WO1998004183A2

WO1998004183A2 - Photodynamic therapy with light emitting particles

Info

Publication number: WO1998004183A2
Application number: PCT/US1997/013109
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: AU3813797A; WO1998004183A3

Abstract

Light for photodynamic therapy is applied by light emitting particles (Figs. 1, 2, and 5) which are inserted into the body of the subject and removed therefrom. The particles may be conveyed by a flowing fluid. The particles may incorporate a luminescent material (22) powered by a radioisotope (20); a long lived phosphorescent material energized while the particles are outside of the body, a chemiluminescent material or electrically actuated light emitting elements (88) such as light emitting diodes.

Description

PHOTODYNAMIC THERAPY WITH LIGHT EMITTING PARTICLES

TECHNICAL FIELD OF THE INVENTION

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 the 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 the 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 the cancerous lesion to light to a far greater degree than the increased sensitivity of the surrounding normal tissues. Thus, the cancerous lesion can be killed without destroying all of the surrounding normal tissues. The practice of photodynamic therapy is described, for example, in the 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 the photodynamic therapy typically is applied from outside of the organs to be treated. For example, where the organ to be treated is the skin, the 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 the body, the treating light may be applied by aiming a fiberoptic probe connected to a laser onto the surface of the organ so that the light impinges on the surface of the lesion. As described, for example in Tockner et al., Intrathoracic 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 throughout the surface of a complex internal body cavity such as the pleural cavity by filling the cavity with a light-diffusing medium and directing the light into the medium. This assures that the light will impinge on the surfaces of lesions distributed throughout the cavity.

Various proposals have been advanced for conducting photodynamic therapy using other light applying devices. As described in U.S. Patent 5,441,497, light can be administered through a guidewire in an angioplasty balloon catheter so as to administer light on the 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 the tissue. As described in U.S. Patent 5,445,608, a fiber optic or a needlelike probe having numerous light emitting diodes thereon can be advanced into the center of a tumor or other lesion to illuminate the surrounding zone of the lesion. U.S. Patent 5,571,152 suggests the use of microminiature illuminators on the order of 5mm diameter or smaller which are implanted in the 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 the patient.

However, there are needs for further improvement in light application devices and methods for use in photodynamic therapy. SUMMARY OF THE INVENTION

One aspect of the present invention provides a method of administering photodynamic therapy to a mammalian subject. The method includes the step of passing light emitting particles into and out of the subject. The particles emit light while disposed in the subject. Preferably, the step of passing particles into and out of the subject includes the step of passing a fluid into and out of the subject so that the particles are carried into and out of the subject with the fluid. The fluid and particles may be passed into and out of the subject either continuously or discontinuously. Thus, in a method according to one embodiment of the invention, the step of passing the fluid and particles into and out of the subject includes the step of passing the fluid and particles through an artificial tube extending within the body of the subject so that the fluid and particles flow substantially unidirectionally through the tube, in an upstream to downstream flow direction. The tube may be configured to provide a tortuous path within the area of the subject to be treated.

Alternatively, the step of passing the fluid and particles into and out of the subject may be performed by passing the fluid and particles into and out of a cavity within the body of the subject so that the fluid and particles contact the tissues of the subject surrounding the cavity. For example, the fluid and particles may be administered intraperitoneally or within the pleural cavity. The fluid and particles may also be administered through a natural opening of the body as, for example, the mouth or nose into a naturally occurring body cavity. The step of passing the fluid and the particles into and out of the cavity may be performed by placing a charge of fluid and particles into the cavity allowing the charge to remain in the cavity for a preselected interval and then withdrawing the charge from the cavity.

In yet another alternative, the step of passing the fluid and particles into and out of the subject includes the step of passing the fluid and particles into and out of a container disposed within the body of the subject, as by placing a charge of the fluid and particles into the container, allowing the charge to remain in the container for an interval and then withdrawing a charge from the container. The container may include a flexible membrane such as a flexible bag. The fluid inflates the membrane into intimate engagement with the surrounding tissues of the subject. A container in the form of a bag may be inserted through a small opening into the subject while the bag is in a deflated condition.

In yet another alternative, the particles may be placed in the body, and withdrawn from the body, by packing the particles into a natural or surgically-created body cavity without using a fluid. The particles can be withdrawn from the body by washing them out of the body using a fluid; by manually retrieving the particles, or by procedures such as suctioning commonly used in surgery for removal of foreign objects. In yet another alternative, the particles are passed into a natural body cavity such as the alimentary or urinary tract and eliminated from the body by natural processes.

