WO1998052610A1 - Therapie photodynamique et sonodynamique et agents et systeme utilises a cet effet - Google Patents

Therapie photodynamique et sonodynamique et agents et systeme utilises a cet effet Download PDF

Info

Publication number
WO1998052610A1
WO1998052610A1 PCT/IL1998/000231 IL9800231W WO9852610A1 WO 1998052610 A1 WO1998052610 A1 WO 1998052610A1 IL 9800231 W IL9800231 W IL 9800231W WO 9852610 A1 WO9852610 A1 WO 9852610A1
Authority
WO
WIPO (PCT)
Prior art keywords
agent
irradiation
releasing
compound capable
biological tissue
Prior art date
Application number
PCT/IL1998/000231
Other languages
English (en)
Inventor
Yoni Iger
Original Assignee
Technion Research And Development Foundation Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Technion Research And Development Foundation Ltd. filed Critical Technion Research And Development Foundation Ltd.
Priority to CA002290450A priority Critical patent/CA2290450A1/fr
Priority to EP98921707A priority patent/EP0983090A1/fr
Priority to AU74475/98A priority patent/AU7447598A/en
Publication of WO1998052610A1 publication Critical patent/WO1998052610A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0028—Disruption, e.g. by heat or ultrasounds, sonophysical or sonochemical activation, e.g. thermosensitive or heat-sensitive liposomes, disruption of calculi with a medicinal preparation and ultrasounds
    • A61K41/0033—Sonodynamic cancer therapy with sonochemically active agents or sonosensitizers, having their cytotoxic effects enhanced through application of ultrasounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
    • A61K41/0071—PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines

Definitions

  • the present invention concerns improvements in photodynamic therapy (PDT) and sonodynamic therapy (SDT).
  • PDT photodynamic therapy
  • SDT sonodynamic therapy
  • Photodynamic therapy involves the use of photosensitizable compounds for the selective destruction of biological tissue, such as for the destruction of tumors, using a photosensitizable drug linked to tumor-localizing agent (for example an antibody), followed by exposure of the target region to light, usually light emitted from a laser (Kopecck, J., Targetable polymeric anticancer drugs- temporal control of drug activity: In Temporal control of drug delivery, eds.: WJ.M. Brushesky, R. Langer and F. Theeuwes, Annals of the New York Academy of Sciences, pp. 335-341 (1991)).
  • a photosensitizable drug linked to tumor-localizing agent for example an antibody
  • Photosensitizable compounds are molecules that are activated by light of a characteristic wavelength, usually from a laser, ultimately resulting in the formation of cytotoxic intermediates such as singlet oxygen or free radicals.
  • the photosensitizable compound acts either at the cell surface, or is internalized, ultimately causing its destructive effect on the membrane at the cell surface or on cellular organella, respectively, both routes leading to cell death.
  • the tumor destruction is believed to proceed via one or both of the following two suggested mechanisms: the intravascular pathway, i.e. collapse of blood vessels which hamper blood perfusion to the tumor and cause deprivation of oxygen and nutrients; and/or the parenchymal tumor pathways wherein destruction is caused due to direct necrotic effects on the tumor cells.
  • Sonodynamic therapy is a new concept which relates to the synergistic effect of drugs and ultrasound in producing cytotoxic effect on tissue, in particular on tumors (Jeffers et al, J. Acoust. Soc. Am., 97:669-676 (1995)).
  • the cytotoxicity of SDT can be enhanced by the presence of sonosensitizable compounds, i.e. agents which can emit singlet oxygen or free radicals in response to irradiation by ultrasound.
  • sonosensitizable compounds for example, porphyrin and porphyrinyl analogs, were found to be able to serve as sonosensitizable agents in cultures of tumor cells (Kessel et al, J. Photochem.
  • the present invention concerns a method and agents for improving the destructive effects of various types of energy irradiation such as ultrasound irradiation alone, light and ultrasound irradiation together, or of other types of energy irradiation, on biological tissue.
  • the present invention provides in accordance with a first aspect thereof a method for the destruction of biological tissue by an energy irradiation comprising exposing the biological tissue to energy irradiation in the presence of an agent capable of being sensitized by said irradiation, and at least one agent selected from the group consisting of:
  • energy irradiation refers to any type of irradiation which is biologically compatible, and includes light, ultrasound, microwave, radio, laser, etc. irradiations.
  • an agent capable of being sensitized by energy irradiation refers to specific agents which can be activated in the presence of energy, i.e. agents which change form in the presence of said irradiation so that they become active and may chemically react with biological tissue. Where the energy is light, this term refers to photosensitizable agents. Where the energy is ultrasound irradiation, this term is refers to sonosensitizable agents, etc.
  • “sonodynamic therapy helper aspect” destruction of the biological tissue is carried out in the presence of ultrasound and sonosensitizable agents, and a helper agent capable of contributing to the destructive affect of ultrasound for example, by releasing free radicals, singlet oxygens, oxidating agents and the like.
  • the present invention provides a method for the destruction of biological tissue by ultrasound irradiation comprising exposing the biological tissue to ultrasound irradiation in the presence of a sonosensitizable agent and at least one agent selected from the group consisting of:
  • the present invention further provides in accordance with a second aspect thereof a method for the destruction of tissue by energy irradiation comprising: exposing the biological tissue to irradiation in the presence of a composition of matter which upon exposure to said irradiation undergoes an exothermic reaction.
  • the present invention provides a method for the destruction of biological tissue by ultrasound irradiation utilizing new sonosensitizable agents capable of undergoing an exothermic reaction.
  • the method for the destruction of the biological tissue comprises: exposing the biological tissue to ultrasound irradiation in the presence of a composition of matter which, upon exposure to said irradiation undergoes an exothermic reaction.
  • the destruction of biological tissue in the presence of a composition capable of undergoing an exothermic reaction should be preferably carried out in the presence of a helper agent selected from the group consisting of: (i) a compound capable of releasing singlet oxygen;
  • Such a helper agent may contribute to the destructive effect as explained above.
  • the sonodynamic therapy exothermic aspect of the invention may be carried out in the presence of at least one other state of the art sonosensitizable compounds, which may contribute to the destructive effects of the exothermic agents.
  • sonosensitizable compounds are specified in Saad, A.H. and Hahn, G.M., Cancer Res., 49:5931-5934 (1989); Miyoshi, N. et al, Radiat. Res., 143:194-202 (1995); Misik V. and Riesz, P., Free Radical Biol. Med, 20: 129-138 (1996); Kessel D. et al, J. Photochem. Photobiol, B28:219-221, (1995); Jeffers, RJ. et al, J. Acoust. Soc. Am., 97:669-676 (1995); Tata, D. et al, J. Acoust. Soc.
  • sonosensitizable compounds examples include gallium-porphyrin, DMSO (dimethylsulfoxide), DMF (dimethylformamide), mesoporphyrin, adramycin and mitomycin as well as other photosensitizable compounds which are known to act as sonosensitizable compounds.
  • helper agents (i) - (iii) above causes the destruction of the biological tissue by chemical interaction of the singlet oxygen, the oxidative or free radicals with biological macromolecules while the exothermic composition cause hyperthermic destruction of the biological tissue as will be explained hereinbelow.
  • the simultaneous use of chemical and thermic destruction greatly enhance the effect of the sonodynamic therapy, either directly by initiating pyrolytic effect at the desired location or indirectly by increasing the local metabolism and the uptake of the sensitizer or increasing the reactivity of particular sensitizer for the desired chemical response.
  • the biological macromolecules attacked by the singlet oxygen, the oxidative or free radicals are usually those with double bonds, or other sites rich in electrons, such as many of the amino acids, unsaturized lipids, phospholipids, cholesterol, guanine and other molecules, which are all parts of membranes, proteins, nucleic acids and the like.
  • the first aspect of the invention may also be intended to enhance the destructive activity of photosensitizable compounds and is termed hereinafter the "photodynamic therapy helper aspect".
  • the present invention concerns a method for the destruction of biological tissue by light, comprising exposing the biological tissue to light in the presence of a photosensitizable compound and at least one agent selected from the group consisting of:
  • the above helper agents contribute to the destructive activity of the photosensitizable aspect.
  • the present invention provides a method for the destruction of biological tissue by light comprising: exposing the biological tissue to light in the presence of a composition of matter which, upon exposure to said light, undergoes an exothermic reaction.
  • composition of matter capable of undergoing an exothermic reaction should preferably be exposed to light in the presence of a helper agent, i.e. an agent selected from the group consisting of:
