline are used. The particles emit blue light at about 420 nanometers. They include a zinc sulfide: silver phosphor. This phosphor has a net 21 % efficiency for converting incoming electrons (including back scattering) to resultant light output.

The particles contain approximately 50% by volume zinc sulfide: silver phosphor (crystal density of 4.1 grams/cm³) and approximately 50% by volume tritium substituted titanium hydride (density 3.9 grams/cm ).

Two cubic centimeters, consisting of approximately 100 billion, 3 micron diameter particles, weighing approximately 8 grams containing 0.43 grams of tritium are administered as discussed above. If all of die particles remain in the tissue at all times , the tritium contained in these particles provide a β-emission power density of .328 watts per gram of tritium. At the 21 % conversion efficiency of the phosphor, the particles yield about 0.06 watts of light per gram of tritium, or about 0.03 watts (0.03 joules/sec) total light output. . 50 grams of tissue would receive 2 joules per gram (100 joules total light energy) in approximately 1 hour. Where some of the particles are in the extracorporeal circulation during part of the time, the treatment time is increased proportionately. Approximately 120 calories of heat would be produced as a byproduct in the treatment area in the hour with a 2.4°C rise in temperature should the heat not be dissipated. The heat can be removed from die blood by treating device 53.

A particle in accordance with another embodiment of the invention includes an electrical circuit 90 is schematically depicted in Fig. 4. Circuit 90 is formed as a monolithic integrated circuit. The circuit includes a first rudimentary radio receiver 92 including a first receiving coil 93 and capacitor 94 forming a resonant circuit having a resonant frequency in die radio frequency CRF") range. A diode 96 acts as die output connection of receiver 92. The diode is connected to one side of a storage capacitor 98. A light emitting diode 102 is connected in series with the source and drain of a field effect transistor 104 across capacitor 98. The control gate of transistor 104 is connected to one side of a control capacitor 106. The opposite side of die control capacitor is connected to the internal ground. A high value bleed resistance 108 is connected in parallel witii capacitor 106. The internal leakage path of die capacitor may serve as this resistance. Capacitor 106 is connected to the output of a second rudimentary radio receiver 110, which includes a receiving coil 112 and capacitor 114 forming a resonant circuit having a second resonant frequency in the RF range different from die first resonant frequency. A rectifying diode 116 serves as die output of second receiver 110.

Capacitor 98 can be charged by applying RF energy to the particle at the first frequency. Upon application of RF energy at the first resonant frequency to receiving coil 93, the coil and capacitor 94 are excited in resonance. Diode 96 rectifies the oscillating voltage in the resonant circuit and charges capacitor 98. FET 104 is normally nonconducting. Upon application of RF energy at the second resonant frequency to receiving coil 112, the coil and capacitor 114 are excited in resonance. Diode 116 rectifies the oscillating voltage in the resonant circuit and charges control capacitor 106 until a sufficient voltage is applied to die control gate of FET 104, whereupon the potential in capacitor 98 is applied across LED 102 and current flows, causing the LED to emit light. The circuit shown in Fig. 4 is merely illustrative. Storage elements other than a capacitor, such as an electrical storage battery, can be substituted for capacitor 98, and die storage element can be charged by inductive, capacitive or conductive coupling to a power source. The rudimentary radio receiving circuits depicted in Fig. 4 can be replaced by other, well-known receiving circuits including single and multistage amplifying receiver circuit and circuits witii more selective tuning capabilities. Likewise, die control element shown as FET 104 can be replaced by other, well-known forms of electronic control elements.

Particles incorporating electrical circuits as described with reference to Fig. 4 can be used in a manner similar to the processes discussed above. However, the excitation cell 60 and irradiation unit 62 (Fig. 3) are arranged to apply RF energy at d e first frequency to die particles as they pass through the cell. Thus, as each particle passes through the excitation cell, its storage capacitor 98 is charged. The charged particles are carried into the bloodstream as discussed above. A source of RF radiation (not shown) at the second frequency is arranged to irradiate the lesion to be treated. As each particle reaches the vicinity of the lesion, die second radio receiver 110 receives die RF energy and triggers conduction through FET 104, causing emission of treating light by LED 102. Thus, the particles store energy in their respective capacitors 98 until they reach the vicinity of the lesion, whereupon they are triggered to release die stored energy in die form of light from LED 102. The ability to control emission of light from me particles minimizes application of light to normal tissues. This is especially useful where the particles are administered systemically, tiiroughout the entire circulatory system, rather than in a limited region as depicted in Fig. 3. In a further alternative, the particles may be activated by contact with die blood. For example, die control circuit in each particle may include a device for sensing die resistance of die surrounding medium, as by detecting the resistance between exposed contacts on die surface of the particle, and actuating the light emitting device when die resistance is below a tiireshold value. If the particles are immersed in the conductive blood immediately prior to introduction into die subject, each particle will begin to emit light as it enters the subject. In yet another alternative, no control circuit is provided; the storage capacitor continuously discharges through the LED at a relatively low rate, set by the internal resistance of the LED.