Methods according to the foregoing aspects of the invention can provide illumination to lesions disposed within regions of the body where the anatomy is complex and where it is consequently difficult to administer light to lesions disposed around the cavity.

The particles may include various means for producing the light to be applied. For example, the particles may incorporate a radioactive material which emits radiation and luminescent material which is responsive to this radiation to emit light. The radioactive material preferably is a beta emitting isotope such as tritium. Alternatively, the method may include the step of supplying energy to the particles while the particles are disposed outside of the subject, so that energy is stored in the particles and at least a part of the stored energy is emitted by the particles as light while the particles are disposed in the subject. For example, the particles may incorporate a phosphorescent material having persistent, long -lived light emission after exposure to energetic radiation. In this case, the method may further include the step of energizing the phosphorescent material of the particles while the particles are disposed outside of the body. For example, the particles may be exposed to x-ray, electron beam or ultraviolet light in order to charge the phosphorescent material. After charging, the phosphorescent material will continue to emit the treating light for a considerable period.

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 step of supplying energy may include the step of 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 the light emitting elements and at least part of such conversion occurs while the particles are disposed in the body. The charging step may be performed by exposing the particles to electromagnetic radiation or by engaging contacts on the particles with a source of electrical potential. The method may further include the step of controlling the conversion of electrical energy to light by the light emitting elements so that this conversion occurs principally while the particles are within the body of the subject. For example, each particle may have a control element responsive to an electromagnetic field and the step of controlling may include the step of applying an electromagnetic field within the body of the subject so that the field impinges on the particles only in a selected region of the 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 the particles. Further aspects of the present invention include apparatus for administering photodynamic therapy. Apparatus according to this aspect of the invention includes a plurality of light emitting particles and means for transferring these particles into and out of the body of the subject. The particles emit light inside the body. The transferring means desirably includes means for directing a slurry of the light emitting particles in a fluid into the body of the subject. Thus, the transferring means may include a tube adapted for placement within the body and means for passing the slurry through the tube in a substantially unidirectional flow, or else may include a container adapted for placement within the body of the subject, such as a flexible bag and means for injecting the slurry into the container, retaining the slurry within the container and then withdrawing the slurry from the container. The apparatus may further include means for energizing light emitting particles while the particles are outside of the body as, for example, by applying radiation thereto or by charging electrical storage elements in the particles. Alternatively, the particle directing means may also include means for directing new particles into the body of the subject and directing used particles withdrawn from the body of the subject to waste.

Further aspects of the present invention include compositions for administering photodynamic therapy. Compositions according to this aspect of the invention desirably include particles as discussed above, such as those having a luminescent material. The luminescent material may include a phosphorescent material having a persistent emission or a chemiluminescent material. Alternatively, the particles may include a radioactive material emitting radiation and a luminescent material responsive to such radiation. In another variant, each particle may include an electrical storage element, an electrically powered light emitting element, and a control element responsive to an electromagnetic field for controlling transmission of power from the storage element to the light emitting element. The particles may further include ferromagnetic elements so that the particles can be steered by application of magnetic fields to desirable locations within the body or within a chamber disposed in the body. The particles may also include coatings which promote adhesion of the particles to certain tissues and discourage adhesion of the particles to other tissues.

These and other objects, features and advantages of the present invention are readily apparent from the detailed description of the preferred embodiment set forth below, taken in conjunction with the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 is a diagrammatic view of a particle in accordance with one embodiment of the invention.

Fig. 2 is a diagrammatic view of a particle in accordance with a further embodiment of the invention.

Fig. 3 is a diagrammatic, partially sectional view depicting apparatus in accordance with a further embodiment of the invention in conjunction with a subject undergoing treatment.

Fig. 4 is a diagrammatic view depicting treatment apparatus in accordance with a further embodiment of the invention in conjunction with a subject.

Fig. 5 is a diagrammatic sectional view of a particle in accordance with a further embodiment of the invention.

Fig. 6 is an electrical schematic of the components incorporated in the particle of Fig. 4.

Fig. 7 is a view similar to Fig. 4, but depicting apparatus in accordance with a further embodiment of the invention.

