GB2514408A - Photodynamic Therapy and Diagnosis - Google Patents
Photodynamic Therapy and Diagnosis Download PDFInfo
- Publication number
- GB2514408A GB2514408A GB1309337.2A GB201309337A GB2514408A GB 2514408 A GB2514408 A GB 2514408A GB 201309337 A GB201309337 A GB 201309337A GB 2514408 A GB2514408 A GB 2514408A
- Authority
- GB
- United Kingdom
- Prior art keywords
- sodium
- chlorin
- pharmaceutical composition
- cancer
- administration
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
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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
- A61K41/0057—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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings
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- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic Table
- C07F1/005—Compounds containing elements of Groups 1 or 11 of the Periodic Table without C-Metal linkages
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Abstract
The present invention relates to Chlorin e4 sodium, preferably with chlorine e4 and sodium in a ratio of 1:2: A process for its preparation preferably comprises reaction of chlorine e4 in methanol with aqueous sodium hydroxide, optionally with addition of an amine base such as thiamine pyrophosphate, followed by lyophilisation. Chlorin e4 sodium may be useful in photodynamic therapy, cytoluminescent therapy and photodynamic diagnosis, for example for treating or detecting a tumour. A pharmaceutical composition comprising chlorin e4 sodium and the use of chlorin e4 sodium in the manufacture of a phototherapeutic or photodiagnostic agent are also detailed.
Description
Photodynamic Therapy and Diagnosis
Technical field
The present invention relates to chiorin e4 sodium and a process for its preparation.
Chiorin e4 sodium is suitable for use in photodvnarnic therapy, cytoluminescent therapy and photodvnamic diagnosis, for example for treating or detecting a tumour. The present invention also relates to a pharmaceutical composition comprising chlorin e4 sodium, to the use of chiorin e4 sodium in the matiufacture of a phototherapeutic or photodiagnostic agent, and to a method of photodynaniic therapy, cytoluniinescent therapy or photodynamic diagnosis, for example for treating or detecting a tumour.
Background art
Porphyrins and their derivatives are known photosensitive chemical compounds, which can absorb light photons and emit them at higher wavelengths. There arc many applications for such unique properties and PI)T (photodynamic therapy) is one of them.
During light activation, a tnolecule goes from the ground state (Se) to a singlet excited state (Si), (SS transition), and then fails hack down to the ground state (SD, (515O transition), emitting light at higher wavelengths in the form of fluorescence. There is another energy state known as the triplet state (T1). The triplet state (T1) cannot be efficiently populated by direct excitation. however, intersysteni crossing S1T1 occurs isoenergetically followed by deactivation to T1.
The S1T1 change is formally spin-forbidden, hut it is a downhill process and in some molecules intersystem crossing occurs so efficiently that fluorescence is quenched. Such compounds are useful for generating excited triplets by excitation transfer (a phenomenon known as sensiti2ation) in molecules where the intersystem crossing is minimal.
Figure 1 shows a modified Jahlonski diagram for a typical photosensith<er, outlining the pnnciple photophysical processes of interest.
At the triplet state (T1) molecules become very unstable and can react with molecular oxygen (3Q,), splitting the latter into two singlet oxvgens (102). Singlet oxygen () is known as a "scavenger" and can destroy abnormal biological cells and remove free radicals.
Such unique properties make many photosensitive molecules good photosensitizers for PDT.
Presently, there are two generations of photosensitizers for PDT. The first generation comprises hem porphyrins (blood derivatives), and the second for the most part are chlorophyll derivatives. The later compounds are known as chlorins and bacteriochlorins.
Chlorins show photophysical properties similar to those of the porphyrin systems, hut have an enhanced, red-shifted Q band (O7Onm) which makes chlorin-containing systems better candidates for PDT. CLiorophyll a, the green photosynthetic pigment, is one prototype of the chlorin class of natural products. It or its derivatives can he extracted from certain Spirnhna P/a/oasis species without any contamination with chlorophyll 1', thus avoiding a tedious chromatographic separation.
A water-soluble chlorophyll derivative, known as tn-sodium copper(II) chlorin e6, has been used in the treatment of various human ailments with no evidence of toxicity, skin sensitization or other serious side effects.
Chlorin e4 was studied recently and was shown to display good photosensitive activity. It \vas indicated that chlorin e4 has a protective effect against indomethacin-induced gastric lesions in rats and TAA-or CC11-induced acute liver injuries in mice. It was therefore suggested that chlorin e4 may be a promising new drug candidate for anti-gastrelcosis and liver injury protection. WE) 2009/040411 suggests the use of a chlorin e4 zinc complex in photodynamic therapy. ff1 ( \)
-N NH
"Ill',.
HOOC
COOJT chlonn e4 However, there is an ongoing need for better photosensitizers. There is a need for compounds that have a high sing'et oxygen quantum yidd and for compounds that have a strong photosensitizing ability, preferably in organic and aqeos media.
There is also a need for compounds that have a high fluorescence quantum yield.
Summary of the invention
A first aspect of the present invention provides chlorin e4 sodium. Preferably the chlorin e4 sodium comprises chiorin e4 and sodium in a ratio of 1:2. Preferab'y the chlorin e4 sodium has the structure: (I ( \ N [H']2 [Na]2 CO2 C02-Preferably the chlorin e4 sodium has the structure: ( / (
NH
(:02 Na CO2 Na The skilled person will appreciate that the negative charges on the chlorin structures shown in the above representations are delocaliaed over the conjugated system.
Chlorin e4 sodium has two chiral centres. The chlorin e4 sodium of the present invention is preferably substantially enantiomerically pure, which means that the chlorin e4 sodium comprises less than I 0% of other stereoisomers, preferably less /0 than 5P/o, preferably less than 3%, preferably less than 2%, preferab'y less than IP/o.
A second aspect of the present invention provides a process of preparing chlorin e4 sodium, comprising the step of reacting chlorin e4 with a sodium compound.
Preferably the chlorin e4 sodium obtained comprises chlorin e4 and sodium in a /5 ratio of 1:2. Preferably the chlorin e4 sodium obtained has the structure: ( / ( \ IH'12 INal2 CO2 CO2 Preferably the chlorin e4 sodium obtained has the structure: ( / (
NIT
CC)2 Na' CO2 Na The skilled person wiTi appreciate that the negative charges on the chiorin structures shown in the above representations are deTocaTi7ed over the conjugated system.
PreferabTy the sodium compound is sodium hydroxide, a carhoxylic acid sodium saTt (such as sodium stearate or sodium acetate), a sodium haTide (such as sodium fluoride) or sodium hydride. More preferably the sodium compound is sodium hydroxide.
Optionally chlorin e4-is reacted with the sodium compound in the presence of a base. Preferably the base is an amine base, preferab'y an aromatic amine base such as thiamine pyrophosphate or DMAP. If used, the base is preferably thiamine pyrophosphate. )
Preferably chlorin e4, the sodium compound and the optional base are used in a molar ratio of 0.15-1 45-60: 0-12.
Preferably chlorin e4 is reacted with the sodium compound in the presence of a solvent. Preferably the solvent is selected from an alcohol (such as methanol, ethanol, n-propanol or isopropanol), water, DMF, chloroform, DMSO, toluene or a mixture thereof. Preferably the solvent is selected from methanol, ethanol, water or a mixture thereof. Preferably the solvent is selected from methano', water or a mixture thereof. Preferably the solvent is a mixture of methanol and water.
Preferably the reaction is carried out at a temperature of 60°C or less. Preferably the reaction is carried out at a temperature in the range of 25-60°C.
Preferably the reaction is carried out over 1 to 12 hours, preferably over 3 to 8 hours.
The chlorin e4 sodium obtained may be purified by filtering, for example through a 43tm Mllhpore fiher. Alternatively or additionally, the chiorin e4 sodium obtained may be purified by chromatography, for example by flash chromatography on a silica gd column. The chlorin e4 sodium may he isolated by lyophillsation.
A third aspect of the present invention provides chorin e4 sodium preparahle by a process according to the second aspect of the present invention. The third aspect of the preseit invention also provides chlorin e4 sodium when prepared by a process according to the second aspect of the present invention.
A fourth aspect of the present invention provides a pharmaceutical composition comprising chlorin e4 sodium according to the first or third aspect of the present invention and a pharmaceutically acceptable carrier or diluent.
Preferably the chiorin e4 sodium according to the first or third aspect of the present invention and the pharmaceutical composition according to the fourth aspect of the present invention are suitable for use in photodynamic therapy or cytoluminescent therapy.
Preferably the chlorin e4 sodium according to first or third aspect of the present invention and the pharmaceutical composition according to the fourth aspect of the present invention are suitable for the treatment of atherosclerosis; multiple sclerosis; diahetes; diabetic retinopathy; arthritis; rheumatoid arthritis; a fungal, viral, chlamydial, bacterial, nanohacterial or parasitic infectious disease; HIV; Aids; infection with sars virus, Asian (chicken) flu virus, herpes simplex or herpes oster; hepatitis; viral hepatitis; a cardiovascular disease; coronary artery stenosis; carotid artery stenosis; intermittent claudication; a dermatological condition; acne; psoriasis; a disease characterised by begin or malignant cellular hyperproliferarion or by areas of neovascularisation; a benign or malignant tumour; early cancer; cervical dysplasia; soft tissue sarcoma; a germ cell tumour; retinohlastoma; age-related macular degeneration; hodgkin's lymphoma; or cancer of the blood, prostate, cervix, uterus, vaginal or other female adnexa, breast, naso-pharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, stomach, bile duct, intestine, colon, colorectum, rectum, bladder, ureter, kidney, liver, gall bladder, spleen, brain, lymphatic system or hones.
Preferably the chlorin e4 sodium according to the first or third aspect of the present invention and the pharmaceutical composition according to the fourth aspect of the present invention are suitable for the treatment of a disease characterised by begin or malignant cellular hyperproliferation or by areas of neovascularisation.
Preferably the chlorin e4 sodium according to the first or third aspect of the present invention and the pharmaceutical composition according to the fourth aspect of the present invention are suitable for the treatment of a benign or malignant tumour.
Preferably the chlorin e4 sodium according to the first or third aspect of the present invention and the pharmaceutical composition according to the fourth aspect of the present invention are suitable for the treatment of early cancer; cervical dysplasia; soft tissue sarcoma; a germ cell tumour; retinobastoma; age-rehted macular degeneration; Hodgkin's lymphoma; or cancer of the b'ood, prostate, cervix, uterus, vaginal or other female adnexa, breast, naso-pharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, stomach, bile duct, intestine, colon, colorectuni, rectum, bladder, ureter, kidney, liver, gall bladder, spleen, brain, lymphatic system or hones.
Preferably the chlorin e4 sodium according to the first or third aspect of the present invention and the pharmaceutical composition according to the fourth aspect of the present invention are suitable for use in photodynamic diagnosis.
