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WO2001082860A2 - Utilisation d'acide ursodeoxycholique pour la potentialisation de l'effet phototoxique de la therapie photodynamique - Google Patents

Utilisation d'acide ursodeoxycholique pour la potentialisation de l'effet phototoxique de la therapie photodynamique Download PDF

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Publication number
WO2001082860A2
WO2001082860A2 PCT/US2001/012813 US0112813W WO0182860A2 WO 2001082860 A2 WO2001082860 A2 WO 2001082860A2 US 0112813 W US0112813 W US 0112813W WO 0182860 A2 WO0182860 A2 WO 0182860A2
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Prior art keywords
photodynamic
potentiator
photosensitizing agent
potentiating
agent
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WO2001082860A3 (fr
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David Kessel
John J. Reiners
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Wayne State University
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Wayne State University
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Priority to AU2001253707A priority Critical patent/AU2001253707A1/en
Priority to US10/257,742 priority patent/US20030212052A1/en
Publication of WO2001082860A2 publication Critical patent/WO2001082860A2/fr
Publication of WO2001082860A3 publication Critical patent/WO2001082860A3/fr
Anticipated expiration legal-status Critical
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
    • A61K41/0071—PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines

Definitions

  • the present invention relates to photodynamic therapy and tools used for photodynamic therapy and the initiation of apoptosis. More specifically, the present invention relates to a method of potentiating phototoxicity of photodynamic therapy for use in the treatment of such diseases as cancer, age-related macular degenerization of the Rl, and for the treatment of atherosclerotic plaque in arteries.
  • Photodynamic therapy (also referred to as PDT, photoradiation therapy, phototherapy or photochemotherapy) is a procedure involving photosensitization of tissues by any of a series of agents with a porphyrin-like structure.
  • the term "photosensitization” refers to a sensitivity exhibited by tissues having an effective concentration of a photoactive agent retained therein through the exposure of light which causes intracellular disruption and potentially a cell killing effect, often referred to as photokilling.
  • Porphyrins are derivatives of the parent tetrapyrrole compound, porphyrin. They are named and classified on the basis of their side chain constituents. The porphyrin ring is present in many heme enzymes and proteins and is also found in chlorophylls of green plant cells.
  • the effective agents utilized in photodynamic therapy localize in neoplastic tissues.
  • Various other agents also show an affinity for atherosclerotic plaques and/or a class of retinal blood vessels that lead to macular degeneration.
  • the photoactive agents Upon irradiation with visible light at a suitable wave length, the photoactive agents catalyze the conversion of oxygen dissolved in the surrounding millue through a highly reactive product, singlet molecular oxygen. These agents can bring about the destruction of cellular organelles in the immediate vicinity. Singlet oxygen is quenched by the first biological molecule that it encounters.
  • a variety of agents can also quench singlet oxygen.
  • vitamin E and glutathione are effective quenchers of singlet oxygen. High levels of these agents can therefore impair a photodynamic response.
  • Other drugs can promote the photokilling. These drugs include the protein kinase C inhibitors, staurosporin and chelerythrine. These agents are toxic and cannot be used in the clinic.
  • Apoptosis is a programmed cell death mechanism that is triggered either by an inherent genetic process or by cell damage. Release of cytochrome c after photodamage mimics the effect of natural or traumatic processes that elicit apoptotic cell death. The process involves activation of a series of enzymes that ultimately fragment cellular DNA in small vessicles that are subsequently engulfed by adjoining cells. Apoptotic death is therefore different from necrosis which involves loss of the outer membrane of the cell, resulting in the release of cellular DNA and lysosomal enzymes into the tissues, ultimately resulting in an inflammatory response.
  • the photosensitizing agent is injected into the blood stream and absorbed by cells all over the body.
  • the agent remains in cancer cells for a longer time than it does normal cells.
  • the photosensitizing agent absorbs the light and produces the active form of oxygen described above but destroys the treated cancer cells.
  • light exposure must be timed carefully so that it occurs when most of the photosensitizing agent has left healthy cells but is still present in the cancer cells.
  • the laser light used can be directed through a fiber optic (a very thin glass strand).
  • the fiber optic is placed close to the cancer to deliver the proper amount of light.
  • the fiber optic can be directed through a bronchoscope into the lung for treatment of lung cancer or through an endoscope into the esophagus for the treatment of esophageal cancer.
  • an advantage of photodynamic therapy is that it causes minimal damage to healthy tissue.
  • the laser light currently in use cannot pass through more than 3 cm. of tissue such therapy is mainly used to treat tumors on or just under the skin or on the lining of internal organs.