Fig. 8 is a electrical schematic of an internal circuit in a particle according to yet another embodiment of the invention MODES FOR CARRYING OUT THE INVENTION A particle according to one embodiment of the invention is depicted in Fig. 1. The particles may be from a few microns to a few cm in diameter. The particle includes a core of a radioactive material 20; a coating of a radio-responsive phosphor 22 on the core and an outer coating of a biocompatible material 24. Alternatively, the radioactive material 20 and phosphor 22 may be combined with one another as a unitary body. Thus, the phosphor and radioactive material may be interspersed with one another. 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 those listed in Table 1 below.

TABLE I

Where the particles are intended to apply light without 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 ( H) is the most preferred isotope. If isotopes having greater decay energies are employed, the resulting particles will emit X-rays along with light. Such X-rays can be utilized as part of the treatment regime. In this case, the particles desirably are administered primarily in the vicinity of the 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 S. Also, the radioisotope and its decay products should have reasonably low toxicity. The phosphors used with 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. In applications where the light must penetrate into the tissues to provide the desired effect, the preferred phosphors are those which emit red or infrared light at wavelengths from about 630 nm to about 1000 nm, and most preferably about 630-700nm. Some photodynamic therapy procedures for treatment of thin tissues, such as the lining of the urinary bladder, do not require appreciable penetration of the treating light into the tissue. For these procedures, light in the blue and ultraviolet regions of the spectrum can be employed.

TABLE II-PHOSPHORS

The particle further includes an outer surface 24. If the particle will contact the tissues of the patient during the treatment, the outer surface desirably is biocompatable. As used in this disclosure with reference to the surface of a particle, the term "biocompatible" means that the particle surfaces can remain in contact with the tissues for a period of time long enough to perform the required treatment without provoking such a severe reaction as to permanently injure or kill the subject. Manifestly, higher degrees of biocompatability are more desirable. 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 other suitable biocompatible material which, at the thickness employed, is transparent or translucent to the light at the treatment wavelength which will be emitted from the 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 thickness 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 unsatu ration

Butadiene (gas) Crosslinked hydrocarbon with conjugated double bonds

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

Trimethylsilane (gas) Similar to HMDS

Dimethylsilane (gas) Similar to HMDS

Hexamethyldisilazane (liquid) Highly crosslinked

Hexamethyldisilane (liquid)

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

Thiophene (liquid) Conductive polymer like electropolymerized material

Aniline (liquid) Conductive polymer like electropolymerized material

Other coatings can be applied by processes commonly used in the pharmaceutical industry for microencapsulation. For example, the particles can be spray-coated with a polymer or coated by coacervation. Other 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. Alternatively, the outer surface of the particle may be formed as a discrete, self-supporting shell such as a molded polymer shell, and the radioactive material and phosphor may be placed within the shell.

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 the 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 in accordance with other embodiments of the invention include a chemiluminescent material or combination of materials. One such combination includes One such combination includes luminol (5- amino, 2,3 dihydro-l,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 then exposing them to oxygen just prior to administration to the subject. Where this approach is employed, the 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. According to a further embodiment, the chemiluminescent materials may be provided in separate compartments within the particle separated by a barrier, and the barrier may be ruptured immediately prior to admimstration of the particles, as by squeezing the particles or subjecting the particles to a change in external pressure.

As shown in Fig. 2, particles in accordance with further embodiments of the invention may include one or more voids 26 within the 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 the mass or masses of active ingredients. For example, the active ingredients may be compounded as microscopic agglomerates with void spaces therein. Alternatively, where the outer surface of the particle is provided as a discrete, self-supporting shell, the active ingredients may be coated on the interior surface of the shell.

A composition for use in administering photodynamic therapy may include particles as described above alone or in admixture with a liquid. The liquid should be suitable for such contact. Preferred liquids for this purpose include isotonic aqueous solutions such as saline or Ringer's solution. Where the composition is to be separated from the tissues during use, other liquids which are not normally used in direct contact with tissues, such as petroleum-based and silicone-based oils can be employed. 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 a chamber 36 for holding a composition such as a slurry of the aforementioned particles. Chamber 36 may be a conventional bag or bottle of the type used in administration of intravenous infusions. Chamber 36 is supported at an elevated location, above the height of the subject. A conduit 38 extending from the tube is provided with a pair of valves 40 and 42. The end of the tube remote from chamber 36 is connected to a suction device 44. A branch conduit 46 joins tube 38 between valves 40 and 42. Branch conduit 46 is connected to a proximal end 48 of an elongated probe 50. Probe 50 has a container in the form of a flexible bag 54 mounted at its distal end. Bag 54 is formed from a biocompatible, flexible material transparent to the wavelengths emitted by the particles. For example, polymers such as polyethylene, polypropylene, saran, polyvinyl chloride and others may be employed. The bag may be a distensible, elastic balloon. Bag 54 in its deflated shape illustrated in broken lines at 54' is relatively small.