Preferably the chlorin e4 sodium according to the first or third aspect of the present invention and the pharmaceutical composition according to the fourth aspect of the present invention are suitable for the detection of atherosclerosis; multiple sclerosis; diabetes; diabetic retinopathy; arthritis; rheumatoid arthritis; a fungal, viral, chlamydia, bacteria', nanohacteria or parasitic infectious disease; HF'!; Aids; infection with sars virus, Asian (chicken) flu virus, herpes simp'ex or herpes zoster; hepatitis; viral hepatitis; a cardiovascular disease; coronary artery stenosis; carotid artery stenosis; intermittent claudication; a dermatological condition; acne; psoriasis; a disease characterised by begin or mahgnant cellular hyperproliferarion or by areas of neovascularisation; a benign or malignant tumour; early cancer; cervical dysplasia; soft tissue sarcoma; a germ cell tumour; retinoblastoma; age-related macular degeneration; Hodgkin's lymphoma; or cancer of the blood, prostate, cervix, uterus, vaginal or other female adnexa, breast, naso-pharynx, trachea, arynx, bronchi, bronchioles, lung, hollow organs, esophagus, stomach, bile duct, intestine, colon, colorectum, rectum, bladder, ureter, kidney, liver, gall bladder, spleen, brain, lymphatic system or bones.
Preferably the chlorin e4 sodium according to the first or third aspect of the lesent invention and the pharmaceutical composition according to the fourth aspect of the present invention are suitable for the detection of an area that is affected by begin or malignant cellu'ar hyperproliferation or by neovascularisation.
Preferably the chlorin e4 sodium according to the first or third aspect of the present invention and the pharmaceutical composition according to the fourth aspect of the present invention are suitable for the detection of a begin or malignant tumour.
Preferably the chlorin e4 sodium according to the first or third aspect of the present invention and the pharmaceutical composition according to the fourth aspect of the present invention are suitable for the detection of early cancer; cervical dysplasia; soft tissue sarcoma; a germ cell tumour; retinoblastonia; age-related macular degeneration; Hodgkin's lymphoma; or cancer of the hood, prostate, cervix, uterus, vaginal or other female adnexa, breast, naso-pharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, stomach, bile duct, intestine, colon, colorectum, rectum, bladder, ureter, kidney, liver, gall bladder, spleen, brain, lymphatic system or bones.
Preferably the chlorin e4 sodium according to the first or third aspect of the present invention and the pharmaceutical composition according to the fourth aspect of the present invention are suitable for the fluorescent or phosphorescent detection of the diseases listed above, preferably for the fluorescent or phosphorescent detection and quantification of the said diseases.
Preferably the chlorin e4 sodium according to the first or third aspect of the present invention and the pharmaceutical composition according to the fourth aspect of the present invention are adapted for administration simuhaneous with or prior to administration of irradiation or sound, preferably for administration prior to administration of irradiation. -10-
If the chlorin c4 sodium according to the first or third aspect of the present invention or the pharmaceutical composition according to the fourth aspect of the present invention are for use in photodynamic therapy or cytolurninescent therapy, then they are preferably adapted for administration 3 to 1(H) hours before the irradiation, preferably 6 to 72 hours before the irradiation, preferably 24 to 48 hours before the irradiation.
If the chlorin e4 sodium according to the first or third aspect of the present invention or the pharmaceutical composition accorJing to the fourth aspect of the present invention are for use in photodynatnic (liagnosis, then they are preferably aJapteci for ajniinistration 3 to 60 hours before the irradiation, preferably B to 40 hours before the irradiation.
Preferably the irradiation used in the photodynaniic therapy, cytoluminescent therapy or photodvnaniic diagnosis is electromagnetic radiation with a wavelength in the rangc of from 500nm to l000nrn, prefcrahly from ôOOnm to 790nm. In one ernbodinient of the Iresent invention, two sources of electroniagnetic radiation are used (for example a laser light and an LED light), one source with a wavelength in the range of froni óOOnni to 690nm, preferably about 660nm, the other source with a wavelength in the range of from 700nm to 79Ontn, preferably about 7OOnm. In another embodiment of the present invention, two sources of electromagnetic radiation arc used (for example a laser light and an LED light), both sources adapted to provide irradiation with a wavelength in the range of from óOOnm to 690nm, preferably about óóOnm, and irradiation with a wavelength in the range of from 700nrn to 79Onni, preferably about 76Onni.
The pharmaceutical composition according to the fourth aspect of the present invention may he in a form suitable for oral, parental (including intravenous, subcutaneous, intramuscular, intradermal, intratracheal, intraperitoneal, intraarticular, intraabdominal, intracranial and epidural), transdertnal, airway (aerosol), rectal, vaginal or topical (including buccal, inucosal and sublingual) administration. Preferably the pharmaceuncal composition is in a form suitable for oral, parental or airxvay administration.
In one preferred embodiment, the pharmaceutical composition is in a form suitable for oral administration. Preferably the pharmaceutical composition is provided iii the form of a tablet, capsule, hard or soft gelatine capsule, caplet, troche or lozenge, as a powder or granules, or as an aqueous solution, suspension or dispersion. More preferably the pharmaceutical composition is provided in the form of an aqueous solution, suspension or dispersion for oral administration, or alternatively in the form of a free7e-dried powder which can be mixed with water before administration to provide an aqueous solution, suspension or dispersion for oral administration.
Preferably the pharniaceutcal composition is in a form suitable for providing 0.01 to 10 mg/kg/day of the chlorin e4 sodium, preferably 0.1 to 5 mg/kg/day, preferably about 3 mg/kg/day.
In another preferred embodiment, the pharmaceutical composition is in a form suitable for parental administration. Preferably the pharmaceutical composition is in a form suitable for intravenous administration. Preferably the pharmaceutical composition is provided in the form of an aqueous solution for parental administration, or alternatively in the form of a free/c-dried powder which can he mixed with water before administration to provide an aqueous solution for parental administration. Preferably the pharmaceutical composition is an aqueous solution or suspension having a pH of from 6 to KS.
In another preferred embodiment, the pharmaceutical composition is in a form suitable for airway administration. Preferably the pharmaceutical composition is provided in the form of an aqueous solution, suspension or dispersion for airway administration, or alternatively in the form of a freeze-dried powder which can he mixed with water before administration to provide an aqueous solution, suspension or dispersion for air\vay administration. Preferably the pharmaceutical composition is in a form suitable for providing 0.01 to 10 mg/kg/day of the chlorin e4 sodium, preferably 0.1 to 5 mg/kg/day, preferably about 3 mg/kg/day. -12-
A fifth aspect of the present invention provides use of chlorin e4 sodium according to the first or third aspect of the present invention in the manufacture of a medicament for the treatment of atherosclerosis; multiple sclerosis; diabetes; diabetic retinopathy; arthritis; rheumatoid arthritis; a funga.l, viral, chlamydial, bacterial, nanobacterial or parasitic infectious disease; HIV; Aids; infection with sars virus, Asian (chicken) flu virus, herpes simplex or herpes 2oster; hepatitis; viral hepatitis; a cardiovascular disease; coronary artery stenosis; carotid artery stenosis; intermittent claudication; a dermatological condition; acne; psoriasis; a disease characterised by begin or malignant cellular hyperproliferation or by areas of neovascularisation; a benign or malignant tumour; early cancer; cervical dysplasia; soft tissue sarcoma; a germ cell tumour; retinoblastoma; age-related macular degeneration; Tlodgkin's lymphoma; or cancer of the blood, prostate, cervix, uterus, vaginal or other female adnexa, breast, naso-pharynx, trachea, brynx, hronchi, hronchioks, lung, hollow organs, esophagus, stomach, bile duct, intestine, colon, colorectum, rectum, bladder, ureter, kidney, liver, gall bladder, spleen, brain, lymphatic system or bones.
The fifth aspect of the eiu invention also provides use of chlorin e4 sodium according to the first or third aspect of the preseit invention in the manufacture of a phototherapeutic agent for use in photodynamic therapy or cytoluminescent therapy. Preferably the phototherapeutic agent is suitable for the treatment of atherosclerosis; muhiple sclerosis; diabetes; diabetic retinopathy; arthritis; rheumatoid arthritis; a fungal, viral, chlaniydial, bacterial, nanohacterial or parasitic infectious disease; HIV; Aids; infection with sars virus, Asian (chicken) flu virus, herpes simplex or herpes zoster; hepatitis; viral hepatitis; a cardiovascular disease; coronary artery stenosis; carotid artery stenosis; intermittent claudication; a dermatological condition; acne; psoriasis; a disease characterised by begin or malignant cellular hyperproliferation or by areas of neovascularisation; a benign or malignant tumour; early cancer; cervical dysplasia; soft tissue sarcoma; a germ cell tumour; retinoblastoma; age-related macular degeneration; Hodgkin's lymphoma; or cancer of the blood, prostate, cervix, uterus, vaginal or other female adnexa, breast, naso-pharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, -13-stomach, bile duct, intestine, colon, col orectum, rectum, bladder, ureter, kid ney, liver, gail bladder, spleen, brain, lymphatic system or bones.
Preferably the medicament or the phototherapeutic agent of the fifth aspect of the present invention is suitable for the treatment of a disease characterised by begin or malignant cellular hyperproliferation or b areas of neovascularisation.
Preferably the medicament or the phototherapeutic agent of the fifth aspect of the present invention is suitable for tile treatment of a begin or malignant tumour.
Preferably the medicanient or the phototherapeutic agent of the fifth aspect of the present invention is suitable for the treatment of early cancer; cervical dysplasia; soft tissue sarcoma; a germ cell tumour; retinohlastoma; age-related macular degeneration; Hodgkin's lymphoma; or cancer of the blood, prostate, cervix, uterus, vaginal or other female adnexa, breast, naso-pharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, stomach, bile duct, intestine, colon, colorectum, rectum, bladder, ureter, kidney, liver, gail bladder, spleen, brain, lymphatic system or bones.
The fifth aspect of the present invention also provides use of chlorin e4 sodium according to the first or third aspect of the present invention in the manufacture of a photodiagnostic agent for use in photodynamic diagnosis.
Preferably the photodiagnostic agent of the fifth aspect of the present invention is suitable for the detection of atherosclerosis; multiple sclerosis; diabetes; diabetic retinopathy; arthritis; rheumatoid arthritis; a fungal, viral, chlamydial, bacterial, nanohacterial or parasitic infectious disease; HIV; Aids; infection with sars virus, Asian (chicken) flu virus, herpes simplex or herpes zoster; hepatitis; viral hepatitis; a cardiovascular disease; coronary artery stenosis; carotid artery stenosis; intermittent claudication; a dermatological condition; acne; psoriasis; a disease characterised by begin or malignant cellular hyperproliferation or by areas of neovascularisation; a benign or malignant tumour; early cancer; cervical dysplasia; soft tissue sarcoma; a germ cell tumour; retinoblastoma; age-related tnacular degeneration; hodgkin's -14-lyniphonia; or cancer of the blood, prostate, cervi, uterus, vaginal or other female adnexa, breast, naso-pharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, stomach, bile duct, intestine, colon, colorectum, rectum, bladder, ureter, kidney, liver, gall bladder, spleen, brain, lymphatic system or bones. )
Preferably the photodiagnostic agent of the fifth aspect of the present invention is suitable for the detection of an area that is affected by begin or malignant cellular hyperprollferation or by neovascularisarion.