  • the photodynamic therapy exothermic aspect of the invention may be carried out in the presence of at least one other state of the art photosensitizable agents.
  • Photosensitizable agents are well known in the art and are described, for example, in Gottfried, V. and Kimmel, S., J. Photochem. Photobiol, B8.419-430 (1991); Gottfried, V., et al, J. Photochem. Photobiol, B30:l 15-121 (1995); Kessel D. et al, J. Photochem. Photobiol, B28:219-221 (1995); Margaron, P. et al, Anticancer Res., 16:613-620 (1996); Orenstein, A. et al, Lasers Surg. Med, 10:334-343, (1990).
  • Such agents are: aromatic compounds including porphyrins, hematoporphyrins, chlorines,, purpurins, phthalocyanines, photofrin, rhodamines, acridine derivated, rhodamines and the like.
  • the method according to the photodynamic therapy exothermic aspect of the invention enhances the cytotoxic effect of photosensitizable compounds by providing substrates for those compounds thus increasing the release of destructive agents such as free radicals, singlet oxygen and oxidatives (by utilizing helper agents (i) - (iii)).
  • the composition of matter capable of undergoing an exothermic reaction in the presence of light actually serve as novel sonosensitizable agents.
  • tissue refers to cytotoxic effect of ultrasound energy irradiation such as, light, microwave or other types of energy source, together with the appropriate compounds at the desired site leading to massive cell death at said site.
  • light refers to any type of light, preferably a monochrome wave of a single length which is chosen in accordance with the specific photosensitizable compound used. More preferably, higher wave length light should be used, such as red or infrared light, due to its higher penetration of biological tissue, in addition to its activation ability.
  • the term "ultrasound” refers to a mechanical wave with frequency above the audible range that propagates by motion of particles within the medium. The motion causes compression and refractions of the particles so that a pressure wave travels along with mechanical disturbance.
  • the helper agents of (i) - (iii) of the above aspects of the invention enhance the destruction activity caused by various types of energy irradiation, optionally together with agents which are sensitized by said energy irradiation.
  • Examples of compounds capable of releasing singlet oxygen are, for example 0 2 , provided by bubbling oxygen into the medium in which the biological compound is present, by using solutions wherein oxygen is a major and unstable component such as H 2 0 2 or by using substances that can release oxygen such as kalium permanganat and the like.
  • Compounds capable of releasing oxidatives are chloride, bromide, fluoride, iodine, alkali metal elements (Na, K, Rb, Cs) and alkali earth metals (Be, Mg, Ca, Sr), oxygen and sulfur.
  • oxidatives are molecules or single atoms which lack electrons or have a tendency to lose electrons in an aqueous solution.
  • Information concerning oxidatives can be found in Dickerson, R.E., Gray, H.B. and Haight, G.P., Chemical principles, The Benjamin Cummings Publishing Company,
  • Compounds which are capable of generating free radicals are, for example, N,N-dimethylbromide (DMF), N-Me formamide (NMF) and dimethyl sulfoxide (DMSO).
  • DMF N,N-dimethylbromide
  • NMF N-Me formamide
  • DMSO dimethyl sulfoxide
  • Ultrasound causes lysis and formation of radicals produced from the water itself.
  • the radical produced from water may attack the above compounds (such as DMSO) to produce more free radicals.
  • the ultrasound may attack directly the above compounds to produce free radicals.
  • exothermic compositions are agents capable of initiating a strong exothermic reaction after being activated by ultrasound or activated by light or other energy source, for example, due to absorbance of energy or mechanical ultrasonic vibration thus achieving activation energy or causing instability resulting in destruction based on hyper-thermal damage.
  • Exothermic compositions may be biologically compatible explosives containing fuel and sufficient oxygen or oxidizer so that upon activation they are capable of undergoing a chemical change at a relatively high rate and speed, or at a speed approaching instant speed, resulting in the production of usable force through chemical change to produce heat and a gaseous product.
  • the exothermic compositions may also be compounds containing fuel and sufficient oxygen or oxidizers which are capable of releasing gases and heat, albeit at a lower rate than the explosives and includes such compositions or components thereof which react or are capable of reacting to yield usable quantities of heat with or without chemical products, including oxidatives.
  • exothermic compositions are NaN 3 polysaccharide resins including organometallic or organo compounds, nitrocellulose and the like, nitrated metallorganic compounds, phosphorus compounds, compounds containing metal hydride with hydrocarbon and the like, inorganic nitrogen-oxygen salts including nitroglycerine, and the like.
  • the activation of the exothermic compositions causes the destruction of the biological tissue by heat or by production of oxidatives, or production of usable mechanical force.
  • helper agents specified in (i)-(iii) above should be mostly used for external applications, for example, where the light and photosensitizable compound, (in the photodynamic aspect) or the ultrasound, with a sonosensitizable compound, (in the sonodynamic aspect) are used to destroy biological tissue present on the external surface of a subject, such as on the skin, digestive tract, reproductive system, etc.
  • the tissue may be epithelial cancerous or precancerous tissue, beauty spots, broken capillaries, birth marks, wrinkles, hair roots, etc.
  • composition of matter capable of undergoing an exothermic reaction may be also used for destruction of internal tissues of the body, if it belongs to the type that releases heat at a relatively slow rate with relatively low or no release of gaseous products, for example, said composition can be administered to a desired location inside the body, such as by injection, and then an ultrasound beam or a light beam carried by an optic fiber is administered to the location of injection. Destruction of an internal location inside a subject may be carried out in order to destroy a tumor, to block blood vessels, to open a blood clot and the like.
  • the methods according to the invention may also be used for enhancing the sterilizing effect of energy irradiation such as light, ultrasound, microwave, etc. when required to destroy undesired microorganisms such as bacteria, protozoa, parasites and the like, and in such a case it is possible for example to add to the solution in which the sterilization by the irradiation also one of the helper agents ((i) - (iii)) or the composition of matter capable of undergoing an exothermic reaction.
  • the term "biological tissue” should be understood as referring also to single cell organisms.
  • energy irradiation such as ultrasound and light
  • an agent capable of being sensitized by said irradiation such as photosensitizable/ sonosensitizable compounds and at least one of the helper agents (i) - (iii) or the composition of matter capable of undergoing an exothermic reaction in order to destroy biological tissue.
  • an energy irradiation such as light, ultrasound or microwave irradiation causes precipitation, decomposition, and/or agglutination of photosensitizable or sonosensitizable compounds, respectively, thus terminating their destructive activity.
  • the method of the third aspect of the invention after administering a photosensitizable or sonosensitizable agent to a subject, and activating it for a desired period of time by an energy irradiation, it is possible to terminate its destructive activity by application of energy, and thus, eliminate or significantly reduce the severe problem of prolonged light sensitivity, which greatly hindered the widespread practice of photodynamic therapy (Orenstein et al, supra).
  • the method of the third aspect of the invention thus enables to control the period in which the photosensitizable/sonosensitizable agent is active only to the period of the medical treatment.