In a method according to one embodiment of the invention a photosensitizer is administered to a mammalian subject such as a human patient 60 having lesions 62 in tissues surrounding a cavity. After opening the cavity to the exterior through a surgical incision 66 and after performing normal surgical procedures preparatory to photodynamic therapy such as partial removing or "debulking" of the lesions, the surgeon inserts the distal end of tube 50 and bag 54, in its deflated condition, into cavity 64. Valve 42 is closed and valve 40 is opened so that fluid and particles are discharged under pressure into balloon 54, thereby inflating the bag and forcing the bag into intimate contact with the walls of the cavity. This places the particles close to all of the lesions 62, including those which are inaccessible to the surgeon. The particles emit light and the light passes through the wall of the and impinges on the lesions. The light penetrates into the lesions and actuates the photosensitizer, which causes regression of the lesions in the normal manner. The fluid and particles can be withdrawn periodically by suction unit 44 To accomplish such withdrawal, valve 40 is closed and valve 42 is opened. After one charge of particles has been administered and withdrawn in this manner, a new charge can be introduced by closing valve 42, reopening valve 40 and reinflating the balloon with additional fluid and particles. This process is repeated so that each charge remains within the subject for an interval and is then withdrawn.

The apparatus illustrated in Fig. 3 does not incorporate any provision for exciting the particles immediately prior to use. Thus, this apparatus is best suited for use with radioisotope-powered or chemiluminescent particles. However, if particles energized by external exciting radiation are employed, such as the persistent-phosphor particles mentioned above, the same may be exposed to exciting radiation of the types discussed below with reference to Fig. 4. Thus, reservoir 36 may be exposed to the exciting radiation continually during the procedure or before the procedure.

The process continues until the desired dose of treating light has been administered to the lesions. The optimum interval for each charge of particles to remain within the subject will depend upon the pattern of emission versus time for the particles; the interval should be chosen so that the particles are removed when the light emission diminishes substantially. The desired dose will vary with the photosensitizer and with the purpose of the treatment. However, for treatment of malignant tumors with typical photosensitizers using red light at about 630-690nm, a dose of about 35 joules/cm of lesion surface area is common. The photosensitizers which can be employed include all of those which can be employed using red and infrared light applied in conventional processes. A few of the more common photosensitizers are listed in Table IV, below.

TABLE IV

Drug Manufacturer WaveExtinction Drug Light lengths coefficient Dosage Dosage

Photofrin QLT 420, 630 5,000 ©630 2mg/kg 135

(hematopoφhryn nm joules/cm2 derivative) 50,000@420n m

ALA DUSA 420, 630 5,000 ©630 5.4-120

(aminolevulinic n acid) 50,000@420 nm

LuTex Phaπnacyclics 450, 732 0.75mg/k 90-240

(lutetium texaphrin)

SnET2 PDT Inc 440, 664 100-300 (tin ethyl etiopurpuriπ)

SnOEBc PDT Inc 430, 691 mTHPC Scotia 400, 670 100,000© 0.2mg/kg 25

(meta- 670 nm jou.es/cm2 tetrahydroxyphenyl chlorin)

NP6 Nippon 400,660 Petrochemical

Benzoporphyrin 360,690 1 mg/kg

Zinc 670 2 mg/kg 150

Phthalocyanine

Disulphonate

Bacteriochlorins 800 100,000© bacteriopurpurans 800 nm & ketochlorins

Where penetration into the tissues is not required, photosensitizers which are sensitive only in wavelength ranges other than red or infrared can be employed. For example, drugs such as oxsoalren and tetracycline, sensitive to blue and ultraviolet, can be employed as photosensitizers in such procedures.

Apparatus according to a further embodiment of the invention (Fig. 4) includes a tube 70 adapted for implantation into the body of the subject 72. Tube 70 may be a flexible tube formed from any biocompatible material transparent or translucent to the light which will be emitted by the particles. As illustrated, tube 70 is bent into a tortuous path, i.e., a path having numerous terms and reversals so as to concentrate a substantial length of the tube in a small area. Tube 70 may be formed integrally with or bonded to a sheetlike member 74 which retains the tube permanently in the tortuous configuration. Alternatively, the tube may be placed in the body of the subject and bent by the surgeon to the tortuous configuration. The tortuous portion of the tube desirably is juxtaposed with the lesions to be treated. This tends to concentrate the light at the lesion, where it is needed. Tube 70 may also be formed from a flexible membrane so that it can be inflated into intimate contact with the tissues.