Preferably the photodiagnostic agent of the fifth aspect of the present invention is suitable for the detection of a begin or malignant tumour.
Preferably the photodiagnostic agent of the fifth aspect of the present invention is suitable for the detection of early cancer; cervical dysplasia; soft tissue sarcoma; a germ cell tumour; reti nohl astorna; age-related niacular degeneration; Hodgkin's lyrnphonia; or cancer of the blood, prostate, cervix, uterus, vaginal or other female adnexa, breast, naso-pharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, stomach, bile duct, intestine, colon, colorectuni, rectum, bladder, ureter, kidney, liver, gall bladder, spleen, brain, lymphatic system or bones.
Preferably the photodiagnostic agent of the fifth aspect of the present invention is suitable for the fluorescent or phosphorescent detection of the said diseases, preferably the fluorescent or phosphorescent detection and quantification of the said diseases.
Preferably the medicament, the phototherapeutic agent or the photodiagnostic agent is adapted for administration simultaneous with or prior to administration of irradiation or sound, preferably for administration prior to administration of irradiation.
If the niedicament or the phototherapeutic agent is for use in photodynaniic therapy or cytoluniinescent therapy, then it is preferably adapted for administration 5 to 100 -15-hours before the irradiation, preferably 6 to 72 hours before the irradiation, preferably 24 to 48 hours before the irradiation.
If the photodiagnostic agent is for use in photodynamic diagnosis, then it is preferably adapted for administration 3 to 60 hours before the irradiation, preferably 8 to 40 hours before the irradiation.
Preferably the irradiation used iti the photodynamic therapy, cytoluminescent therapy or photodynarnic diagnosis is electromagnetic radiation with a wavelength in the range of from 500nm to 1 000nni, preferably from 600nni to 79Onni. In one embodiment of the present invention, two sources of electromagnetic radiation are used (for example a laser light and an LET) light), one source with a wavelength in the range of from ôOOnm to 690nm, preferably about 660nm, the other source with a wavelength in the range of from 700nm to 790nm, preferahy about 760nm. In another embodiment of the present invention, two sources of electromagnetic radiation are used (for example a laser light and an LED light), both sources adapted to provide irradiation with a wavelength in the range of froni ñOOnm to 690nm, preferably about 660nm, and irradiation with a wavelength in the range of from 700nm to 79Onni, preferably about 760nm.
A sixth aspect of the present invention provides a method of treating atherosclerosis; muhiple sclerosis; diabetes; diabetic retinopathy; arthritis; rheumatoid arthritis; a fungal, viral, chlamydial, bacterial, nanohacterial or parasitic infectious disease; HIV; Aids; infection with sars virus, Asian (chicken) flu virus, herpes simplex or herpes zoster; hepatitis; viral hepatitis; a cardiovascular disease; coronary artery stenosis; carotid artery stenosis; intermittent claudication; a dermatological condition; acne; psoriasis; a disease characterised by begin or malignant cellular hyperproliferation or by areas of neovascularisation; a benign or malignant tumour; early cancer; cervical dysplasia; soft tissue sarcoma; a germ cell tumour; retinoblastoma; age-related macular degeneration; Hodgkin's lymphoma; or cancer of the blood, prostate, cervix, uterus, vaginal or other female adnexa, breast, naso-pharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, stomach, bile duct, intestine, colon, colorectum, rectum, bladder, ureter, kidney, -16-liver, gall bladder, spleen, brain, lymphatic system or hones; the method comprising administering a therapeutically effective amount of chlorin e4 sodium according to the first or third aspect of the present invention to a human or animal in need thereof. )
The sixth aspect of the present invention also provides a method of photodynamic therapy or cytouminescent therapy of a human or animal disease, the method comprising administering a therapeutically effective amount of chlorin e4 sodium according to the first or third aspect of the present invention to a human or animal in need thereof. Preferably the human or animal disease is atherosclerosis; multiple sclerosis; diabetes; diabetic retinopathy; arthritis; rheumatoid arthritis; a fungal, viral, chlaniydial, bacterial, nanohacterial or parasitic infectious disease; TIIV; Aids; infection with sars virus, Asian (chicken) flu virus, herpes simpkx or herpes zoster; hepatitis; viral hepatitis; a cardiovascular disease; coronary artery stenosis; carotid artery stenosis; intermittent claudication; a dermatological condition; acne; psoriasis; a disease characterised by begin or malignant cellular hyperproliferarion or by areas of neovascularisation; a benign or malignant tumour; early cancer; cervical dysplasia; soft tissue sarcoma; a germ cell tumour; retinohlastoma; age-related macular degeneration; Hodgkin's lymphoma; or cancer of the blood, prostate, cervix, uterus, vaginal or other female adnexa, breast, naso-pharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, stomach, bile duct, intestine, colon, colorectum, rectum, bladder, ureter, kidney, liver, gall bladder, spleen, brain, lymphatic system or hones.
Preferably the method of the sixth aspect of the present invention is a method of treating begin or malignant cellular hyperproliferation or areas of ne ova s culari sation.
Preferably the method of the sixth aspect of the present invention is a method of treating a benign or malignant tumour.
Preferably the method of the sixth aspect of the present invention is a method of treating early cancer; cervical dysplasia; soft tissue sarcoma; a germ cell tumour; -17-retinoblastoma; age-related macular degeneration; I Iodgkin's lyrnphoma; or cancer of the blood, prostate, cervix, uterus, vaginal or other female adnexa, breast, naso-pharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, stomach, bile duct, intestine, colon, colorectum, rectum, bladder, ureter, kidney, liver, gall bladder, spleen, brain, lymphatic system or hones.
The sixth aspect of the present invention also provides a method of photodynamic diagnosis of a human or animal disease, the method comprising administering a diagnostically effective amount of chlorin e4 sodium according to the first or third aspect of the present invention to a human or animal. Preferably the human or animal disease is atherosclerosis; multiple sclerosis; diabetes; diabetic retinopathy; arthritis; rheumatoid arthritis; a fungal, viral, chl amydial, bacterial, nanohacterial or parasitic infectious disease; l-lI\; Aids; infection with sars virus, Asian (chicken) flu virus, herpes simplex or herpes zoster; hepatitis; viral hepatitis; a cardiovascular disease; coronary artery stenosis; carotid artery stenosis; intermittent claudication; a dermatological condition; acne; psorasis; a disease characterised by begin or malignant cellular hyperproliferation or by areas of neovascularisation; a benign or malignant tumour; early cancer; cervical dysplasia; soft tissue sarcoma; a germ cell tumour; retinoblastoma; age-related rnacular degeneration; Hodgkin's lymphoma; or cancer of the blood, prostate, cervix, uterus, vaginal or other female adnexa, breast, naso-pharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, stomach, bile duct, intestine, colon, colorectum, rectum, bladder, ureter, kidney, liver, gall bladder, spleen, brain, lymphatic system or hones. Preferably the human or animal disease is characterised by begin or malignant cellular hyperproliferation or by areas of neovascularisation. Preferably the human or animal disease is a begin or malignant tumour. Preferably the human or animal disease is early cancer; cervical dysplasia; soft tissue sarcoma; a germ cell tumour; retinoblastoma; age-related macular degeneration; Hodgkin's lymphoma; or cancer of the blood, prostate, cervix, uterus, vaginal or other female adnexa, breast, naso-pharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, stomach, bile duct, intestine, colon, colorectum, rectum, bladder, ureter, kidney, liver, gall bladder, spleen, brain, lymphatic system or bones. Preferably the method of photodynamic diagnosis is suitable for the fluorescent or phosphorescent detection -18-of the said diseases, preferably for the fluorescent or phosphorescent detection and quantification of the said diseases.
In any of the methods of the sixth aspect of the present invention, the human or animal is preferably further subjected to irradiation or sound simultaneous with or after the administration of the chiorin e4 sodium. Preferably the human or animal is subjected to irradiation after tile administration of the chlorin e4 sodium.
If the method is a method of photodynamic therapy or cytoluminescent therapy, then the human or animal is preferably subjected to irradiation 5 to 100 hours after administration of the chlorin e4 sodium, preferably 6 to 72 hours after administration, preferably 24 to 48 hours after administration.
If the method is a method of photodynamic diagnosis, then the human or animal is preferably subjected to irradiation 3 to 60 hours after administration of the chlorin e4 sodium, preferably 8 to 40 hours after administration.
Preferably the irradiation is electromagnetic radiation with a wavelength in the range of from SOOnm to 1 000nm, preferably from óOOnrn to 7YOnni. In one embodiment of the present invention, two sources of electromagnetic radiation are used (for example a laser light and an LED light), one source with a wavelength in the range of from 600nm to 690nm, preferably about 660nm, the other source with a wavelength in the range of from 700nm to 790nm, preferably about 760nm. In another embodiment of the present invention, two sources of electromagnetic radiation are used (for example a laser light and an LED light), both sources adapted to provide irradiation with a wavelength in the range of from 600nm to 690nm, preferably about 660nm, and irradiation with a wavelength in the range of from 700nm to 790nm, preferably about 760nm.
Preferably the human or animal is a human. -19-
Brief description of the drawings
Figure 1 shows a modified jablonski diagram for a typical photosensiti2er, outlining the principle photophysical processes of interest. )
Figure 2 depicts schematically the metalation and demetalation of a porphyri ring.
Figure 3 depicts schematically the reaction of l,3-diphenylisohenzofuran (DPIBF) Figure 4 shows the absorption spectrum of a chlorin e4 sodium solution (about 10 1iM) in ethanol.
Figure 5 shows the ahsorptton spectrum of a chlorin e4 sodium solution (about 10 tiM) in water.
Figure 6 shows the ahsorptton spectrum of a chlorin e4 sodium solution (about 10 tiM) in water with 0.2 M detergent sodium dodecyl sulphate (SDS).
Figure 7 shows the fluorescence spectrum of a chlorin e4 sodium solution (about 10 tN1) in ethanol. Excitation wavelength was 403 nm; the absorbance at this wavelength was 0.10; cuvette size 1cm.
Figure 8 sho\vs the fluorescence spectrum of a chlorin e4 sodium solution (about 10 1.d\1) in water. Excitation wavelength was 403 nm; the absorhance at this wavelength was 0.13; cuvette si.e 1 cm.
Figure 9 sho\vs the fluorescence spectrum of a chlorin e4 sodium solution (about 10 1iM) in water with 0.2 M detergent sodium dodecyl sulphate (SDS). Excitation wavelength was 403 nm; the absorbance at this wavelength was 0.13; cuvette si?.e 1 cm.
-20 -Figure 10 shows the fluorescence excitation spectrum of a chlorin e4 sodium solution (about 10 1iM) in ethanol. Fluorescence was measured at 710 nm; the absorbance at 403 nm was 0.15 in 1 cm; the optical path was 0.5 cm.
Figure 11 shows the absorption spectra of a solution of DPI]JF and chlorin e4 sodium in ethanol before and 14 minutes after irradiation by red light (660 tim).
Figure 12 shows kinetic traces (1) and the spectrum (2) of singlet oxygen phosphorescence after pulsed laser excitation of chlorin e4 sodium in ethanol.
Figure 13 shows kinetic traces (1) and the spectrum (2) of singlet oxygen phosphorescence after pulsed laser excitation of chlorin e4 sodium in water.