  • the present invention concerns a method for terminating the destructive activity of photosensitizable/sonosensitizable compounds, by application of an energy irradiation pulse capable of precipitating, or cause decomposition or agglutination of said photosensitizable compounds.
  • the parameters of the pulse for example, light, ultrasound microwave
  • the parameters of the pulse may be determined empirically, for example, by direct measurement of the fluorescence activity of the sensitizer under different irradiation regimes, or by measuring the slope of effect evoked on final substract of the sensitizer activity, such a tryptophan, under different radiation regimes which change may be easily determined by a fluorescence or activity effect on substrate.
  • the parameters of energy irradiation which are sufficient to terminate or significantly reduce said change in fluorescence can be used, in accordance with the fifth aspect of the invention.
  • the range of the ultrasound pulse required for the deactivation of a common photosensitizable compound such as po ⁇ hyrins, hematoporphyrins, chlorines, purpurins, phtalocyanines, photofrin, rhodamines, acridine derivated, rhodamines and the like or sonosensitizers (including e.g.
  • gallium-porphyrin gallium-porphyrin, DMSO (dimethylsulfox- ide), DMF (dimethylformamide), mesoporphyrin, adramycin and mitomycin and the like are as follows: Frequency: 20 KHz to 20 MHz, preferably 0.1 MHz to 10 MHz, most preferably 0.5 MHz to 5 MHz.
  • Intensity 0.1 w/cm 2 to 500 w/cm 2 , preferably 0.5 w/cm 2 to 100 w/cm 2 , most preferably 2 w/cm 2 to 8 w/cm 2 .
  • the photosensitizable/sonosensitizable compound may be deactivated by application of unfocused wave of ultrasound.
  • the photosensitizable compound is administered to deeper regions of the body, for example, by injection, perfusion or transdermal delivery as disclosed in co-pending Israel Application 119827 inco ⁇ orated herein by reference, and is activated by light, for example, from an optic fiber or by ultrasound irradiation
  • the deactivation should be carried out by utilizing ultrasound capable of penetrating deep inside the body, for example, as disclosed in co-pending Israel Application 120079 inco ⁇ orated herein by reference, or by unfocused ultrasound.
  • the photosensitizable or sonosensitizable agent may also be destmcted by ultrasound irradiation having the resonance frequency of the particular sensitizer used. Such resonance frequency may also cause decomposition, agglutination or precipitation of the sensitizer. Generally, the state of the art sensitizer is in the range of 1 MHz to 10 GHg.
  • irradiation of the resonance frequency for activation of initially inactive photo- or sonosensitizers.
  • the sensitizers are applied in an inactive form, for example, conjugated to an inactivating moiety. Irradiation of the resonance frequency caused cleavage of the active sensitizer from the inactivating moiety, thus causing its activation.
  • a fourth aspect of the invention there is provided a method for terminating the destructive activity of photosensitizable and/or sonosensitizable compounds by activating exothermic compositions in the vicinity of said photosensitizable or sonosensitizable compounds thereby causing decomposition of the compounds.
  • the photosensitizable or sonosensitizable compound is destroyed by compositions of matter capable of pertaining a exothermic reaction as explained above.
  • the exothermic compositions should be administered before, together with, or after the photosensitizable or sonosensitizable compounds.
  • composition of matter capable of undergoing an exothermic reaction When the composition of matter capable of undergoing an exothermic reaction is delivered for cease of activity together with the actual sensitizer, then levels of energy irradiation such as light and/or ultrasound irradiation having such parameters which are capable of activating the photosensitizable compound without activating the composition of matter capable of undergoing an exothermic reaction should be used during treatment so as to cause the controlled destruction of biological tissue.
  • energy irradiation such as light and/or ultrasound irradiation having such parameters which are capable of activating the photosensitizable compound without activating the composition of matter capable of undergoing an exothermic reaction should be used during treatment so as to cause the controlled destruction of biological tissue.
  • an effective energy irradiation such as light or ultrasound irradiation level should be applied which is sufficient to activate the composition of matter capable of undergoing an exothermic reaction so as to produce sufficient heat, which can then decompose the photosensitizable or sonosensitizable agent and terminate or significantly reduce its destructive activity.
  • the levels of irradiation should be empirically determined. In the following, the invention will be disclosed with reference to some non limiting examples.
  • Fig. 1 shows reduction of fluorescence of 1x10° M Tryptophan in the presence of 2x10 "6 M of the photosensitizable compound TPPS 2 after ultrasound irradiation of 3 MHz, continuous wave, 2.2 w/cm , for 20 mins, at 23°C;
  • Fig. 2 shows reduction of fluorescence of lxlO "3 M Tryptophan in the presence of lxlO "6 M of the photosensitizable compound TPPS 2 after ultrasound irradiation of 1 MHz, continuous wave, 1.7 w/cm 2 , for 2 mins, at 23 °C;
  • Fig. 3 shows reduction of fluorescence of 1x10° M Tryptophan in the presence of 2x10 "6 M of the photosensitizable compound TPPS 2 after ultrasound irradiation of 1 MHz, continuous wave, 2.2 w/cm 2 , for 2 mins, at 23°C; carried out after bubbling oxygen into the solution (for 60 sees.) thus elevating the oxygen concentration of the solute from 8 to 20 ppm;
  • Fig. 4 shows reduction of fluorescence of 1x10° M Tryptophan in the presence of 2x10 "6 M of the photosensitizable compound TPPS 2 after ultrasound irradiation of 1 MHz, carried out after bubbling of oxygen as described above.
  • the compounds were subjected to two ultrasound pulses of continuous wave the first for 2 min. at 1.7 w/cm without oxygen bubbling and the second for another 1 min. at 2.2 w/cm during bubbling of oxygen;
  • Fig. 5 shows reduction of fluorescence of 2xl0 "6 M of the photosensitizable compound TPPS 2 in the presence of lxlO "5 M Tryptophan after ultrasound irradiation of 1 MHz, continuous wave, 1.7 w/cm , for 30 mins, at 23 °C; Fig.
  • Fig. 7 shows a schematic representation for a system for use in the method of the invention where the energy source is ultrasound:
  • Fig. 8 shows reduction of fluorescent levels of tryptophan alone (10 "5 M); tryptophan (10 "5 M) and TPPS 4 (10 "5 M); and TPPS 4 alone; after microwave irradiation of 2450 MHz, 34.4 W for 1 min.
  • Example 1 Improved activation and deactivation of photo- and sonosensitizable compounds
  • TPPS 2 Three typical photosensitizable compounds, TPPS 2 , TPPS and AlPcS 3 at concentrations of 10 "7 -10 "5 M were used for ultrasound activation and deactivation. Qualitatively similar results were found when tryptophan was ultrasonically irradiated in the presence of each of the above-mentioned sensitizers.
  • a Mertler sonicator 720 was used and the ultrasonic parameters were intensities of 1-2.2 W/cm continuous wave; 1 or 3 MHz applied for different periods - up to 60 mins. Occasionally irradiation was carried out during or after bubbling of oxygen (0 2 ) into the solution and elevation of the oxygen content from 8 up to 25 ppm.
  • Tryptophan serves an acceptor for activated oxygen, when produced by the photosensitizable compounds.
  • the oxygen affects mostly double-bonds of the tryptophan thus reducing the concentration of the original form of tryptophan and this is revealed by decrease in the tryptophan fluorescence activity at the specific wave length.
  • the remaining measured fluorescence is relevant to the concentration of tryptophan that remained in its original form, i.e. that was not changed by the sonosensitizable compounds.