Tube 70 has an upstream end 76 and a downstream end 78. A pump 82, storage container 80, and excitation cell 84 are connected in series between the ends of the tube so that the tube, storage container pump and excitation cell so cooperatively form a closed loop. Storage tank 80 is equipped with temperature control devices (not shown) for maintaining the stored material at or slightly above the normal body temperature of subject 72 Cell 84 is an elongated conduit transparent to radiation which is used to excite the particles. For example, where the particles include a persistent phosphor be excited by ultraviolet radiation, cell 84 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 thin sheet of a metal foil or a ceramic foil such as boron nitride hydride.

An excitation irradiation source 86 is arranged to apply exciting radiation to particles in cell 84. Source 86 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. In a method utilizing the apparatus of Fig. 4, a composition including particles incorporating persistent phosphors is circulated through the closed loop while tube 70 is disposed within the patient. The composition is maintained at an appropriate temperature by the temperature control devices associated with storage tank 80. As the composition passes through excitation cell 84, the particles are exposed to excitation radiation. For example, where the particles incorporate a persistent phosphor excited by ultraviolet radiation, the radiation source 86 applies UV radiation to the particles as they pass through cell 84. The particles begin to emit light as they pass downstream towards the tube 70 and as they pass from the upstream end 76 of the tube to the downstream end of the tube. The light emitted by the particles impinges on the lesions within the subject. However, because the particles are remote from the subject when the excitation radiation is delivered by source 86, the subject is not exposed to the excitation radiation.

As shown in Fig. 5, a particle 88 in accordance with a further embodiment of the invention includes a microelectronic circuit 90 having a pair of electrically conductive contacts 92 and 94 at spaced apart locations on its surface. Microelectronic circuit 90 may be formed as a monolithic integrated circuit or "chip" ,or may include discrete components packaged on a microminiature circuit board or flexible circuit panel. The particle further includes a ferromagnetic element 96. The circuit 90 and ferromagnetic element 96 are covered by a coating such as one of the coatings discussed above. Contacts 92 and 94 are exposed through the coating. Particle 88 preferably has a shape other than spherical, i.e., it may be formed as an elongated, rodlike element or as a flat, disklike element.

The electrical circuit 90 is schematically depicted in Fig. 6. Contacts 92 and 94 are connected to opposite sides of a storage capacitor 98. A polarity control diode 100 is connected in series with one of the contacts. 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 the control capacitor is connected to the internal ground. A high value bleed resistance 108 is connected in parallel with capacitor 106. The internal leakage path of the capacitor may serve as this resistance. Capacitor 106 is connected to the output of a rudimentary radio receiver 110. As illustrated, radio receiver 110 includes a receiving coil 112 and capacitor 114 forming a tuned resonant circuit and a rectifying diode 116.

Capacitor 98 can be charged by applying an electrical potential across terminals 92 and 94. FET 104 is normally nonconducting. Upon application of RF energy 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 capacitor 106 until a sufficient voltage is applied to the 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. 6 is merely illustrative. Storage elements other than a capacitor, such as an electrical storage battery, can be substituted for capacitor 98. The rudimentary radio receiving circuit 110 depicted in Fig. 6 can be replaced by other, well-known receiving circuits including single and multistage amplifying receiver circuit and circuits with more selective tuning capabilities. Likewise, the control element shown as FET 104 can be replaced by other, well-known forms of electronic control elements.

Apparatus for use with the particles of Figs. 5 and 6 is schematically depicted in Fig. 7. The apparatus includes a storage tank 120 and pump 122 similar to the coπesponding elements of apparatus depicted in Fig. 4. However, in the apparatus of Fig. 7, the excitation cell 84 (Fig. 4) is replaced by a charging cell 124 having metallic conductors 126 and 128 exposed to the fluid path of the cell. Conductors 126 and 128 are provided in pairs, spaced apart from one another in a pattern matching the layout of the contacts 92 and 94 on the particles. An electrical potential source 130 is connected to these contacts so that the contacts are at opposite polarities. The downstream end of charging cell 124 is connected to a first catheter 132, whereas storage tank 120 is connected to a second catheter 134. The apparatus further includes an RF transmitter 136 linked to an antenna 138 adapted to direct RF energy from the transmitter to a focused region. Additionally, the apparatus includes means such as a large permanent magnet or electromagnet with opposed poles 140 for applying a magnetic field in predetermined spatial relationship to a subject.