Figure 14 shows kinetic traces of singlet oxygen phosphorescence after pulsed laser excitation of chlorin e4 sodium in water with 0.2 M detergent sodium dodecyl sulphate (SDS).
Detailed description of the invention
Metal insertion into the central part of a porphyrin or chlorin ring is known as metalation and the general chemical process is depicted in Figure 2. Porphyrins and chlorins can form complexes with a wide variety of metals (M). These metal complexes not only protect the inner nitrogen atoms from electrophiic reagents and strong bases, hut also have a pronounced effect on the reactivity of the macrocycles.
A common geometry of these coniplexes is octahedral, with the metal ions occupying the centre of the N4 porphyrin plane and the metal ligands being in trans positions (Figure 2).
Chlorin e4 has nine side chains, two of which carry a carhoxylic acid moiety. These carboxylic acid moieties can form salts with a wide variety of metals (M). -21 -
Experimental details Example -general synthetic details Method 1: (hl5-lrnmol of chiorin e4 is dissolved in 60-lOOmi of methanol. To this solution, I 5-20m1 of sodium hydroxide. (31\I water solution) is added. The mixture is stirred until the synthesis is complere after about 6 hours. Then the mixture is filtered through a 45im Millipore filter. The product is purified by flash chromatography with a methanol mobile phase. Then the solutioti is distilled and lyophiliaed. In a preferred embodiment of the ies invention, the reaction is carried out at a temperature in the range of 25-60°C.
Method 2: 0.15-Immol of chlorin e4 is dissolved in 60-lOOmI of methanol. To this solution, 15-20m1 of sodium hydroxide (3M water solution) is added. Separately, 5- 1 2mmol of thiamine pyrophosphate is dissolved in 40-6Gm] of water, and the latter solution is added to the previous one. The mixture is stirred until the synthesis is complete after about 6 hours. Then the mixture is filtered through a 45jim Millipore filter. The product is purified by Hash chromatography with a methanol mobile phase. Then the solution is distilled and lyophilized. In a preferred embodiment of the preseit invention, the reaction is carried out at a temperature in the range of 25-60°C.
Example -synthesis of chlorin e4 sodium Method I: 0.Smmol (276mg) of chlorin e4 was dissolved in 60m1 of methanol, and the solution was stirred slowly for 10 minutes at 40°C. 1 5m1 of sodium hydroxide (3M water solution) was added, and stirring was continued for a further 6 hours at 60°C. Then the reaction mixture was filtered through a 45jim Millipore filter. The product was purified by flash chromatography on a dry silica gel column using a methanol mobile phase. Then the solution \vas reduced in volume on a rotary evaporator and the product was isolated as a dry powder by lyophiization in 85°/o yield.
-22 -Method 2: 0.Sniniol (276mg) of chlorin e4-was dissolved in 6Onil of methanol, and the solution was stirred siowly for 10 minutes at 40°C. lSml of sodium hydroxide (3M water solution) was added, and stirring was continued for a further 20 minutes.
Separately, ômmol (378mg) of thiamine pyrophosphate was dissolved in 50m1 of water, and the solution was stirred at 60°C. The thiamine pyrophosphate solution was added to the chlorin e4 solution, and the reaction mixture was stirred slowly for 6 hours at 60°C. Then the reaction mixture was filtered through a 45tm Millipore filter. The product was purified by flash chromatography on a dry silica gel column using a methanol mobile phase. Then the solution was reduced in volume on a rotary evaporator and the product was isolated as a dry povder by lvophilization in 85% yield.
Example -in vitro studies The following experiments were carried out to study the absorption and fluorescence spectra of chlorin e4 sodium, the quantum yields of chiorin e4 sodium iluorescence and the photosensitizing ability of chlorin e4 sodium in three systems -solutions in ethanol, pure water and water containing detergent sodium dodecyl sulfate (SDS).
Absorption and Jiuoivscence measuremenis Absorption spectra were recorded using computerized spectrophotometers Hitachi 3400 Gapan) and SF-2000 (Russia). Fluorescence spectra were measured with a computerized spectroiluorimeter Perkin-Elmer MPF-44B. 10 mm \vide quartz cuvettes were used for absorption and fluorescence measurements. Fluorescence was detected at a right angle to the excitation beam. The spectral bandwidth of the monochromator was 3 nm. To avoid fluorescence re-absorption by the pigment molecules, diluted chlorin e4 sodium solutions were used with absorhance at 403 nm which did not exceed 0.2 cm in the 1 cm cuvette. The fluorescence quantum yields (F) were determined using as a reference, solutions of TPPS (m-tetrakis(p-sulfonatophenyl)porphine) in ethanol. According to the literature, the most likely fluorescence quantum yield of TPPS in air-saturated water and ethanol is equal to -23 - 0.08 (TK. Kalyanasundarani and MI. Neuniann-Spallart, Photophysical and redox properties of water soluble porphyrins in aqueous media, J. Phys. Chem., 1982, 86, 5163-5169; and AT. Gradyushko, A.N. Sevchenko, K.N. Solovyov and M.P.
Tsvirko, Energetics of photophysical processes in chlorophyll-like molecules, Photochem. Photohiol., 1970, 11, 387-400). The fluorescence of the samples was excited by the monochromatic light corresponding to the maximum of the Soret bands: 415 nm for TPPS in ethanol and 413 nm for TPPS in water, and 403 nm for chlorin e4 sodium in water and ethanol. The monochromator handwidth was 3 nm.
The fluorescence quantum yields () were calculated using the following equation: = . S (I -i0' ) /( -1O°) 5TPP where TPP is the quantum yield of TPPS fluorescence, S is the square under the fluorescence spectrum of the chlorin e4 sodium sample, is the square under the fluorescence spectrum of TPPS, and D and DTPF are absorbance (optical density) of the chlorin e4 sodium and TPPS respectively at the excitation wavelengths. The /5 obtained results were collated using relative units of intensity of the excited light at the excitation wavelengths. The intensities of the monochromatic light were measured using a cahbrated silicon detector from Optical Power Meter System ThorLahs (Karisfeld, Germany).
Detection of singlet oxygen phosphorescence Singlet oxygen phosphorescence was detected using measurement of infrared phosphorescence at 1270 nni corresponding to the transition of oxygen molecules from the singlet to the triplet state. Phosphorescence was recorded at room temperature with the laser phosphorescence spectrometer described at A.A.
Krasnovsky Jr., Photodynamic action and singlet oxygen, Biofi7ika, 2004, 49, 305- 321; and A.A. Krasnovsky Jr., Singlet oxygen and primary mechanisms of photodynamic therapy and photodynamic diseases, In: Photodynamic therapy at the cellular level, ed. \.13. U2densky, Research Singpost, IKerala, India, 2007, 17-62. For iv excitation, nanosecond pulses of 511 nm radiation from a copper-vapour laser (Troitzk, Physics Institute of the Russian Academy of Science) were employed.
Laser radiation passed additionally through a green light filter SZS-22 (4 mm), -24 -which transmitted laser light and cut off JR laser radiation caused by heating of the laser tube. Pulse duration was 20 ns, Pulse energy varied from 18 to 40 iJ and the pulse repetition rate was 12 kHz. The laser light was collimated on the surface of a 1 cm rectangular quartz cuvette. The diameter of the illuminated spot on the surface of the cell was 5 mm. For kinetic measurements another spectrometer was used without a monochromator. In this case, phosphorescence resulting from the right angle to tile excitation beam was focused on the photocathode of a cooled S-I photornultiplier (FELJ-I 12) through a cut-off IR light filter and an interference filter with the transmission maximum at 1270 rim. The phosphorescence spectra were measured using a MS-SO high throughput grid rnonochroniator. In this case, phosphorescence was focused on the entry slit of this nionochromator. The bandwidth of the mnonochromator corresponded to a 20 nm spectral interval. The monochromatic light was focused on the photocathode of a cooled S-I photomultiplier (JILLJ-83). The photomultiplier signal was registered using time-correlated single photon counting and averaged over many laser pulses. In most experiments, one-channel on time was equal to 81 its. When the pigment bleaching reached l00/u, the solution was replaced hy a fresh one and measurement was continued. As chlorin e4 sodium bleached rather rapidly, the solutions were changed after each 60-180 s irradiation. Reasonable phosphorescent curves were obtained after 10-20 minutes signal accumulation and therefore samples were changed many times. As described previously (D.A. Butorina, A.A. Krasnovsky Jr.
and A.V. Priez7ev, Investigation of the kinetic parameters of singlet molecular oxygen in aqueous porphyrin solutions, Influence of detergents and the quencher sodium azide, Biofizika, 2003, 48, 189-196; A.A. Krasnovsky Jr., Luminescence and photochemical studies of singlet oxygen photonics, J. Photochem. Photohiol. A: Chem., 2008, 196, 210-218; and N. Kuznetsova, I). Makarov, 0. Yuzhakova, A. Strizhakov, Y. Rounrhal, L. LJlanova, A. Krasnovsky and 0. Kaliya, Photophysical properties and photodynamic activity of octacationic oxotitanium(IV) phthalocyanines, Photochemical Photohiological Sciences, 2009, 8, 1724-1733), for computer analysis the following two-exponential equation was used: 1(t) = 1 -[e'xp( -kdECfl, . t) -exp(-k, -t)] + n where aecay and krise are the rate constants of the decay and rise phases of the phosphorescence curves after a laser pulse, n is the off noise of the photomultiplier, -25 -I is the 7ero-tlnle phosphorescence intensity, and 1(t) is the phosphorescence intensity at time t. To reduce contribution of the luminescence of the pigment in the (]uartz cuvette, which was observed shortly after laser pulses, readings were taken starting from 400 ns after laser pulses in ethanol and I pcs in water. In addition, phosphorescence and kinetic traces were measured also from the control chlorin e4 sodium solutions containing high concentration of sodium a2ide, which completely quenched singlet oxygen. This procedure revealed a strong rapidly decaying component of delayed luminescence in the chlorin e4 sodium solutions, which was not so easily quenched by sodium azide. The luminescent curves obtained from the control solutions were approximated by exponentials and subtracted from the experimental kinetic traces obtained for the chlorin e4 sodium solutions where sodium azide was not add ed.
For measurements, Origin 6.0 software was used. This software operates using the least-square approximation method. Origin allowed variation of the parameters l, kdCC,Y, kri,c and n in order to obtain their values corresponding to the minimum coefficient x2. In chlorin e4 sodium solutions, measurements always yielded kdccay, which was somewhat shorter than in the reference solutions of TPPS in the same solvents. Tn the solvents used in this study, the lifetime of singlet oxygen, which is responsible for kdecav, is independent of the gn1s. Therefore this result indicates that "the azide control" does not allow to fully eliminate the rapidly decaying component from the overall decay curves. It is possible that luminescence responsible for this component is partially quenched by sodium azide. In order to eliminate the error caused by this effect, for final measurements of phosphorescent curves in chlorin e4 sodium solutions, fixed kjccay obtained in the TPPS solutions was used. In this case as Origin indicated, the correlation coefficient R2 was not less than 98°/o and error of k1.1, determination was less than 1 5% in all solvents.