As numerous variations and combinations of the features described above can be utilized witiiout departing from the present invention as defined by the claims, the foregoing description of the preferred embodiments should be taken by way of illustration rather than by way of limitation of the invention. For example, the coating on the particles can be made to be hydrophilic, hydrophobic, or magnetically or electrically active to allow for selective sequestration and locating of die particles in the desired treatment area.

Claims

CLAIMS:

1. A method of administering photodynamic tiierapy to a mammalian subject comprising die step of delivering light emitting particles in the bloodstream of e subject.

2. A method as claimed in claim 1 wherein said particles are less than about 5μ in diameter.

3. A metiiod as claimed in claim 1 wherein said particles include a radioactive material emitting radiation and a luminescent material responsive to said radiation to emit light.

4. A method as claimed in claim 3 wherein said radioactive material emits β radiation.

5. A method as claimed in claim 4 wherein said radioactive material includes tritium.

6. A method as claimed in claim 4 wherein said luminescent material is selected from die group consisting of Zn(P0₄):Mn Zn₃(P0₄)₂:Mn;Y₂0₂S:Eu+3;InBθ₃:Tb; LaOC Tb

Y₃Al₆0₁₂:Tb;Y₃(Al,Ga)₅θ,₂:Tb;Y₂Si0₃:Tb; Y₂0₂S:Pr+3; Gd₂0₂S:Pr Zn₂Si0₄:Mn,As; Gd₂0₂S:Tb-l-3; La₂0₂S:Tb-l-3; Y₂0₃:Eu+3 YV0₄:Eu+3; YV0₄:[V]:Eu; Gd₂0₂S:Eu; YV0₄:Nd; BaFC Eu (ZnCd)S:Ag; ZnS:Ag; Y₂0₃:Gd and combinations thereof.

7. A method as claimed in claim 1 wherein said particles include a phosphorescent material having persistent emission, die metiiod further comprising die step of energizing the phosphorescent material of said particles while said particles are disposed outside of d e body of die subject, said delivering step including die step of delivering particles from outside of die body to die bloodstream of the subject so that the persistent emission of said particles continues after introduction of the particles into the bloodstream of the subject.

8. A metiiod as claimed in claim 7 wherein said phosphorescent material is responsive to radiation and wherein said energizing step includes die step of exposing the particles to radiation while the particles are disposed outside of die body of die subject.

9. A method as claimed in claim 8 wherein said phosphorescent material is a photoluminescent material responsive to energizing light, and wherein said step of exposing die particles to radiation includes die step of exposing the particles to energizing light while the particles are disposed outside of die body of die subject.

10. A method as claimed in claim 9 wherein said energizing light includes ultraviolet light of less tiian about 400 nm wavelength.

11. A method as claimed in claim 7 further comprising die steps of withdrawing blood containing said particles from the body of the subject, separating the particles from the blood prior to said energizing step and returning the energizing particles to the bloodstream of die subject after said energizing step.

12. A metiiod as claimed in claim 1 wherein each said particle includes an electrical storage element and an electrically powered light emitting element.

13. A method as claimed in claim 12 further comprising the step of charging the storage element in each said particle while such particle is outside of die patient's body, die energy stored in said storage elements being converted to light by die light emitting elements.

14. A method as claimed in claim 13 further comprising the step of controlling conversion of electrical energy to light by said emitting elements so that such conversion occurs principally while the particles are within the body of die subject.

15. A method as claimed in claim 14 wherein each said particle has a control element responsive to an electromagnetic field and wherein said controlling step includes die step of applying an electromagnetic field within the body of die subject so that said field impinges on said particles in the vicinity of a selected region of the body.

16. A method as claimed in claim 13 wherein said charging step includes die step of applying radiofrequency power to said particles while said particles are disposed outside of the subject's body.

17. A metiiod as claimed in claim 1 wherein said delivering step is performed so that said particles are delivered by die bloodstream to less an all of the subject's body.

18. A method as claimed in claim 17 wherein said delivering step includes die step of perfusing only a selected portion of the subject's body with blood containing said particles.

19. A method as claimed in claim 18 wherein said perfusing step is performed by passing blood containing said particles into an artery serving the selected portion of the subject's body and recovering said blood from a vein serving such portion.

20. A method as claimed in claim 17 wherein said delivering step includes the step of diverting said particles away from one or more organs of the subject's body.