  • fluorescence activity specific to the original forms of sensitizer was determined and the reduction of this activity after irradiation was measured.
  • Fig. 2 utilizing ultrasound irradiation with continuous wave, intensity of 1.7 W/cm at 1 MHz, for different periods up to 60 mins. 23 °C was used.
  • the sensitizer used was TPPS 2 at concentration of 1x10 ⁇ M and tryptophan was at the concentration of lxlO "5 .
  • Measurements of fluorescence activity were carried out during 60 mins. The irradiation caused a significant and time dependent decrease of about 49% in the concentration of the original form of tryptophan.
  • a continuous wave of ultrasound irradiation 1 MHz, at 23 °C constant was used, and the sensitizer TPPS 2 at concentration of lxlO "6 M, and tryptophan at concentration of 1x10 " were utilized.
  • Irradiation was carried out after bubbling oxygen (0 2 ) in the solution to concentrations similar to those mentioned in relation to the previous example.
  • the first irradiation was for 2 minutes at intensity of 1.7 W/cm" and was resulted in decrease of 43 % of the tryptophan concentration.
  • the same solution was re-irradiated for another 1 min. at intensity of 2.2 W/cm 2 during bubbling of oxygen. This was followed by another reduction of about 27% in the fluorescence activity of tryptophan and the total reduction during the 3 minutes of irradiation was of 70%.
  • the reduction of the concentration of the original fo ⁇ n of the sensitizer was expected to cause a reduction in the slope (i.e. in the rate) of tryptophan response, as was found in Example 6, and is therefore directly associated to reduction in its effectiveness.
  • the reduced activity of the sensitizer has the meaning of immediate reduction in the delayed sensitivity to light or ultrasound. According to another example summarized in Fig. 6, continuous wave of ultrasound irradiation having intensity of 1.7 W/cm at 1 MHz was used, for different periods of up to 50 mins. at 23 °C constant, the sensitizer was TPPS 5xl0 "7 M, and tryptophan concentration lxlO "5 . Fluorescence activity of both tryptophan and TPPS were measured every 10 mins.
  • Example 2 A system for administration of ultrasound Fig. 7 shows a system for carrying out the method of the invention, for destruction of biological tissue by ultrasound irradiation.
  • the system 1 is composed of a treatment container device 2; an energy irradiation radiation source 3 (being in the present case an ultrasonic energy source); an energy delivery member 4, being in the present case an ultrasonic transducer; a first reservoir 5 containing the medicament or sensitizable agent; a second reservoir 6 containing the helper agents; and a computerized control unit 7.
  • Treatment container device 2 which hold the active agents preferably made of plexyglass and sensitized by the irradiation source (for example sonosensitizable agents) is in the form of a container
  • the opening 8 of container 2 is placed on the tissue to be treated, for example a skin region of the patient which is to be destroyed due to malignancy.
  • the sonosensitizable agents within the container are activated by ultrasonic irradiation originating from source 3, comprising a signal generator, an amplifier and optionally a matching unit.
  • the ultrasonic energy is then transferred to energy delivery member 4 which in the present case is an ultrasonic transducer.
  • the container 2 is attached to a member 4 through irradiation area 9 which preferably is in the form of a plate.
  • Ultrasonic irradiation delivery member 4 is composed of at least one transducer capable of producing either a regular or focused beam of different frequencies, intensities, pulse modes and duration, for the activation and/or decomposition of said sonosensitizable agent.
  • the distance between the energy delivery member 4 and opening 8 is adjustable, by use of threadings 10 and motor 11, which can change the overall length of container 2. Said change alters the position of the ultrasonic energy in relation with opening 8, and thus determine the place or depth in which the focus of the ultrasonic beam will be created, or the distribution of the ultrasound energy.
  • Container 2 has two openings therein: outlet 12 and inlet 13.
  • Solution is circulated between the two openings, through filter 16 and reservoir 5, by the aid of pump 14.
  • Filter 16 is intended to purify the circulating solution from various impurities which may be due to release of various components from the treated biological tissue (for example, skin cells), or agglutinates of the sonosensitizable compositions or helper agents.
  • Outlet 12 and inlet 13 can each be independently closed according to the desired affect. According to one application, inlet 13 is closed while pump 14 is active resulting in a suction affect of the solution and cellular debris from opening 8 attached to the target tissue, and thus via tube 15 through filter 16, the solution reaches the reservoir 5.
  • the level of the active components which are present in the solution recycled into reservoir 5, is detected using probes 17 and 21.
  • Said probes are suitable to detect the level of the sonosensitizable helper agent, (or any other additive agent) so that the solution may be replenished, in order to maintain a predefined level of helper or additive.
  • the probe may be an oxygen electrode. If the level of the helper agent (i.e. 0 2 ) is too low as detected by the probes, additional 0 2 rich agents can be pumped by pump 18 from second reservoir 6 into first reservoir 5, and from there to the container 2. In reservoir 5, the added solution is mixed with the recycled solution by stirrer 19.
  • samples of the solutions present in reservoir 5 can be obtained to an external container by tap 20 for various monitoring and chemical determination.
  • the whole system is controlled by computerized control unit 7 which measures and collects information from detectors 17 and 21, measures the level and volume of the components in reservoirs 5 and 6 and in treatment container device 2.
  • the system can detect the appearance of undesired bubbles in the epical part of container 2 close to opening 8.
  • Computerized control unit 7 controls the activity of pumps 14 and 18 and of motor 11, which determines the distance between unit 4 and opening 8.
  • the computerized system also controls the operation of irradiation source 3 coupled to transducer 4, and determines the intensity, frequency and duration of the pulses given.
  • the system as shown in the figure is applicable for external tissues such as epithelial tissues, as well as moist epithelial tissues of the digestive tract, reproductive system, eye epithelium, and the like.
  • this system may also be used for internal pu ⁇ oses, wherein the container treatment device 2 is minimized and constructed in a manner suitable for internal applications.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Oncology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une méthode et un système de destruction de tissus biologiques à l'aide de divers types d'irradiations tels que par ultrasons ou par de la lumière, utilisant un agent auxiliaire ou une combinaison d'agents, optionnellement avec un agent pouvant être sensibilisé par l'irradiation. L'agent auxiliaire peut libérer de l'oxygène singulet, des composés oxydants, des radicaux libres ou il peut être un agent capable de subir une réaction exothermique. La présente invention concerne également une méthode mettant un terme à l'activité destructive de divers agents pouvant être sensibilisés par de l'énergie.
PCT/IL1998/000231 1997-05-22 1998-05-20 Therapie photodynamique et sonodynamique et agents et systeme utilises a cet effet WO1998052610A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
CA002290450A CA2290450A1 (fr) 1997-05-22 1998-05-20 Therapie photodynamique et sonodynamique et agents et systeme utilises a cet effet
EP98921707A EP0983090A1 (fr) 1997-05-22 1998-05-20 Therapie photodynamique et sonodynamique et agents et systeme utilises a cet effet
AU74475/98A AU7447598A (en) 1997-05-22 1998-05-20 Photodynamic and sonodynamic therapy and agents and system for use therefor