The quantum yields (A) of singlet oxygen photogeneration by chlorin e4 sodium were determined from comparison of the overall singlet oxygen PhosPhoresce1ce intensities in the chlorin e4 sodium solutions and the reference solutions of TPPS in the same solvents. According to the literature, the most probable values of quantum yields of singlet oxygen photogeneration by TPPS are 0.6 in water and 0.7 in ethanol and detergent containing water (F'. Wilkinson, W.P. Ilelman and A.B. -26 -
Ross, Quantum yields of the photosensitl7ed formation of the lowest electronically excited singlet states of molecular oxygen, J. Phys. Chem. Ref. Data, 1993, 22(2), 113-262; and C. Tanielian, C. Wolf and M. Lsch, Singlet oxygen production in water: Aggregation and charge transfer effects, J. Phys. Chem., 1996, 100, 6555- 6560). The overall phosphorescence intensity was calculated by integrating the phosphorescence kinetic traces. The absorbance of the pigment solutions at 511 nm was usually about 0.1-0.2 in 5 mm cuvette. This corresponded to a pigment concentration equal to about 20 tM.
Dc/cc/ion ojsingle/ oxygen n.th chemical confuga/es The second method of singlet oxygen detection was based on photosensitized oxygenation of the singlet oxygen conjugate 1,3-diphenylisohen2ofuran (DPIB1') (Acros Organics, United Kingdom). DPIB] chemically hinds to two singlet oxygens (10,) (Figure 3). This method was applied to chlorin e4 sodium solutions in ethanol. The major absorption band of I)PIBF is located at 41 4-415 rim. The molar absorption coefficient in this maximum, EDPIBF, is known to be 23500 Ni'cni'.
Tested solutions were irradiated by the monochromatic light from a xenon lamp using the excitation system of the spectrofluorimeter Perkin-Elmer MPF-4413, the spectral width of the monochromator bandwidth corresponding to 5 nm. Radiant power was measured using the calibrated detector ThorLabs PM-tOO (Germany).
The singlet oxygen quantum yields (D) were calculated according to the equation: V.N -rr
I
hv(l-i) where ADDPIBF is the reduction in the optical density of DPIIJF at 414 nm during the irradiation time, SDP1BF is the molar absorption coefficient of DPIB1' at 414 nm, 1 is the optical path equal to 1 cm, V is the volume of tested solutions (usually 1.2- 1.5 nil), NA is the Avogadro constant, 111r is the radiant power (in W) of the monochromatic light from the excitation system of the Perkin-Elmer spectrofluorimeter that includes the xenon lamp and the excitation monochromator with the bandwidth corresponding to the 3 nni wavelength interval, h is the energy -27 -of one photon in J, (1-T) is the absorption factor of the tested so] utions, t1 is the irradiation time in seconds, and, is the fraction of 10 molecules which is captured by DPIBE in the studied solutions. This parameter was calculated using known kinetic equations for singlet oxygen consumption by chemical conjugates and the rate constant of singlet oxygen reaction with DPIIJF equal to l0 M1s1 (see A.A. Krasnovsky Jr., Y.V. Roumbal and A.A. Strizhakov, Rates of production upon direct excitation of molecular oxygen by 1270 nm laser radiation in air-saturated alcohols and micellar aqueous dispersions, Chem. Phys. Lett., 2008, 458, 193-199; and references therein).
Rcu11s Absorption spectra of chlorin e4 sodium in ethanol, pure water and water containing detergent sodium dodecyl sulfate (SDS) are shown in Figures 4-6. The major absorption bands are]isted in Tah]e 1. The strongest are the Soret band at 403 rim and the red band at 654-662 run. Ana]ysis of the absorption spectra suggests that chlorin e4 sodium was mostly monomeric in all solvents. In water having no detergent, the red absorption maximum was s]ight]y shifted to the shorter wave]ength region (from 662 to 654 nm) and a weak shou]der at about 665-670 was seen. Tn addition, the observed absorbance in the green region was increased compared to ethanol and detergent containing solutions. These data indicate that the solution in water having no detergent may contain aggregated (dimeric and ohgomeric) molecules of chlorin e4 sodium, which disaggregate in the presence of the detergent.
Solvents Absorption maxima Fluorescence maxim __________________ (nm ± 1 nm) (nm ± 1 nm) Ethanol 403, 504, 606, 662 666, 720 Water 402, 504, 602, 654 637, 710 Water + 0.2 M SDS 403, 504, 608, 662 665, 720 Table I -Positions of the major absorption and ti uorescence bands of ch]orin e4 sodium so] utions Fluorescence measurements supported this assumption (Figures 7-9). The JO fluorescence spectra were rather similar in ethanol and SDS containing water. -28 -
Figure 10 shows the excitation spectrum of chiorin e4 sodium flaorescence in ethanol. It is seen that it practically coincides with the absorption spectrum of this pigment. This observation indicates that fluorescence belongs to cifiorin e4 sodium.
In water without SDS, the fluorescence maximum was shifted to shorter wavekngths and a shoulder at ahout 710 nm became markedly scronger than in ethanol. The fluorescence quantum yield was found to be highest in ethanol, slightly less in SUS containing water and the smallest in water without SUS. These data indicate that aggregation of chlorin e4 sodium occurs in water. However, the chlorin e4 sodium fluorescence quantum yield was still high iii water without 51)5, showing that an appreciable amount of monomeric ch]orin e4 sodium molecules are present in aqueous so] utions without (letergent. These experiments show that chlorin e4 sodium is a highly fluorescent pigment anJ emits a large quantity of photons. Hence chlorin e4 sodium can he used efficiently as a fluorescent pigment for phorodynamic diagnosis.
Singlet oxygen generation was studied in ethanol solutions using both chemical singlet oxygen conjugate DPIB] and measurement of chlorin e4 sodium photosensitized phosphorescence of singlet oxygen at 1270 nni. Figure ii illustrates the experinient with I)PIBF. The absorption maxinium of DPIBF lies at 420 ni-n. Tt is seen froni Figure 11 that irradiation of an ethanol solution containing both chlorin e4 sodium and DPIBF' by red light (660 nm), which is absorbed by chlorin e4 sodium but not by DPIBF, caused bleaching of the DPIBF maximum at 420 nm. This effect results from reaction of DPIB]F with singlet oxygen, which is formed upon irradiation of chlorin e4 sodium. The quantum yield of singlet oxygen generation ohtained from this experiment was shown to he 0.68 ± 0.05 in ethanol.
TCinetic traces of chlorin e4 sodium photosensitiied phosphorescence of singlet oxygen after laser pulses are shown in Figures 12-14. Table 2 summarizes kinetic parametets of the phosphorescent curves. The rise time reflects thc rate of sing'et oxygen generation by triplet pigment niolecules. Tt corresponds with the lifetime of the pignient triplet state in air-saturated pigment solution. In ethanol, the rise time was equal to 300 us. The decay time corresponds with the singlet oxygen lifetime in ethanol (13.5 s). The singlet oxygen quantum yield in ethanol determined using these kinetic curves was equal to 0.63 ± 0.05, which is close to that obtained using -29 -DPTBF. Thus both methods provided similar results. Table 2 indicates that chlorin e4 sodium is a potent photosensitizer of singlet oxygen formation in alcoholic as well as aqueous systems, though in water \vithOUt SDS the photosensitiaing activity was lower than in ethanol. This effect may have been due to partial aggregation of pigment molecules, which is known to lead to the loss of photosensitizing activity.
These experiments show that chlorin e.4 sodium has strong photosensitizing ability in organic solvent (alcohol) and in aqueous media, with a high singlet oxygen quantum yield. Hence chlorin e4 sodium can he used efficiently in photodvnamic therapy.
Solvents Rise time, ps Decay time, is Ethanol 0.3 ± 0.3 13.5 ± 0.3 Water 1.3 ± 0.4 3.3 ± 0.3 Water + 0.2 M SDS 1.2 ± 0.3 3.35 ± 0.3 Table 2 -Kinetic parameters of photosensitized singlet oxygen phosphorescence in air saturated chlorin e4 sodium solutions
Conclusion
Chlorin e4 sodium shows strong fluorescence and strong photosensitiaing ability in organic solvent (alcohol) and in aqueous media. In xvater, the chlorin e4 sodium photosensitizing activity decreases due to aggregation of pigment molecules, hut is still high. Addition of detergent causes disaggregation and an increase of both fluorescence and photosensitizing ability. This shows that chlorin e4 sodium is active in both hydrophilic and aqueous media. Therefore this pigment is promising for application in photodynamic medicine.
Example -in vivo studies The following cancer patients were treated successfully with chlorin e4 sodium. -30-
Fxamhle / A 70 year old female patient with invasive ductile breast cancer and lymph node metastases in the right arm pit, was treated successfully. Prior to treatment a large cancer mass in the right breast was observed and a small cancer mass in the right attn pit. The treatment consisted of three courses. For each course, five doses of 62.5-137.5mg chlorin e4 sodium were administered orally over the course of eight days. 24-48 hours after each oral dose of chlorin e4 sodium, the patient was treated with laser and LED light having a wavelength of 660nm and 7óOnm. /0
Following treatment, (loppler ultrasounJ analysis showeJ that the large cancer mass in the breast showed almost no vascalarity, no blooJ vessels leading to it. The c2nccr mass h2d not reduced in size, however, the outline of the mass was solid and smooth, indicating an inactive, non-growing turnout. The smaller lymph node cancer mass also showed almost no vascularity and it had reduced in sue froni 1.9cm to 1cm.
flxarnhle 2 A 62 year old male patient with naso pharyngeal carcinonia with extension to the lymph node in the left neck, was treated successfully. The treatment consisted of three courses. For each course, five doses of 62.5-187.5mg chlorin e4 sodium were administered orally over the course of eight days. 24-48 hours after each oral dose of chlorin e4 sodium, the patient Was treated with laser and LED light having a wavelength of 660nm and 760nm.
Immediately following treatment, a biopsy of the treated lymph node of the neck showed a henign or non-cancerous lymph node, no cancer cells were detected. This was confirmed by another biopsy ten months after treatment. A comparison of CT scans, obtained one nionth before and ten nionths after treatment, showed no spread of tumour and that the size of the tumour was reduced. -31 -
Fxamhle I A 71 year old male patient with advanced metastatic kidney disease with metastases in the gall bladder, liver and lung, was treated successfully. The treatment consisted of three courses. For each course, five doses of 62.5-187.5mg chlorin e4 sodium were administered orally over the course of eight days. 24-48 hours after each oral dose of chlorin e4 sodium, the patient was treated with laser and LED light having a wavelength of 660nm and 760nm.
CT and PET scans, obtained just before treatment and two months, three months, live months and 15 months after treatment, showed that throughout the lxtflU's body sonic tunioLlrs disappeared altogether and the remaining tuniours reduced in size. No further metastasis was observed.
flxarnhle 4 A 21) year old female patient with stage I\/B Hodgkin's lymphoma with cancer to the liver, lymphatic system, spleen, lung and bones, was treated successfully. The treatment consisted of three courses. For each course, five doses of 62.5-1 87.5mg chlorin e4 sodium were administered orally over the course of eight days. 24-48 hours after each oral dose of chloriti e4 sodium, the patient was treated with laser and LED light having a wavelength of 660nm and 760nm.