In a process according to a further embodiment of the invention, a fluid containing particles 88 as depicted in Figs. 5 and 6 is passed from storage unit 120 through pump 122 and charging cell 124. The terminals 92 and 94 on at least some of the particles engage conductive elements 126 and 128. Multiple sets of such conductive elements may be provided in different locations and different orientations along the charging cell so as to assure that as each particle traverses the charging cell, it has a high probability of engaging the conductive elements 126 and 128. As the terminals of each particle engage the conductive elements, the potential on the terminals charges capacitor 98 (Fig. 6) within the particle. The charged particles then pass into a cavity 142 within the body of subject 144 through the first catheter 132. The subject is positioned relative to magnet 140 and antenna 138 so that the lesion 146 to be treated lies within a region of strong magnetic field and also lies within the region irradiated by RF energy by antenna 138. The strong magnetic field tends to guide the particles into the region immediately suπounding the lesion. As each particle reaches this region, the radio receiver 110 receives the 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 the stored energy in the form of light from LED 102. The used particles are carried out of the patient through the second catheter and returned to the system.

Preferably, the fluid carrying the particles through the charging or excitation cell 124 is a substantially dielectric fluid. The fluid circuit may be provided with elements (not shown) for removing water and other bodily fluids and trained in the dielectric fluid during its passage through the body of the subject. Alternatively, the flowing fluid may be physically isolated from the body of the subject by providing a barrier such as a tube 70 of the type used in Fig. 4. In a further alternative, the particles may be removed from the fluid before passage through the charging cell. If the particles are removed from the fluid before charging, they may be activated by contact with the fluid. For example, the control circuit in each particle may include a device for sensing the resistance of the surrounding medium, as by detecting the resistance between exposed contacts on the surface of the particle, and actuating the light emitting device when the resistance is below a threshold value. The circuit may be made through the conductive medium. If the particles are immersed in a conductive fluid immediately prior to introduction into the subject, each particle will begin to emit light as it enters the subject.

A particle according to a further embodiment of the invention, shown in Fig. 8, has an electrical circuit without external contacts. In this alternative, a rudimentary radio receiver 160 similar to the receiver 110 described with reference to Fig. 6 is used to charge the storage capacitor 162. The storage capacitor continuously discharges through LED 164 at a relatively low rate, set by the internal resistance of the LED. A particle with such a circuit can be charged by subjecting it to strong RF energy in an excitation chamber similar to the chamber 84 of Fig. 4, and applying RF irradiation.

As will be readily appreciated, numerous variations and combinations of the features described above can be utilized. For example, the process of Fig. 3, wherein a discreet charge of particles and fluid is placed into the patient and then allowed to dwell within the patient and subsequently discharged, can be practiced without the use of a liner or bag as depicted in Fig. 3. Thus, the particles and fluid can be placed into the body by means of a catheter such as that shown in Fig. 7 and can be subsequently drained from the body by the same or a different catheter. The electrically charged or RF-charged particles discussed above with reference to Figs. 5-8 can be used in the process of Fig. 3 as well. Also, the use of ferromagnetic mass and magnetic field to direct the particles can be applied in conjunction with non-electrical particles as described with reference to Figs. 1 and 2.

According to yet another variation of the invention, the fluid and particles can be placed in a sealed bag, and the sealed bag or container can be surgically placed into the patient, so that the particles emit light within the body. In a further variant, the particles can be packed into a surgically-created or natural body cavity without use of a carrier fluid, and can be allowed to remain in the body for the desired interval, then removed. For example, the particles can be removed by suctioning; by washing the cavity with a fluid; or by manually retrieving them. This approach can be used, for example, in treatment of the respiratory system, urinary tract, skeletal joints, or reproductive organs. In a further variant, the particles can be placed in the digestive system or urinary tract so that they are passed out of the body by excretion. As these and other variations and combination of the features discussed above can be utilized without departing from the present invention, the foregoing description of the preferred embodiments should be taken by way of illustration rather than by way of limitation of the invention as defined by the claims.