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IL12089197A IL120891A0 (en) 1997-05-22 1997-05-22 Photodynamic and sonodynamic therapy and agents for use therefor
IL120891 1997-05-22

Publications (1)

Publication Number Publication Date
WO1998052610A1 true WO1998052610A1 (fr) 1998-11-26

Family

ID=11070161

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IL1998/000231 WO1998052610A1 (fr) 1997-05-22 1998-05-20 Therapie photodynamique et sonodynamique et agents et systeme utilises a cet effet

Country Status (5)

Country Link
EP (1) EP0983090A1 (fr)
AU (1) AU7447598A (fr)
CA (1) CA2290450A1 (fr)
IL (1) IL120891A0 (fr)
WO (1) WO1998052610A1 (fr)

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0965350A1 (fr) * 1997-03-31 1999-12-22 Katsuro Tachibana Procede d'excitation de matiere photosensible
WO2000001413A1 (fr) * 1998-07-06 2000-01-13 Pharmacyclics, Inc. Sensibiliseurs intracellulaires pour traitement sonodynamique
WO2000040266A2 (fr) * 1999-01-04 2000-07-13 The General Hospital Corporation D/B/A Ciblage de follicules sebaces utilise por traiter des troubles de la glande sebacee
WO2000041727A1 (fr) * 1999-01-15 2000-07-20 Light Sciences Corporation Traitement photodynamique transcutane de cellules cibles
WO2001049328A1 (fr) * 2000-01-05 2001-07-12 The American National Red Cross Inactivation photodynamique de pathogenes dans le sang par des phenothiazines et de l'oxygene
WO2002060483A2 (fr) * 2001-01-30 2002-08-08 Governors Of The University Of Alberta Perylenequinones utilisees comme photosensibilisants et sonosensibilisants
US6498945B1 (en) * 1997-05-19 2002-12-24 Amersham Health As Sonodynamic therapy using an ultrasound sensitizer compound
WO2003063901A1 (fr) * 2002-01-29 2003-08-07 Altachem Pharma, Ltd. Hypocrellines amino-substituees utilisables en tant qu'agents sonosensibilisants
EP1393775A1 (fr) * 2002-08-28 2004-03-03 Hitachi, Ltd. Appareil à ultrasons pour utilisation thérapeutique
US6897238B2 (en) 2000-08-16 2005-05-24 General Hospital Corporation Topical aminolevulinic acid-photodynamic therapy for the treatment of acne vulgaris
GB2415373A (en) * 2004-06-23 2005-12-28 Destiny Pharma Ltd Porphyrins for sonodynamic therapy
WO2006019848A1 (fr) * 2004-07-21 2006-02-23 Boston Scientific Scimed, Inc. Revêtements anti-infectieux activés par ultrasons et dispositifs réalisés à partir de ceux-ci
US7244841B2 (en) 2002-12-23 2007-07-17 Destiny Pharma Limited Porphyrin derivatives and their use in photodynamic therapy
US8454991B2 (en) 2006-07-24 2013-06-04 Quest Pharmatech Inc. Method and device for photodynamic therapy
US8506931B2 (en) 2005-08-10 2013-08-13 Quest Pharmatech Inc. Perylenequinone derivatives and uses thereof
US9108045B2 (en) 2007-06-27 2015-08-18 The General Hospital Corporation Method and apparatus for optical inhibition of photodynamic therapy
US11813330B2 (en) 2021-03-04 2023-11-14 Theralase Technologies, Inc. Sonodynamic therapy using sonodynamically activated coordination complexes of transition metals as sensitizing agents

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH01146829A (ja) * 1987-12-01 1989-06-08 Koshiro Umemura 超音波による腫瘍治療用生理作用増強剤
WO1998001131A1 (fr) * 1996-07-05 1998-01-15 Hitachi, Ltd. Medicaments induisant une action ultrasonore et appareil d'utilisation de ces medicaments

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH01146829A (ja) * 1987-12-01 1989-06-08 Koshiro Umemura 超音波による腫瘍治療用生理作用増強剤
WO1998001131A1 (fr) * 1996-07-05 1998-01-15 Hitachi, Ltd. Medicaments induisant une action ultrasonore et appareil d'utilisation de ces medicaments