CT scans showed that in the areas of the patient's body that were treated with laser and LED light so far, some turnours disappeared altogether and some tumours reduced in sue.
Exam/e 5 A 82 year old male patient with lung cancer was treated successfully. The treatment consisted of one course of five doses of 62.5-187.5mg chlorin e4 sodium administered orally over the course of eight days. 24-48 hours after each oral dose -32 -of chlorin e4 sodium, the patient was treate(l with laser an(l LET) light having a wavelength of 660nm and 760nm.
Three months after treatment, the patient was coughing up blood and tumour tissue. A CT scan showed tumour breakdown.
Examble 6 A 46 year old male patient with lung cancer was treated successfully. The treatment consisted of three courses. For each course, five (loses of 62.5-187.5mg chlorin e4 sodium were administered orally over the course of eight (lays. 24-48 hours after each oral (lose of chlorin e4 sodium, the patient was treated with laser and LED light having a wavelength of ñáOnm and 7GOnm.
A CT scan, obtained immediately after the last treatment course, showed complete recovery from lung cancer.
It will he understood that the present invention has been described above by way of example only. The examples are not intended to limit the scope oF the invention.
Various modifications and embodiments can he made \vithout departing from the scope and spirit of the invention, which is defined by the following claims only.
Claims (1)
- -33 -Claims 1. Chlorin e4 sodium.2. Chiorin e4 sodium, comprising chiorin e4 and sodium in a ratio of 1:2.3. Chiorin e4 sodium, having the structure: (I ( \ [H]2 [Na]2 (:02 C02- 4. Chlorin e4 sodium, having the structure: ( / ( SNH U''''U(:02 Na' (:02 Na -34 - 3. A process of preparing chiorin e4 sodium, comprising the step of reacting chiorin e4 with a sodium compound.6. The process of claim 5, wherein the cifiorin e4 sodium obtained comprises chiorin e4 and sodium iii a ratio of 1:2.7. The process of c'aim 5 or 6, wherein the chiorin e4 sodium obtaitied has the structure: ( / ( I'I2 II2 (02 co /0 8. The process of any one of claims 3 to 7, wherein the chioriri e4 sodium obtained has the structure: (I ( Nil II'.CO2 Na' CO2 Na -35 - 9. The process of any one of claims 5 to 8, wherein the sodium compound is sodium hydroxide.10. The process of any one of claims 5 to 9, wherein chlorin e4 is reacted with the sodium compound in the presence of a base.11. The process of claim 10, wherein the base is an amine base.12. The process of claim 11, wherein the amine base is thiamine pyrophosphate.13. The process of any one of claims 5 to 12, wherein chiorin e4, the sodium compound and the optional base are used in a molar ratio of 0.15-1 45-60 0-12.14. The process of any one of claims 5 to 13, wherein chlorin e4 is reacted with the sodium compound in the presence of a solvent.15. The process of claim 14, wherein the solvent is selected from methanol, ethanol, water or a mixture thereof.16. The process of any one of claims 5 to 15, wherein the reaction is carried out at a temperature of 60°C or less.17. The process of any one of claims 5 to 16, wherein the reaction is carried out over I to 12 hours.18. The process of any one of claims 5 to 17, wherein the chlorin e4 sodium obtained is purified by filtering.19. The process of any one of claims 5 to 18, wherein the chlorin e4 sodium obtained is purified by chromatography.20. Chlorin e4 sodium preparable by a process of any one of claims 5 to 19.-36 - 21. Chlorin e4 sodium when prepared by a process of any one of claims 5 to 19.22. The chlorin e4 sodium of any one of claims 1-4 or 20-21, for use in photodynamic therapy or cytoluminescent therapy. )23. The chlorin e4 sodium of any one of claims 1-4 or 20-22, for the treatment of atherosckrosis; multiple sclerosis; diabetes; diabetic retinopathy; arthritis; rheumatoid arthritis; a fungal, viral, chlanwdial, bacterial, nanobacterial or parasitic infectious disease; HIV; Aids; infection with sars virus, Asian (chicken) flu virus, herpes simplex or herpes zoster; hepatitis; viral hepatitis; a cardiovascular disease; coronary artery stenosis; carotid artery stenosis; intermittent claudication; a dermatological condition; acne; psoriasis; a disease characterised by begin or malignant cellular hyperproliferation or by areas of neovascularisation; a benign or malignant tumour; early cancer; cervical dysplasia; soft tissue sarcoma; a germ cell tumour; retinoblastonia; age-related rnacular degeneration; Hodgkin's lymphonia; or cancer of the blood, prostate, cervix, uterus, vaginal or other female adnexa, breast, naso-pharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, stomach, bile duct, intestine, colon, colorectum, rectum, bladder, ureter, kidney, liver, gall bladder, spleen, brain, lymphatic system or bones.24. The chlorin e4 sodium of any one of claims 1-4 or 20-23, for the treatment of a disease characterised by begin or nullgnant cellular hyperproliferation or by areas of neovascularisation.25. The chlorin e4 sodium of any one of claims 1-4 or 20-24, for the treatment of a benign or malignant tumour.26. The chlorin e4 sodium of any one of claims 1-4 or 20-25, for the treatment of early cancer; cervical dysplasia; soft tissue sarcoma; a germ cell tumour; retinohlastoma; age-related niacular degeneration; Hodgkin's lymphoma; or cancer of the blood, prostate, cervix, uterus, vaginas or other fenul.e adnexa, breast, naso-pharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, -3/ -stomach, bile duct, intestine, colon, col orectum, rectum, bladder, ureter, kid ney, liver, gail bladder, spleen, brain, lymphatic system or bones.27. The chlorin e4 sodium of any one of claims 1-4 or 20-21, for use in photodynamic diagnosis.28. The chlorin e4 sodium of claim 27, for the detection of atherosclerosis; multiple sclerosis; diabetes; diabetic retinopathy; arthritis; rheumatoid arthritis; a fungal, viral, chlamydial, bacterial, nanobacterial or parasitic infectious disease; HIV; Aids; infection with sars virus, Asian (chicken) flu virus, herpes simplex or herpes 7oster; hepatitis; viral hepatitis; a cardiovascular disease; coronary artery stenosis; carotid artery stenosis; intermittent claudication; a derniatological condition; acne; psoriasis; a disease characterised hy begin or malignant celJular hyperproliferation or by areas of neovascularisation; a benign or malignant tumour; early cancer; cervical dysplasia; soft tissue sarcoma; a germ cell tumour; retinoblastonia; age-related rnacular degeneration; Hodgkin's lymphorna; or cancer of the blood, prostate, cervix, uterus, vaginal or other female adnexa, breast, naso-pharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, stomach, bile duct, intestine, colon, colorectuni, rectum, bladder, ureter, kidney, liver, gall bladder, spleen, brain, lymphatic system or bones.29. The chJorin e4-sodium of claim 27 or 28, for the detection of an area that is affected by begin or malignant cellular hyperproliferation or by neovascularisation.30. The chlorin e4 sodium of any one of claims 27 to 29, for the detection of a begin or malignant tumour.31. The chlorin e4 sodium of any one of claims 27 to 30, for the detection of early cancer; cervical dysplasia; soft tissue sarcoma; a germ cell tumour; retinoblastoma; age-related niacular degeneration; Hodgkin's lymphonia; or cancer of the blood, prostate, cervix, uterus, vaginal or other fenule adnexa, breast, naso-pharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, -38 -stomach, bile duct, intestine, colon, col orectuni, rectum, bladder, ureter, kid ney, liver, gail bladder, spleen, brain, lymphatic system or bones.32. The chlorin e4 sodium of any one of claims 27 to 31, for the fluorescent or phosphorescent detection of the said diseases.33. The chiorin e4 sodium of claim 32, for the fluorescent or phosphorescent detection and quantification of the said diseases.34. The chlorin e4 sodium of any one of claims 22 to 33, wherein the chlorin e4 sodium is adapted for administration simultaneous with or prior to administration of irradiation or sound.35. The chiorin e4 sodium of claim 34, wherein the chiorin e4 sodium is adapted for administration prior to administration of irradiation.36. The chlorin e4 sodium of claim 35, wherein the chlorin e4 sodium is for use in photodynamic therapy or cytolum inescent therapy, and wherein the chlorin e4 sodium is adapted for administration 5 to 100 hours before the irradiation.37. The chlorin e4 sodium of claim 35, wherein the chlorin e4 sodium is for use in photodynatnic diagnosis, and wherein the chlorin e4 sodium is adapted for administration 3 to 60 hours before the irradiation.38. The chlorin e4 sodium of any one of clainm 34 to 37, wherein the irradiation is electromagnetic radiation with a wavelength in the range of from SOOnrn to 1 000nm.39. A pharmaceutical composition comprising chlorin e4 sodium of any one of claims 1-4 or 20-38 and a pharmaceutically acceptable carrier or diluent.40. The pharmaceutical composition of claim 39, for use in photodynamic therapy or cytoluntinescent therapy.-39 - 41. The pharmaceutical composition of claim 39 or 40, for the treatment of atherosclerosis; multiple sclerosis; diabetes; diabetic retinopathy; arthritis; rheumatoid arthritis; a fungal, viral, chiarnydial, bacterial, nanobacterial or parasitic infectious disease; I-IIV; Aids; infection with sars virus, Asian (chicken) flu virus, herpes simplex or herpes zoster; hepatitis; viral hepatitis; a cardiovascular disease; corollary artery stenosis; carotid artery stenosis; intermittent claudication; a dermatological condition; acne; psoriasis; a disease characterised by begin or malignant cellular hyperproliferation or by areas of neovascularisation; a benign or malignant turnout; early cancer; cervical Jysplasia; soft tissue sarcoma; a genii cell turnout; retinoblastorna; age-relateJ rnacular degeneration; Tlodgkin's lvrnphorna; or cancer of the blood, prostate, cervix, uterus, vaginal or other female adnexa, breast, naso-pharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esoph2gus, stomach, bile duct, intcstine, colon, colorectum, rectum, hl2ddcr, ureter, kidncy, liver, gall bladder, spleen, brain, lymphatic systeni or bones.42. Thc pharmaceutical composition of any one of claims 39 to 41, for the treatment of a disease characterised by begin or malignant cellular hyperproliferatton or by areas of neovasculari sation.43. The pharmaceutical composition of any one of claims 39 to 42, for the treatment of a benign or malignant tumour.44. The pharmaceutical composition of any one of claims 39 to 43, for the treatment of early cancer; cervical dysplasia; soft tissue sarcoma; a germ cell tumour; retinoblastorna; age-related niacular degeneration; Hodgkin's lymphonia; or cancer of the blood, prostate, cervix, uterus, vaginal or other female adnexa, breast, pharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, stomach, bile duct, intestine, colon, colorectum, rectum, bladder, ureter, kidney, liver, gall bladder, spleen, brain, lvmphtic systeni or bones.45. The pharmaceutical composition of claim 39, for use in photodynamic diagnosis.