  • Photodynamic therapy makes the skin and eyes sensitive to light for about six weeks or more after treatment. Patients are advised to avoid direct sunlight and bright indoor light for at least six weeks. If patients must go outdoors, they are advised to wear protective clothing, including sunglasses. Even with these precautions, skin can become blistered, red or swollen. Other temporary side effects are related to the treatment of specific areas and can include coughing, trouble swallowing, abdominal pain, and painful breathing or shortness of breath.
  • a method of potentiating the phototoxicity of photodynamic therapy by co-administering a photosensitizing agent with a photodynamic potentiator which is a member of the group consisting of ursodeoxycholic acid (UDCA) and analogues and conjugates thereof having phototoxicity potentiating effect, allowing for retention of the co-administered agent and acid in a target tissue, and then irradiating the target tissue.
  • the present invention further provides a tool for potentiating apoptosis consisting of the photosensitizing agent and a non- toxic photodynamic potentiator.
  • the present invention further provides a method of potentiating drug induced apoptosis by administering the photosensitizing agent and decreasing the threshold of responsiveness of a target tissue to a photokilling effect of the photosensitizing agent.
  • Figure 1 is a chart demonstrating UDCA enhancement of SnT2 PDT cell killing
  • Figure 2 is a bar graph showing UDCA enhancement of SnT2 PDT- mediated caspase-3 activation
  • Figure 3 is a bar graph showing the influence of time of UDCA exposure on enhancement of SNT2 PDT-mediated caspase-3 activation.
  • the present invention provides a method of potentiating the phototoxicity of photodynamic therapy by co-administering a photosensitizing agent with a photodynamic potentiator.
  • phototoxicity is used herein to mean the killing of cells during irradiation of the cells wherein the cells have retained therein a photosensitizing agent.
  • Photodynamic therapy is the therapeutic use of phototoxicity involving photosensitization of target tissues by any of the series of photosensitizing agents.
  • the agents referred to herein as "photosensitizing agents", preferably have a porphyrin-like structure to localizing tumors.
  • Utility of a porphyrin to help in the early diagnosis of previously undiscovered neoplasms in a patient was recognized. Policard, A. Etudes sur les aspects offerts par des tufmeurs experimentales examine' es a la lumie ' re de Wood. Compt. Rend. Sos. Biol. 9J.: 1423 (1924). To this day, the reasons for the localization of the porphyrin-like agents in the neoplastic tissues is not fully understood. It is also known that photosensitizing agents show an affinity for atherosclerotic plaque and a class of retinal blood vessels that lead to macular degeneration. Accordingly, the present invention finds utility in the treatment of these diseases.
  • non-porphyrin structures are a series of Texaphyrins developed by Jonathan Sessler at the University of Texas. These are currently being marketed by Pharmacyclics (Sunyvale CA).
  • the texaphyrin structure is somewhat similar to the porphyrins, but has an expanded ring system.
  • Some phthalocyanines have also been suggested as sensitizers; these have a porphyrin-like ring system, but with N replacing C in the structures that join the pyrrole rings together. None of these has as yet made a clinical impact, but a silicon phthalocyanine is being tested by the NIH (developed at Case Western Reserve University). This agent is said to have a mitochondrial target. It is possible that structures not based on the porphyrin or porphyrin-like systems will eventually be developed.
  • the preferred photosensitizing agent for use in the course of the present invention is Photofrin® (product of Sanofi Pharmaceuticals, Inc., New York, New York).
  • Photofrin is porfimer-sodium and is administered by injection.
  • the compound is a photosensitizing agent used in photodynamic therapy of tumors.
  • Photofrin is not a single chemical entity, but rather is a mixture of oligomers formed by ether and ester linkages of up to eight porphyrin units.
  • the cyotoxic and anti-tumor actions of Photofrin are light and oxygen dependent.
  • Photodynamic therapy utilizing photosensitizing agents such as Photofrin is a two stage process.
  • the first stage is intravenous injection of the drug. Clearance from a variety of tissues occurs over 40 to 72 hours, but tumors, skin, and organs of the reticuloendothelial system (including liver and spleen) retain such drugs for longer period of time. Illumination with laser light, preferably at 630 nm constitutes the second stage of therapy.
  • Tumor selectivity and treatment occurs through a combination of selective retention of the drug and selective delivery of the light.
  • Cellular damage caused by the drug is a consequence of the propagation of radical reactions. Radical initiation can occur after a drug absorbs light to form a porphyrin excited state. Spin transfer from the drug to molecular oxygen can then generate a singlet oxygen. Subsequent radical reactions form super oxide and hydroxyl radicals.