21. A metiiod as claimed in claim 17 wherein said delivering step is performed so as to substantially exclude said particles from the subject's liver.

22. A method as claimed in claim 1 further comprising the step of recovering the particles from the subject's blood.

23. A metiiod as claimed in claim 22 wherein said recovering step includes the steps of withdrawing blood from die subject and centrifuging the wididrawn blood to separate die particles therefrom.

24. A method as claimed in claim 22 wherein said recovering step includes die steps of withdrawing blood from die subject and filtering die wididrawn blood to separate die particles therefrom.

25. A method as claimed in claim 1 further comprising die step of administering a photosensitizer to the subject so that the photosensitizer is present in the subject when the light is emitted.

26. A method as claimed in claim 25 wherein said photosensitizer includes tetracycline.

27. A method as claimed in claim 25 wherein said step of administering the photosensitizer is performed selectively so as to administer die photosensitizer only to a target portion of the subject's body.

28. A method as claimed in claim 1 or claim 25 or claim 26 wherein said particles emit light at a wavelengtii outside of die red and infrared regions of the spectrum.

29. A method as claimed in claim 28 wherein said particles emit light at a wavelength of less than about 600 nm.

30. A method as claimed in claim 1 wherein said particles have a transparent biocompatible coating thereon.

31. A method as claimed in claim 30 wherein said coating is selected from the group consisting of cross-linked hydrocarbon polymers; halogenated hydrocarbon polymers; silicone polymers, and glass.

32. A method as claimed in claim 30 wherein said coating degrades in die body of the subject and wherein said luminescent material is dissipated into die body of die subject.

33. A method as claimed in claim 32 wherein said luminescent material contains one or more metals, the method further comprising the step of administering a chelating agent to die subject to bind said metals.

34. A method as claimed in claim 1 wherein said particles have specific gravity approximately equal to the specific gravity of the subject's blood.

35. A metiiod as claimed in claim 1 wherein said particles have specific gravity different from the specific gravity of the subject's blood.

36. A composition of matter for providing photodynamic therapy comprising biocompatible particles less than about 5 microns in diameter, said particles containing a luminescent material.

37. A composition as claimed in claim 36 further comprising a diluent pharmaceutically acceptable for infusion into the blood.

38. A composition as claimed in claim 37 wherein said particles are in suspension in said diluent.

39. A composition as claimed in claim 36 wherein said particles include a radioactive material emitting radiation and a luminescent material responsive to said radiation to emit light.

40. A composition as claimed in claim 39 wherein said radioactive material emits β radiation.

41. A composition as claimed in claim 40 wherein said radioactive material includes tritium.

42. A composition as claimed in claim 40 wherein said luminescent material is selected from die group consisting of Zn(P0₄):Mn; Zn₃(P0₄)₂:Mn;Y₂0₂S:Eu+3;InB0₃:Tb; LaOCl:Tb; Y₃Al₆0₁₂:Tb;Y₃(Al,Ga)₅0₁₂:Tb;Y₂Siθ₃:Tb; Y₂0₂S:Pr-l-3; Gd₂0₂S:Pr Zn₂Si0₄:Mn,As; Gd₂0₂S:Tb-l-3; La₂0₂S:Tb+3; Y₂0₃:Eu+3 YV0₄:Eu+3; YV0₄:[V]:Eu; Gd₂0₂S:Eu; YV0₄:Nd; BaFC Eu (ZnCd)S:Ag; ZnS:Ag; Y₂0₃:Gd and combinations thereof.

43. A composition as claimed in claim 36 wherein said particles include a chemiluminescent composition.

44. A composition as claimed in claim 36 wherein said particles include a phosphorescent material having persistent emission.

45. A composition as claimed in claim 44 wherein said phosphorescent material is responsive to radiation.

46. A composition as claimed in claim 36 wherein said particles have a biocompatible coating thereon.

47. A composition as claimed in claim 36 wherein said coating is selected from the group consisting of cross-linked hydrocarbon polymers; halogenated hydrocarbon polymers; silicone polymers, polythiophene and polyanaline.

48. A composition as claimed in claim 36 wherein said particles have diameters less tiian about 1 micron.

49. A composition as claimed in claim 36 wherein said luminescent material is adapted to emit light at a wavelength of less than about 600 nm.

50. Apparatus for administering photodynamic therapy to a mammalian subject comprising:

(a)means for delivering light-emitting particles into the blood of die subject so that the particles pass through at least some portions of the subject's body in the blood; and

(b)means for separating said light emitting particles from the blood of die subject after passage through the body of die subject.

51. Apparatus as claimed in claim 50 wherein said separating means includes a centrifuge.

52. Apparatus as claimed in claim 50 wherein said separating means includes a filter.