Claims

CLAIMS:

1. A method of administering photodynamic therapy to a mammalian subject comprising the step of passing light emitting particles into and out of the subject, said particles emitting light while in the subject.

2. A method as claimed in claim 1 wherein said step of passing particles into the body includes the step of manually placing the particles in a cavity within die body of the subject.

3. A method as claimed in claim 1 wherein said step of passing particles into the body includes the step of administering the particles within the alimentary or urinary tract of the subject and wherein the particles are passed out of the subject by natural processes.

4. A method as claimed in claim 1 wherein said step of passing particles includes the step of passing a fluid into and out of the subject so that the particles are carried into and out of the subject with the fluid.

5. A method as claimed in claim 5 wherein step of passing said fluid and particles into and out of the subject includes the step of passing said fluid and said particles through an artificial tube extending within the body of the subject so that the fluid and particles flow substantially unidirectionally through the tube.

6. A method as claimed in claim 5 wherein said tube is configured to provide a tortuous path within an area of the subject to be treated.

7. A method as claimed in claim 4 wherein said step of passing said fluid and particles into and out of the subject includes the step of passing said fluid and said particles into and out of a cavity within the body of the subject so that said fluid and said particles contact the tissues of the subject surrounding such cavity.

8. A method as claimed in claim 7 wherein said fluid and said particles are administered intraperitoneally.

9. A method as claimed in claim 7 wherein said fluid and said particles are administered though a natural opening of the body.

10. A method as claimed in claim 7 wherein said step of passing said fluid and said particles into and out of said cavity includes the steps of placing a charge of said fluid and particles into said cavity, allowing said charge to remain in said cavity for an interval, and then withdrawing said charge from said cavity.

11. A method as claimed in claim 4 wherein said step of passing said fluid and particles into and out of the subject includes the step of passing said fluid and said particles into and out of a container disposed within the body of the subject by placing a charge of said fluid and particles into said container, allowing said charge to remain in said container for an interval, and then withdrawing said charge from said container.

12. A method as claimed in claim 11 wherein said container includes a flexible membrane and said fluid inflates said membrane into intimate engagement with surrounding tissues of the subject.

13. A method as claimed in claim 12 wherein said membrane is a flexible bag, the method further comprising the step of inserting the bag into the subject in a deflated condition.

14. A method 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.

15. A method as claimed in claim 14 wherein said radioactive material emits β radiation.

16. A method as claimed in claim 15 wherein said radioactive material includes tritium.

17. A method as claimed in claim 15 wherein said luminescent material is selected from the group consisting of Zn(P04):Mn; Zn3(P04)2:Mn;Y202S:Eu+3;YV04:Eu+3; YV04:[V]:Eu; Gd202S:Eu; YV04:Nd; BaFC Eu; and combinations thereof.

18. A method as claimed in claim 4 further comprising the step of supplying energy to said particles while said particles are disposed outside of the subject so that said energy is stored in said particles and so that at least a part of said stored energy is emitted by said particles as light while said particles are disposed in the subject.

19. A method as claimed in claim 18 wherein said particles include a phosphorescent material having persistent emission, the method further comprising the step of energizing the phosphorescent material of said particles while said particles are disposed outside of the body of the subject

20. A method as claimed in claim 18 wherein said phosphorescent material is responsive to radiation and wherein said energizing step includes the step of exposing the particles to radiation while the particles are disposed outside of the body of the subject.

21. A method as claimed in claim 20 wherein said phosphorescent material is a photoluminescent material responsive to energizing light, and wherein said step of exposing the particles to radiation includes the step of exposing the particles to energizing light while the particles are disposed outside of the body of the subject.

22. A method as claimed in claim 21 wherein said energizing light includes ultraviolet light of less than about 400 nm wavelength.

23. A method as claimed in claim 18 wherein each said particle includes an electrical storage element and an electrically powered light emitting element, said step of supplying energy includes the step of charging the storage element in each said particle while such particle is outside of the patient's body, the energy stored in said storage elements being converted to light the light emitting elements.

24. A method as claimed in claim 23 f rther 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 the subject.

25. A method as claimed in claim 24 wherein each said particle has a control element responsive to an electromagnetic field and wherein said controlling step includes the step of applying an electromagnetic field within the body of the subject so that said field impinges on said particles in the vicinity of a selected region of the body.

26. A method as claimed in claim 23 wherein said charging step includes the step of applying radiofrequency power to said particles while said particles are disposed outside of the subject's body.