-40 - 46. The pharmaceutical composition of claim 45, for the detection of atherosclerosis; multiple sclerosis; diabetes; diabetic retinopathy; arthritis; rheumatoid arthritis; a fungal, viral, chiarnydial, bacterial, nanobacterial or parasitic infectious disease; I-IIV; Aids; infection with sars virus, Asian (chicken) flu virus, herpes simplex or herpes zoster; hepatitis; viral hepatitis; a cardiovascular disease; corollary artery stenosis; carotid artery stenosis; intermittent claudication; a dermatological condition; acne; psoriasis; a disease characterised by begin or malignant cellular hyperproliferation or by areas of neovascularisation; a benign or malignant turnout; early cancer; cervical Jysplasia; soft tissue sarcoma; a gemi cell turnout; retinoblastorna; age-relateJ rnacular degeneration; Tlodgkin's lvrnphorna; or cancer of the blood, prostate, cervix, uterus, vaginal or other female adnexa, breast, naso-pharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, csoph2gus, stomach, bile duct, intcstine, colon, colorectum, rectum, hl2ddcr, ureter, kidncy, liver, gall bladder, spleen, brain, lymphatic systeni or bones.47. Thc pharmaceutical composition of claim 45 or 46, for thc detection of an area that is affected by begin or malignant cellular hyperproliferation or by neovascularisat ion.48. The pharmaceutical composition of any one of claims 43 to 47, for the detection of a begin or malignant tumour.49. The pharmaceutical composition of any one of claims 45 to 4, for the detection of early cancer; cervical dysplasia; soft tissue sarcoma; a germ ccli tumour; retinohlastoma; age-related niacular degeneration; Hodgkin's lymphonia; or cancer of the blood, prostate, cervix, uterus, vaginal or other female adnexa, hrcast, naso-pharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, stomach, bile duct, intestine, colon, colorectum, rectum, bladder, ureter, kidney, liver, gall bladder, spleen, brain, lvmphtic systeni or bones.50. The pharmaceutical composition of any one of claims 43 to 49, for the fluorescent or phosphorescent detection of the said diseases. -41 -51. The pharmaceutical composition of claim 50, for the fluorescent or phosphorescent detection and cluantification of the said diseases.52. The pharmaceutica' composition of any one of claims 39 to 51, wherein the pharmaceutical composition is adapted for administration simultaneous with or prior to administration of irradiation or sound.53. The pharmaceutical composition of claim 52, wherein the pharmaceutical composition is adapted for administration prior to administration of irradiation.54. The pharmaceutical composition of claim 53, wherein the pharmaceutical composition is for use in photodynamic therapy or cytouminescent therapy, and wherein the pharmaceutical composition is adapted for administration 5 to 100 hours before the irradiation.55. The pharmaceutical composition of claim 53, wherein the pharmaceutical composition is for use in photodynamic diagnosis, and wherein the pharmaceutical composition is adapted for administration 3 to 60 hours before the irradiation.56. The pharmaceutica' composition of ally one of claims 52 to 55, wherein the irradiation is electromagnetic radiation with a wavdength in the range of from SOOnm to l000nm.57. The pharmaceutica' composition of any one of claims 39 to 56, wherein the Pharmaceutical composition is in a form suitable for oral, parental (including intravenous, subcutaneous, intramuscu'ar, intradernlal, intratrachea, intraperitonea, intraarticular, intraahdominal, intracranial and epidural), transdermal, airway (aerosol), rectal, vaginal or topical (including huccal, mucosal and sublingual) administration.58. The pharmaceutical composition of claim 57, wherein the pharmaceutical composition is in a form suitable for oral administration.-42 - 59. The pharmaceutical composition of claim 58, wherein the pharmaceutical composition is provided in the form of a tablet, capsule, hard or soft gelatine capsule, caplet, troche or lozenge, as a powder or granules, or as an aqueous solution, suspension or dispersion.60. The pharmaceutical composition of claim 58 or 59, wherein the pharmaceutical composition is in a form suitable for providing 0.01 to 10 mg/kg/day of the chlorin e4 sodium.61. The pharmaceutical composition of claim 57, wherein the pharmaceutical composition is in a form suitable for parental administration.62. The pharmaceutical composition of claim 61, wherein the pharmaceutical composition is in a form suitable for intravenous administration.63. The pharmaceutical composition of claim 61 or 62, wherein the pharmaceutical composition is an aqueous solution or suspension having a pH of from 6 to 8.5.64. Use of chlorin e4 sodium of any one of claims 1-4 or 20-38 in the manufacture of a medicament for the treatment of atherosclerosis; multiple sclerosis; diabetes; diabetic retinopathy; arthritis; rheumatoid arthritis; a fungal, viral, chlamydial, bacterial, nanobacterial or parasitic infectious disease; Hill; Aids; infection with sars virus, Asian (chicken) flu virus, herpes simplex or herpes zoster; hepatitis; viral hepatitis; a cardiovascular disease; coronary artery stenosis; carotid artery stenosis; intermittent claudication; a dermatological condition; acne; psoriasis; a disease characterised by begin or malignant cellular hyperproliferation or by areas of neovascularisation; a benign or malignant tumour; early cancer; cervical dysplasia; soft tissue sarcoma; a germ cell tumour; retinohlastoma; age-related macular degeneration; hodgkin's lymphoma; or cancer of the blood, prostate, cervix, uterus, vaginal or other female adnexa, breast, naso-pharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, stomach, bile duct, intestine, colon, -43 -colorectum, rectum, bladder, ureter, kidney, liver, gall bladder, spleen, brain, lymphatic system or bones.65. Use of chlorin e4 sodium of any one of claims 1-4 or 20-38 in the manufacture of a phototherapeutic agetit for use in photodynamic therapy or cytolunnnescent therapy.66. The use of claim 65, wherein the phototherapeutic agent is for the treatment of atherosclerosis; multiple sclerosis; diabetes; diabetic retinopathy; arthritis; rheumatoid arthritis; a fungal, viral, chlaniydial, bacterial, nanohacterial or parasitic infectious disease; TiflT; Aids; infection with sars virus, Asian (chicken) flu virus, herpes simplex or herpes zoster; hepatitis; viral hepatitis; a cardiovascular disease; coronary artery stenosis; carotid artery stenosis; intermittent claudication; a dermatological condition; acne; psoriasis; a disease characterised by begin or malignant cellular hyperproliferation or by areas of neovascularisation; a benign or malignant tumour; early cancer; cervical dysplasia; soft tissue sarcoma; a germ cell tumour; retinohlastoma; age-related macular degeneration; Hodgkin's lymphoma; or cancer of the blood, prostate, cervix, uterus, vaginal or other female adnexa, breast, naso-pharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, stomach, bile duct, intestine, colon, colorectum, rectum, bladder, ureter, kidney, liver, gall bladder, spleen, brain, lymphatic system or bones.67. The use of any one of claims 64 to 66, wherein the medicament or the phototherapeutic agent is for the treatment of a disease characterised by begin or malignant cellular hyperproliferation or by areas of neovascularisation.68. The use of any one of claims 64 to 67, wherein the medicament or the phototherapeutic agent is for the treatment of a begin or malignant tumour.69. The use of any one of claims 64 to 68, wherein the medicament or the phototherapeutic agent is for the treatment of early cancer; cervical dysplasia; soft tissue sarcoma; a germ cell tumour; retinoblastoma; age-related macular degeneration; hodgkin's lymphoma; or cancer of the blood, prostate, cervix, uterus, -44 -vaginal or other female adnexa, breast, naso-pharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, stomach, bile duct, intestine, colon, colorectum, rectum, bladder, ureter, kidney, liver, gall bladder, spleen, brain, lymphatic system or bones. )70. Use of chlorin e4 sodium of any one of claims 1-4 or 20-38 in the manufacture of a photodiagnostic agent for use in photodvnamic diagnosis.71. The use of claim 70, wherein tile photodiagnostic agent is for the detection of atherosclerosis; multiple sclerosis; diabetes; diabetic retinopathy; arthritis; rheumatoid arthritis; a fungal, viral, chlaniydial, bacterial, nanohacterial or parasitic infectious disease; Thy; Aids; infection with sars virus, Asian (chicken) flu virus, herpes simplex or herpes zoster; hepatitis; viral hepatitis; a cardiovascular disease; coronary artery stenosis; carotid artery stenosis; intermittent claudication; a derrnatological condition; acne; psoriasis; a disease characterised by begin or malignant cellular hyperproliferation or by areas of neovascularisation; a benign or malignant tumour; early cancer; cervical dysplasia; soft tissue sarcoma; a germ cell tumour; retinoblastonia; age-related rnacular degeneration; Hodgkin's lymphoma; or cancer of the blood, prostate, cervix, uterus, vaginal or other female adnexa, breast, naso-pharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, stomach, bile duct, intestine, colon, colorectum, rectum, bladder, ureter, kidney, liver, gall bladder, spleen, brain, lymphatic system or bones.72. The use of claim 70 or 71, wherein the photodiagnostic agent is for the detection of an area that is affected by begin or malignant cellular hyperproliferation or by neovascularisation.73. The use of any one of claims 70 to 72, wherein the photodiagnostic agent is for the detection of a begin or malignant tumour.74. The use of any one of claims 70 to 73, wherein the photodiagnostic agent is for the detection of early cancer; cervical dysplasia; soft tissue sarcoma; a germ cell tumour; retinoblastoma; age-related macular degeneration; I hodgkin's lynlphoma; or -45 -cancer of the blood, prostate, cervix, uterus, vaginal or other female adnexa, breast, naso-pharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, stomach, bile duct, intestine, colon, colorectum, rectum, bladder, ureter, kidney, liver, gail bladder, spleen, brain, lymphatic system or bones. )75. The use of any one of claims 70 to 74, wherein the photodiagnostic agent is for the fluorescent or phosphorescent detection of the said diseases.76. The use of claim 75, wherein the photodiagnostic agent is for the fluorescent or phosphorescent detection and quantification of the said diseases.77. The use of any one of claims 64 to 76, wherein the irnedicanient, the phototherapeutic agent or the photodiagnostic agent is adapted for administration simultaneous with or prior to administration of irradiation or sound.78. The use of claim 77, wherein the medicament, the phototherapeutic agent or the photodiagnostic agent is adapted for administration prior to administration of i r r ad i a do ii.79. The use of claim 78, wherein the rnedicarnent or the phototherapeutic agent is adapted for administration 5 to 100 hours before the irradiation.80. The use of claim 78, wherein the photodiagnostic agent is adapted for administration 3 to 60 hours before the irradiation.81. The use of any one of claims 77 to 80, wherein the irradiation is electromagnetic radiation with a wavelength in the range