  • Tumor death also occurs through ischemic necrosis secondary to vascular occlusion that appears to be partly mediated through thrombaxane A 2 release.
  • the laser treatment induces a photo chemical but not a thermal effect.
  • the necrotic reaction and associated inflammatory response can evolve over several days.
  • the photosensitizing agent is co-administered with a photodynamic potentiator.
  • photodynamic potentiator is used herein to mean a non-toxic compound which increases the efficacy of a dose of photosensitizing agent. That is, the photodynamic potentiator decreases the threshold of responsiveness of the photosensitizing agent to irradiation. Accordingly, in a dose responsive manner, co- administration of the photodynamic sensitizer with the photosensitizing agent results in the need for less of the photosensitizing agent to achieve the target cell killing effect. Concomittant with the potentiation of phototoxicity is the need for less porphyrin to obtain a desired target cell kill.
  • the photodynamic potentiators of the present invention are preferably selected from the group, including ursodeoxycholic acid (UDCA) and analogs and conjugates thereof having the phototoxicity potentiating effect.
  • UDCA ursodeoxycholic acid
  • the structure of UDCA and its close structural relative, deoxycholic acid are shown below.
  • UDCA UDCA
  • URSO® product of Axcan Pharma U.S. Inc., Minneapolis, MN and others
  • UDCA or URSO diol is a naturally occurring bile acid found in small quantities in normal human bile and in larger quantities in the biles of certain species of bears. It is a bitter tasting white powder consisting of crystaline particles freely soluble in ethanol and glacial acetic acid, slightly soluble in chloraform, sparingly soluble in ether, and practically insoluble in water.
  • UDCA is normally present in a minor fraction of the total bile acids of humans (about 5%).
  • UDCA UDCA
  • the majority of UDCA is absorbed by passive diffusion but its absorption is incomplete
  • the compound undergoes hepatic extraction to the extent of about 50% in the absence of liver disease.
  • the liver it is conjugated with glycine or tau ⁇ ne, then secreted into the bile.
  • the conjugates are absorbed in the small intestine by passive and active mechanisms.
  • the conjugates can also be deconjugated in the ileum by intestinal enzymes.
  • UDCA tablets are presently indicated for the treatment of patients with primary bil lar cirrhosis.
  • UDCA has been in medical practice for a quite long period of time, mainly for the dissolving of gallstones and for the treatment of certain liver diseases.
  • Drugs other than the photodynamic potentiators of the present invention can promote the photokilling by photosensitizing agents such as Photofrin. These include the protein kinase C inhibitors staurosporin and chelerythrine. These are toxic agents and cannot be used clinically.
  • Apoptosis is a programmed cell-death mechanism that is triggered either by an inherent genetic process or by cell damage. Release of citochrome c after photo damage mimics the effect of natural or traumatic processes that elicit apoptotic cell death. The process involves activation of a series of enzymes that ultimately fragment cellular DNA into small vessicles that are subsequently engulfed by adjoining cells. Apoptotic death is therefore different from necrosis which involves loss of the outer cell membrane of the cell, resulting in release of cellular DNA and lysosomal enzymes into the tissues and an inflammatory response.
  • the photosensitizing agent such as Photofrin which is approved by the FDA
  • Photofrin which is approved by the FDA
  • a reduction in the dose of the photosensitizing agent needed for a therapeutic effect can alleviate this problem.
  • the photokilling affect of the photosensitizing agent derives from cells receiving a sufficient level of drug and of light for apoptosis to occur. Any adjuvant treatment that decreases the threshold of responsiveness, such as the photodynamic potentiators of the present invention, is expected to promote efficacy.
  • the photosensitizing and photodynamic agents of the present invention are co-administered and dosed in accordance with good medical practice, taking into account the clinical condition of the individual patient, the site and method of administration, scheduling of administration, patient age, sex, body weight and other factors known to medical practitioners.
  • the pharmaceutically "effective amount" for purposes herein is thus determined by such considerations as are known in the art.
  • the drugs can be administered in various ways. It should be noted that the drugs can be administered as the compound or as pharmaceutically acceptable salt and can be administered alone or as an active ingredient in combination with pharmaceutically acceptable carriers, diluents, adjuvants and vehicles.
  • the compounds can be administered orally, subcutaneously or parenterally including intravenous, intraarte ⁇ al, intramuscular, intrape ⁇ toneally, and intranasal administration as well as intrathecal and infusion techniques. Implants of the compounds are also useful The patient being treated is a warm-blooded animal and, in particular, mammals including man.