27. A method as claimed in claim 4 wherein each said particle includes an electrically-powered light emitting element and an antenna coupled to such element, the method further comprising the steps of irradiating the subject with electromagnetic radiation so that said electromagnetic radiation impinges on said particles and energizes said light emitting elements while the particles are in the subject's body.

28. A method as claimed in claim 4 further comprising the step of controlling the temperature of the fluid while the fluid is outside of the subject's body.

29. A method as claimed in claim 4 wherein said particles have substantially neutral buoyancy in said fluid.

30. A method as claimed in claim 4 wherein said particles have specific gravity different from the specific gravity of the subject's blood.

31. A method as claimed in claim 1 further comprising the step of administering a photosensitizing agent to the subject.

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

(a) a plurality of light emitting particles

(b)means for transferring the light emitting particles into and out of the body of the subject so that the particles emit light inside the body.

33. Apparatus as claimed in claim 32 wherein said means for transferring includes means for directing a slurry of said light emitting particles in a fluid into the body of the subject.

34. Apparatus as claimed in claim 33 wherein said means for transferring includes a tube adapted for placement within the body of the subject and means for passing said slurry through said tube in substantially unidirectional flow.

35. Apparatus as claimed in claim 34 further comprising means for maintaining said tube in a tortuous path adjacent a region of the subject to be treated.

36. Apparatus as claimed in claim 33 wherein said means for transferring includes a container adapted for placement within the body of the subject, and means for injecting said slurry into said container, retaining said slurry within said container and then withdrawing said slurry from said container.

37. Apparatus as claimed in claim 36 wherein said container includes a flexible membrane.

38. Apparatus as claimed in claim 32 further comprising means for energizing said light emitting particles while said particles are outside of the body.

39. Apparatus as claimed in claim 38 wherein said particles include a luminescent material responsive to radiation and said energizing means includes means for applying said radiation to said particles while said particles are outside of the patient's body.

40. Apparatus as claimed in claim 38 wherein each said particle includes an electrical storage element and an electrically powered light emitting element, and wherein said means for energizing includes means for charging the storage elements of said particles while the particles are disposed outside of the body.

41. Apparatus as claimed in claim 40 wherein said means for charging includes means for directing electromagnetic fields onto said particles.

42. Apparatus as claimed in claim 33 wherein each said particle includes an electrical storage element, an electrically powered light emitting element, and a control element responsive to an electromagnetic field, the apparatus further comprising means for applying an electromagnetic field within the body of the subject so that said field impinges on said particles in the vicinity of a selected region of the body.

43. Apparatus as claimed in claim 33 wherein said means for directing includes means for directing new particles into the body of the subject and directing used particles withdrawn from the body of the subject to waste.

44. Apparatus as claimed in claim 43 wherein said particles include a chemiluminescent material.

45. Apparatus as claimed in claim 33 wherein said means for directing includes means for recovering particles after passage from the subject and redirecting the recovered particles into the subject.

46. Apparatus as claimed in claim 33 wherein said means for directing includes means for segregating said particles from said slurry after passage of said slurry out of the subject's body.

47. Apparatus as claimed in claim 33 further comprising means for regulating the temperature of the slurry introduced into the body of the subject.

48. A composition for administering photodynamic therapy comprising a plurality of particles, each said particle comprising a luminescent material adapted to emit treating light at a treatment wavelength and a biocompatible coating substantially transparent to said treating light.

49. A composition as claimed in claim 48 wherein said luminescent material includes a phosphorescent material having persistent emission.

50. A composition as claimed in claim 48 wherein said luminescent material includes a chemiluminescent material.

51. A composition for administering photodynamic therapy comprising a plurality of particles, each said particle comprising an electrical storage element, an electrically powered light emitting element, and a control element responsive to an electromagnetic field for controlling transmission of power from said storage element to said light emitting element.

52. A composition as claimed in claim 51 wherein said particles include a radioactive material emitting radiation and a luminescent material responsive to said radiation to emit light.

53. A composition as claimed in claim 52 wherein said radioactive material emits β radiation.

54. A composition as claimed in claim 53 wherein said radioactive material includes tritium.

55. A composition as claimed in claim 53 wherein said luminescent material is selected from the group consisting of Zn(P04):Mn; Zn3(P04)2:Mn;Y202S:Eu+3;YV04:Eu+3; YV04:[V]:Eu; Gd202S:Eu; YV04:Nd; BaFC Eu; and combinations thereof.