Non-Patent Citations (12)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 123, no. 12, 18 September 1995, Columbus, Ohio, US; abstract no. 152697, MALIK, Z. ET AL: "Topical application of 5-aminolevulinic acid, DMSO and EDTA: protoporphyrin IX accumulation in skin and tumors of mice" XP002077405 *
CHEMICAL ABSTRACTS, vol. 124, no. 9, 26 February 1996, Columbus, Ohio, US; abstract no. 105881, MISIK, VLADIMIR ET AL: "Peroxyl radical formation in aqueous solutions of N,N- dimethylformamide, N-methylformamide, and dimethylsulfoxide by ultrasound: implications for sonosensitized cell killing" XP002077404 *
CHEMICAL ABSTRACTS, vol. 125, no. 15, 7 October 1996, Columbus, Ohio, US; abstract no. 185070, MISIK, VLADIMIR ET AL: "EPR spin trapping study of the decomposition of azo compounds in aqueous solutions by ultrasound: potential for use as sonodynamic sensitizers for cell killing" XP002077406 *
FREE RADICAL BIOL. MED. (1996), 20(1), 129-38 CODEN: FRBMEH;ISSN: 0891-5849, 1996 *
FREE RADICAL RES. (1996), 25(1), 13-22 CODEN: FRARER;ISSN: 1071-5762 *
J. PHOTOCHEM. PHOTOBIOL., B (1995), 28(3), 213-18 CODEN: JPPBEG;ISSN: 1011-1344, 1995 *
KESSEL D ET AL: "Modes of photodynamic vs. sonodynamic cytotoxicity.", JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY. B, BIOLOGY, (1995 JUN) 28 (3) 219-21. JOURNAL CODE: JLI. ISSN: 1011-1344., Switzerland, XP002077400 *
MIYOSHI N ET AL: "Sonodynamic toxicity of gallium-porphyrin analogue ATX-70 in human leukemia cells.", RADIATION RESEARCH, (1997 JUL) 148 (1) 43-7. JOURNAL CODE: QMP. ISSN: 0033-7587., United States, XP002077402 *
MIYOSHI, N. ET AL: "Effect of gallium-porphyrin analog ATX-70 on nitroxide formation from a cyclic secondary amine by ultrasound: On the mechanism of sonodynamic activation", PHOTOMED. PHOTOBIOL. (1995), 17, 139-40 CODEN: PHPHEA;ISSN: 0912-232X, XP002077399 *
R.J. JEFFERS ET AL.: "Dimethylformamide as an enhancer of cavitation-induced cell lysis in vitro.", J. ACOUSTICAL SOC. AMER., vol. 97, no. 1-6, 1995, pages 669 - 676, XP002077403 *
SHIN-ICHIRO UMEMURA ET AL: "SONOCHEMICAL ACTIVATION OF HEMATOPORPHYRIN: A POTENTIAL MODALITY FOR CANCER TREATMENT", PROCEEDINGS OF THE ULTRASONICS SYMPOSIUM, MONTREAL, OCT. 3 - 6, 1989, vol. VOL. 2, no. -, 3 October 1989 (1989-10-03), MCAVOY B R, pages 955 - 960, XP000139558 *
SUZUKI, TOSHIO ET AL: "A study on sonodynamic therapy-antitumor effect of novel sonodynamic compounds under ultrasound", HETEROCYCLES (1994), 38(6), 1209-11 CODEN: HTCYAM;ISSN: 0385-5414, XP002077401 *

Cited By (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0965350A4 (fr) * 1997-03-31 2000-04-05 Katsuro Tachibana Procede d'excitation de matiere photosensible
EP0965350A1 (fr) * 1997-03-31 1999-12-22 Katsuro Tachibana Procede d'excitation de matiere photosensible
US6498945B1 (en) * 1997-05-19 2002-12-24 Amersham Health As Sonodynamic therapy using an ultrasound sensitizer compound
WO2000001413A1 (fr) * 1998-07-06 2000-01-13 Pharmacyclics, Inc. Sensibiliseurs intracellulaires pour traitement sonodynamique
WO2000040266A2 (fr) * 1999-01-04 2000-07-13 The General Hospital Corporation D/B/A Ciblage de follicules sebaces utilise por traiter des troubles de la glande sebacee
WO2000040266A3 (fr) * 1999-01-04 2001-01-18 Gen Hospital Corp D B A Ciblage de follicules sebaces utilise por traiter des troubles de la glande sebacee
US6183773B1 (en) 1999-01-04 2001-02-06 The General Hospital Corporation Targeting of sebaceous follicles as a treatment of sebaceous gland disorders
US6600951B1 (en) 1999-01-04 2003-07-29 The General Hospital Corporation Targeting of sebaceous follicles as a Treatment of sebaceous gland disorders
WO2000041727A1 (fr) * 1999-01-15 2000-07-20 Light Sciences Corporation Traitement photodynamique transcutane de cellules cibles
US6602274B1 (en) 1999-01-15 2003-08-05 Light Sciences Corporation Targeted transcutaneous cancer therapy
WO2001049328A1 (fr) * 2000-01-05 2001-07-12 The American National Red Cross Inactivation photodynamique de pathogenes dans le sang par des phenothiazines et de l'oxygene
US6897238B2 (en) 2000-08-16 2005-05-24 General Hospital Corporation Topical aminolevulinic acid-photodynamic therapy for the treatment of acne vulgaris
WO2002060483A2 (fr) * 2001-01-30 2002-08-08 Governors Of The University Of Alberta Perylenequinones utilisees comme photosensibilisants et sonosensibilisants
WO2002060483A3 (fr) * 2001-01-30 2003-12-24 Univ Alberta Perylenequinones utilisees comme photosensibilisants et sonosensibilisants
WO2003063901A1 (fr) * 2002-01-29 2003-08-07 Altachem Pharma, Ltd. Hypocrellines amino-substituees utilisables en tant qu'agents sonosensibilisants
EP1393775A1 (fr) * 2002-08-28 2004-03-03 Hitachi, Ltd. Appareil à ultrasons pour utilisation thérapeutique
US7125387B2 (en) 2002-08-28 2006-10-24 Hitachi, Ltd. Ultrasonic apparatus for therapeutical use
US7244841B2 (en) 2002-12-23 2007-07-17 Destiny Pharma Limited Porphyrin derivatives and their use in photodynamic therapy
US8084602B2 (en) * 2002-12-23 2011-12-27 Destiny Pharma Limited Porphyrin derivatives and their use in photodynamic therapy
GB2415373A (en) * 2004-06-23 2005-12-28 Destiny Pharma Ltd Porphyrins for sonodynamic therapy
WO2006019848A1 (fr) * 2004-07-21 2006-02-23 Boston Scientific Scimed, Inc. Revêtements anti-infectieux activés par ultrasons et dispositifs réalisés à partir de ceux-ci
US7356368B2 (en) 2004-07-21 2008-04-08 Boston Scientific Scimed, Inc. Light-activated anti-infective coatings and devices made thereof
US8506931B2 (en) 2005-08-10 2013-08-13 Quest Pharmatech Inc. Perylenequinone derivatives and uses thereof
US8758725B2 (en) 2005-08-10 2014-06-24 Quest Pharmatech Inc. Perylenequinone derivatives and uses thereof
US8454991B2 (en) 2006-07-24 2013-06-04 Quest Pharmatech Inc. Method and device for photodynamic therapy
US9108045B2 (en) 2007-06-27 2015-08-18 The General Hospital Corporation Method and apparatus for optical inhibition of photodynamic therapy
US11813330B2 (en) 2021-03-04 2023-11-14 Theralase Technologies, Inc. Sonodynamic therapy using sonodynamically activated coordination complexes of transition metals as sensitizing agents