  • the pharmaceutically acceptable carriers, diluents, adjuvants and vehicles as well as implant carriers generally refer to inert, non-toxic sold or liquid fillers, diluents or encapsulating material not reacting with the active ingredients of the invention.
  • the drugs When administering the drugs parenterally, the drugs will generally be formulated in a unit dosage injectable form (solution, suspension, emulsion).
  • the pharmaceutical formulations suitable for injection include sterile aqueous solutions or dispersions and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • the carrier can be a solvent or dispersing medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.
  • Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Nonaqueous vehicles such as cottonseed oil, sesame oil, olive oil, soybean oil, corn oil, sunflower oil, or peanut oil and esters, such as isopropyl myristate, may also be used as solvent systems for compound compositions.
  • various additives which enhance the stability, sterility, and isotonicity of the compositions including antimicrobial preservatives, antioxidants, chelating agents, and buffers, can be added.
  • a pharmacological formulation of the drugs can be administered to the patient in an injectable formulation containing any compatible carrier, such as various vehicle, adjuvants, additives, and diluents; or the compounds utilized in the present invention can be administered parenterally to the patient in the form of slow-release subcutaneous implants or targeted delivery systems such as monoclonal antibodies, vectored delivery, iontophoretic, polymer matrices, liposomes, and microspheres. Examples of delivery systems useful in the present invention include: U.S.
  • Many other such implants, delivery systems, and modules are well known to those skilled in the art.
  • a pharmacological formulation of the drugs utilized in the present invention can be administered orally to the patient.
  • Conventional methods such as administering the compounds in tablets, suspensions, solutions, emulsions, capsules, powders, syrups and the like are usable.
  • Known techniques which deliver the drugs orally or intravenously and retain the biological activity are preferred.
  • the drugs can be administered initially by intravenous injection to bring blood levels of drugs to a suitable level.
  • the patient's levels are then maintained by an oral dosage form, although other forms of administration, dependent upon the patient's condition and as indicate above, can be used.
  • the quantity of drugs to be administered will vary for the patient being treated and will vary from about 100 ng/kg of body weight to 100 mg/kg of body weight per day and preferably will be from 10 ⁇ g/kg to 10 mg/kg per day. More specifically, and preferably, Photofrin is administered in the two stage process discussed above.
  • the first stage of photodynamic therapy is intravenous injection of Phorofrin at 2 mg/kg.
  • UDCA is presently administered as 250 mg film coated tablets, delivered orally. It is expected that the dosage of Photofrin will be decreased with the administration of increased amounts of UDCA and/or its conjugats and analog.
  • Illumination with laser light 40-50 hours following injection with Photofrin constitutes the second stage of the therapy.
  • the second laser light application can be given 96 to 120 hours after injection, proceeded by general debndement of residual tumor.
  • Patients may receive a second course of treatment a minimum of thirty days after the initial therapy and up to three courses of treatment can be given, each separated by a minimum of thirty days.
  • Photofrin should be administered as a single slow intravenous injection over three to five minutes at 2 mg. per body weight. The product must be protected from bright light and used immediately once reconstituted.
  • Photofrin has been found effective in at least the treatment of esophageal cancer and endobronchial cancer as well as the treatment of other cancers.
  • the present invention also provides a tool for potentiating apoptosis, consisting of the photosensitizing agent and the non-toxic photodynamic potentiator.
  • apoptosis can be initiated and potentiated in various systems, outside of therapeutic uses, in accordance with the present invention.
  • Apoptosis in cell lines as well as in situ environments can be potentiated and used as a tool in the laboratory, as well as the clinic.
  • the present invention provides a method of potentiating drug induced apoptosis by the administration of the photosensitizing agent and then decreasing the threshold of responsiveness of a target tissue to the photokilling effect of the photosensitizing agent.
  • the following experimental data demonstrates the utility of the present invention. Specifically, the data shows that increasing the amount of the photodynamic potentiator administered decreases the time of irradiation needed for the target tissue to produce a similar effect. Further, increasing the amount of photodynamic potentiator will decrease the dose of photosensitizing agent required to maintain an effective photokilling effect of the photosensitizing agent. Accordingly, therapeutic co-administration of the drugs in accordance with the present invention can decrease skin photosensitization by allowing for a decreased amount of the photosensitizing agent to be required.
  • Oell lines Studies have been carried out with the murine leukemia L1210 and murine hepatoma hepa 1 c1 c7 cell lines along with primary rat hepatocyte cultures. Except for the latter, cells are grown in tissue culture.