of from SOOnm to l000nm.82. A method of treating atherosclerosis; multiple sclerosis; diabetes; diabetic retinopathy; arthritis; rheumatoid arthritis; a fungal, viral, chlamydial, bacterial, nanobacterial or parasitic infectious disease; lIlY; Aids; infection with sars virus, Asian (chicken) flu virus, herpes simplex or herpes aoster; hepatitis; viral hepatitis; a cardiovascular disease; coronary artery stenosis; carotid artery stenosis; intermittent -46 -claLidication; a derniatological condition; acne; psoriasis; a disease characterised by begin or malignant cellular hyperproliferation or by areas of neovascularisation; a benign or malignant tumour; early cancer; cervical dysplasia; soft tissue sarcoma; a germ cell tumour; retinoblastoma; age-related macular degeneration; Hodgkin's lymphoma; or cancer of the blood, prostate, cervix, uterus, vaginal or other female adnexa, breast, naso-pharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, stomach, bile duct, intestine, colon, colorectum, rectum, bladder, ureter, kidney, liver, gall bladder, spleen, brain, lymphatic system or hones; the method comprising administering a therapeutically effective amount of chlorin e4 sodiLLni of any one of claims 1-4 or 20-38 to a human or animal in need thereof.83. A method of photodynamic therapy or cytoluniinescent therapy of a human or animal disease, the method comprising administering a therapeutically effective amount of chlorin e4 sodium of any one of claims 1-4 or 20-38 to a human or animal in need thereof.84. The method of claim 83, wherein the human or animal disease is atherosclerosis; multiple sclerosis; diabetes; diabetic retinopathy; arthritis; rheumatoid arthritis; a fungal, viral, chlaniydial, bacterial, nanobacterial or parasitic infectious disease; HIV; Aids; infection with sars virus, Asian (chicken) flu virus, herpes simplex or herpes zoster; hepatitis; viral hepatitis; a cardiovascular disease; corollary artery stenosis; carotid artery stenosis; intermittent claudication; a dermatological condition; acne; psoriasis; a disease characterised by begin or malignant cellular hyperproliferation or by areas of neovascularisation; a benign or malignant tumour; early cancer; cervical dysplasia; soft tissue sarcoma; a germ cell tumour; retinoblastoma; age-related rnacular degeneration; Hodgkin's lyniphoma; or cancer of the blood, prostate, cervix, uterus, vaginal or other female adnexa, breast, naso-pharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, stomach, bile duct, intestine, colon, colorecturn, rectum, bladder, ureter, kidney, liver, gall bladder, spleen, brain, lymphatic system or bones.-47 - 85. The method of any one of claims 82 to 84, wherein the human or animal disease is characterised by begin or malignant cellular hyperproliferation or by areas of neovascularisation.86. The method of any one of cJaims 82 to 85, wherein the human or animal disease is a benign or malignant tumour.87. The method of any one of cJaims 82 to 86, wherein the human or animal disease is early cancer; cervical dyspasia; soft tissue sarcoma; a germ cell tumour; retinohlastoma; age-related niacular degeneration; Hodgkin's lyrnphoma; or cancer of the blood, prostate, cervix, uterus, vaginal or other female adnexa, breast, naso-pharynx, trachea, larynx, bronchi, bronchioles, lung, holl ow organs, esophagus, stomach, bile duct, intestine, colon, colorectum, rectum, bladder, ureter, kidney, liver, gail hladder, spken, brain, lymphatic system or hones.88. A method of photodynaniic diagnosis of a human or animal disease, the method comprising administering a diagnostically effective amount of cEilorin e4 sodium of any one of claims 1-4 or 20-38 to a human or animal.89. The method of claim 88, wherein the human or animal disease is atherosclerosis; muhiple sclerosis; diabetes; diabetic retinopathy; arthritis; rheumatoid arthritis; a fungal, viral, chlaniydial, bacterial, nanobacterial or parasitic infectious disease; HIV; Aids; infection with sars virus, Asian (chicken) flu virus, herpes simplex or herpes zoster; hepatitis; viral hepatitis; a cardiovascular disease; coronary artery stenosis; carotid artery stenosis; intermittent cJaudication; a dermatological condition; acne; psoriasis; a disease characterised by begin or malignant cellular hyperprollferation or by areas of neovascularisation; a benign or malignant tumour; early cancer; cervical dysplasia; soft tissue sarcoma; a germ cell tumour; retinoblastonia; age-related macular degeneration; Hodgkin's lymphoma; or cancer of the blood, prostate, cervix, uterus, vaginal or other female adnexa, breast, naso-pharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, stomach, bile duct, intestine, colon, colorectum, rectum, bladder, ureter, kidney, liver, gall b'adder, spken, brain, lymphatic system or bones.-48 - 90. The method of claim 88 or 89, wherein the human or animal disease is characterised by begin or malignant cellular hyperproliferation or by areas of neovascularisation. )91. The method of ally one of claims 88 to 90, wherein the human or animal disease is a begin or malignant tumour.92. The method of any one of claims 88 to 91, wherein the human or animal disease is early cancer; cervical dysplasia; soft tissue sarcoma; a germ cell tumour; retinoblastoma; age-related niacular degeneration; I Iodgkin's lyniphorna; or cancer of the blood, prostate, cervix, uterus, vaginal or other female adnexa, breast, naso-pharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, stomach, bile duct, intestine, colon, colorectum, rectum, bladder, ureter, kidney, liver, gall bladder, spleen, brain, lymphatic system or bones.93. The method of any one of claims 88 to 92, for the fluorescent or phosphorescent detection of the said diseases.94. The method of claim 93, for the fluorescent or phosphorescent detection and quantification of the said diseases.95. The method of any one of claims 82 to 94, wherein the human or animal is further subjected to irradiation or sound simultaneous with or after the administration of the chlorin e4 sodium.96. The method of claim 95, wherein the human or animal is subjected to irradiation after the administration of the chlorin e4 sodium.97. The method of claim 96, wherein the method is a method of photodynamic therapy or cytoluminescent therapy, and wherein the human or animal is subjected to irradiation 5 to 100 hours after administration of the chlorin e4 sodium.-49 - 98. The niethoJ of claim 96, wherein the method is a method of photoclynaniic diagnosis, and wherein the human or animal is subjected to irradiation 3 to 60 hours after administration of the chiorin e4 sodium.99. The method of any one of claims 95 to 98, wherein the irradiation is electromagnetic radiation with a wavelength in the range of from SOOnm to l000nm.100. The method of any one of claims 82 to 99, wherein the human or animal is a hum an. /0
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| PCT/GB2013/053285 WO2014091241A1 (en) | 2012-12-14 | 2013-12-13 | Chlorin derivative useful in photodynamic therapy and diagnosis |
| NZ749124A NZ749124A (en) | 2012-12-14 | 2013-12-13 | Chlorin derivative useful in photodynamic therapy and diagnosis |
| AU2013357030A AU2013357030B2 (en) | 2012-12-14 | 2013-12-13 | Chlorin derivative useful in photodynamic therapy and diagnosis |
| US14/651,271 US20150315202A1 (en) | 2012-12-14 | 2013-12-13 | Chlorin derivative useful in photodynamic therapy and diagnosis |
| CA2894968A CA2894968C (en) | 2012-12-14 | 2013-12-13 | Chlorin derivative useful in photodynamic therapy and diagnosis |
| SG11201504595UA SG11201504595UA (en) | 2012-12-14 | 2013-12-13 | Chlorin derivative useful in photodynamic therapy and diagnosis |
| CN201811587683.XA CN110003225A (en) | 2012-12-14 | 2013-12-13 | The useful chlorin derivative in photodynamic therapy and diagnosis |
| MYPI2015001526A MY180320A (en) | 2012-12-14 | 2013-12-13 | Chlorin derivative useful in photodynamic therapy and diagnosis |
| CN201380072967.4A CN105008372B (en) | 2012-12-14 | 2013-12-13 | Chlorin derivatives useful in photodynamic therapy and diagnosis |
| KR1020157017350A KR102242404B1 (en) | 2012-12-14 | 2013-12-13 | Chlorin derivative useful in photodynamic therapy and diagnosis |
| ES13821500T ES2791004T3 (en) | 2012-12-14 | 2013-12-13 | Chlorine derivative useful in photodynamic therapy and diagnosis |
| MEP-2020-94A ME03725B (en) | 2012-12-14 | 2013-12-13 | Chlorin derivative useful in photodynamic therapy and diagnosis |
| HUE13821500A HUE048861T2 (en) | 2012-12-14 | 2013-12-13 | Chlorin derivative useful in photodynamic therapy and diagnosis |
| JP2015547147A JP6396919B2 (en) | 2012-12-14 | 2013-12-13 | Chlorine derivatives useful for photodynamic therapy and diagnosis |
| EP13821500.9A EP2931728B1 (en) | 2012-12-14 | 2013-12-13 | Chlorin derivative useful in photodynamic therapy and diagnosis |
| RS20200533A RS60225B1 (en) | 2012-12-14 | 2013-12-13 | Chlorin derivative useful in photodynamic therapy and diagnosis |
| PT138215009T PT2931728T (en) | 2012-12-14 | 2013-12-13 | Chlorin derivative useful in photodynamic therapy and diagnosis |
| DK13821500.9T DK2931728T3 (en) | 2012-12-14 | 2013-12-13 | CHLORINE DERIVATIVE USED FOR PHOTODYNAMIC THERAPY AND DIAGNOSIS |
| SI201331722T SI2931728T1 (en) | 2012-12-14 | 2013-12-13 | Chlorin derivative useful in photodynamic therapy and diagnosis |
| LTEP13821500.9T LT2931728T (en) | 2012-12-14 | 2013-12-13 | Chlorin derivative useful in photodynamic therapy and diagnosis |
| PL13821500T PL2931728T3 (en) | 2012-12-14 | 2013-12-13 | Chlorin derivative useful in photodynamic therapy and diagnosis |
| IL239347A IL239347B (en) | 2012-12-14 | 2015-06-11 | Chlorin derivative useful in photodynamic therapy and diagnosis |
| PH12015501341A PH12015501341A1 (en) | 2012-12-14 | 2015-06-15 | Chlorin derivative useful in photodynamic therapy and diagnosis |
| HK16104558.8A HK1216534A1 (en) | 2012-12-14 | 2016-04-20 | Chlorin derivative useful in photodynamic therapy and diagnosis |
| AU2018282411A AU2018282411A1 (en) | 2012-12-14 | 2018-12-20 | Chlorin derivative useful in photodynamic therapy and diagnosis |
| CY20201100411T CY1122834T1 (en) | 2012-12-14 | 2020-05-05 | CHLORINE DERIVATIVES USEFUL IN PHOTODYNAMIC THERAPY AND DIAGNOSIS |
| HRP20200734TT HRP20200734T1 (en) | 2012-12-14 | 2020-05-07 | Chlorin derivative useful in photodynamic therapy and diagnosis |
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| GB1309337.2A GB2514408A (en) | 2013-05-23 | 2013-05-23 | Photodynamic Therapy and Diagnosis |
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| GB2514408A true GB2514408A (en) | 2014-11-26 |
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| WO2009040411A1 (en) * | 2007-09-28 | 2009-04-02 | Photo Diagnostic Devices (Pdd) Limited | Photodynamic therapy and diagnosis using a chlorin e4 zinc complex |
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| WO2009040411A1 (en) * | 2007-09-28 | 2009-04-02 | Photo Diagnostic Devices (Pdd) Limited | Photodynamic therapy and diagnosis using a chlorin e4 zinc complex |
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| Journal of Pharmacology and Experimental Therapeutics, Vol.155(1), 1967, Wong et al., pages 50-7. * |
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