Also Published As

Publication number Publication date
EP0983090A1 (fr) 2000-03-08
CA2290450A1 (fr) 1998-11-26
AU7447598A (en) 1998-12-11
IL120891A0 (en) 1997-09-30

Similar Documents

Publication Publication Date Title
WO1998052610A1 (fr) Therapie photodynamique et sonodynamique et agents et systeme utilises a cet effet
Gibson et al. Effects of various photoradiation regimens on the antitumor efficacy of photodynamic therapy for R3230AC mammary carcinomas
US5817048A (en) Ultrasonic alternative to laser-based photodynamic therapy
Mojzisova et al. Photosensitizing properties of chlorins in solution and in membrane-mimicking systems
Cincotta et al. Benzophenothiazine and benzoporphyrin derivative combination phototherapy effectively eradicates large murine sarcomas
US20210177970A1 (en) Multifunctional Treatment And Diagnostic Compositions And Methods
Rovers et al. Effective treatment of liver metastases with photodynamic therapy, using the second-generation photosensitizer meta-tetra (hydroxyphenyl) chlorin (mTHPC), in a rat model
Canaparo et al. The bright side of sound: Perspectives on the biomedical application of sonoluminescence
EP2722057A2 (fr) Série de médicaments utilisant du photofrin pour catalyser la décomposition du peroxyde d'hydrogène
Aveline Primary processes in photosensitization mechanisms
Reshetnickov et al. Novel drug form of chlorin e6
CA2270558C (fr) Traitement de maladies auto-immunes par photochimiotherapie
Rezzoug et al. Parameters affecting photodynamic activity of Foscan® or meta-tetra (hydroxyphenyl) chlorin (mTHPC) in vitro and in vivo
Waterfield et al. Wavelength‐dependent effects of benzoporphyrin derivative monoacid ring A in vivo and in vitro
Nonell et al. QUANTUM YIELD OF PRODUCTION OF SINGLET MOLECULAR OXYGEN (xδg) IN AQUEOUS DISPERSIONS OF SMALL UNILAMELLAR LIPID VESICLES. A TIME‐RESOLVED NEAR‐IR PHOSPHORESCENCE STUDY
Masumoto et al. Tissue distribution of a new photosensitizer ATX-S10Na (II) and effect of a diode laser (670 nm) in photodynamic therapy
Camerin et al. Metallo‐naphthalocyanines as photothermal sensitisers for experimental tumours: in vitro and in vivo studies
Istomin et al. Uptake and phototoxicity of tricarbocyanine indolenine dye covalently bound with glucose (TICS) under acidification of tumor cells environment
Leach et al. Effectiveness of a lysyl chlorin p6/chlorin p6 mixture in photodynamic therapy of the subcutaneous 9L glioma in the rat
Henry et al. Synergistic enhancement of the efficacy of the bioreductively activated alkylating agent RSU-1164 in the treatment of prostatic cancer by photodynamic therapy
Heier et al. Tissue sensitizers
Webber et al. Photodynamic therapy using endogenous photosensitization for gastrointestinal tumors
Bazin et al. Superoxide dismutase as an amplifier of the chemical reactivity of porphyrin radical‐cations
Kirveliene et al. Fluence-rate-dependent photosensitized oxidation of NADH
Shopova et al. Photodynamic therapy of experimental tumours with Zn (II)-phthalocyanine and pulsed laser irradiation

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GE GH GM GW HU ID IL IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
ENP Entry into the national phase

Ref document number: 2290450

Country of ref document: CA

Ref country code: CA

Ref document number: 2290450

Kind code of ref document: A

Format of ref document f/p: F

WWE Wipo information: entry into national phase

Ref document number: 1998921707

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 09447442

Country of ref document: US

WWE Wipo information: entry into national phase

Ref document number: 74475/98

Country of ref document: AU

NENP Non-entry into the national phase

Ref country code: JP

Ref document number: 1998550201

Format of ref document f/p: F

WWP Wipo information: published in national office

Ref document number: 1998921707

Country of ref document: EP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWW Wipo information: withdrawn in national office

Ref document number: 1998921707

Country of ref document: EP