  • the L1210 cell line is grown in suspension culture in Fischer's medium containing 10% horse serum.
  • the murine hepatoma 1 c1 c7 cell line was obtained from Dr. J. Whitlock, Jr. (Stanford University, CA). Cells were cultured on either commercially available plastic tissue cutureware, or poly-L- lysine coated glass coverslips or discs, and grown at 37°C in a-minimal essential medium (aMEM) containing 5% fetal bovine serum and antibiotics. Cultures were passaged by incubation with a trypsin + EDTA solution (0.25% trypsin, 1 mM EDTA in Hank's Balanced Salts Solution).
  • aMEM a-minimal essential medium
  • ALA this pro-drug, aminolevu nic acid, is converted by cellular enzymes into protoporphy ⁇ n
  • HPPH a hexyl pheophorbide ester
  • CPO a porphycene
  • mTHPC metal- hydroxyphenyl porphine
  • Photofrin a mixture of porphynn-related structures.
  • LCI is another chlonn that localizes in both the outer membrane and in lysosomes.
  • MCP is a monocationic porphyrin that partitions only to the outer membrane.
  • Photofrin and ALA currently have FDA approval for some indications, LuTex and SnET2 are in various stages of clinical trials.
  • the cells were then lysed and leveis of caspase-3 activity are assessed using a fluorescent plate reader.
  • the substrate is DEVD-afc or DEVD-rhodamine 1 10. These substrates were cleaved by caspase-3 to form fluorescent products that were then detected.
  • the plate readers take periodic readings of the emerging fluorescence, permitting a rate to be assessed.
  • the general procedure involved quadruplicate samples, with the mean ⁇ standard deviation automatically plotted. Protein levels in the lysates were also determined, so that the net result was in terms of caspase-3 activity per mg protein per minute.
  • Photokilling was assessed by clonogenic assays involving the plating of known numbers of cells. After several days in cell culture, the number of resulting colonies reflected the number of viable cells that survive PDT. Freshly prepared suspensions of 1 c1 c7 cells were plated in 60 mm culture dishes at a density of 500 cells/dish. Approximately 18 hours later cultures were treated with PDT sensitizer and/or UDCA After 30 minutes of incubation culture dishes were washed once with complete medium and then refed with complete medium Refed cultures were subsequently irradiated and returned to incubators Cultures were refed every third day, and stained with crystal violet once colonies were of sufficient size to score
  • the assay measures the conversion of Ac-DEVD-AMC to the fluorescent product 7-amino-4-methyl coumarin. This same assay was used with L1210 cells, or a similar assay where the fluorophore was rhodamine - 110.
  • UDCA UDCA or any of its analogs were added during the initial incubation with the photosensitizing agent, after irradiation, or both.
  • concentration of the bile salts was varied from 10- 100 ⁇ M. All bile salts were prepared as 100 mM solutions in 200 nM NaOH to minimize solvent effects. The single exception was lithocholic acid that must be dissolved in DMSO. When this agent was used, controls of DMSO alone were added to test for the effect of the solvent on PDT-induced cell killing.
  • Figure 1 shows 1c1c7 cultures plated 18 hours earlier that were exposed to varying concentrations of UDCA, and, as specified, the photosensitizing agent SnET2 (2-mM). After irradiation of 270mJ/cm 2 at 630- 700 nm, the plates were incubated and the colonies were counted four days later. The data represents the mean ⁇ a standard deviation of three to four plates.
  • Figure 1 shows a clear dose dependent response resulting in a decrease of 12 ⁇ 5 colonies to 1 ⁇ 0.7 colonies (a decrease of 20 % to 1.3%) with an increase in UDCA of 10 micromoles to 100 micromoles. No significant difference is seen between control and the addition of UDCA at the same varying concentrations.
  • UDCA enhancement of SnT2 PDT-mediated caspase-3 activation is shown in Figure 2. Two day old subconfluent 1 c1 c7 cultures were exposed to SnET2 (2 ⁇ M concentration and/or varying concentrations of UDCA as specified).
  • Figure 3 demonstrates the influence of time of UDCA exposure on the enhancement of photosensitizing agent mediated caspase-3 activation.
  • Two day old subconfluent 1 c1c7 cultures were exposed to vehicle alone, SnET2 (2 mM), and/or 100 mM UDCA. Some cultures were irradiated (270 mJ/cm2).
  • UDCA was present either before, after or both before and after irradiation.
  • Cultures were harvested for preparation of extracts for caspase-3 (AEVDase DEVD) activation at varied times after irradiation. Data represent mean ⁇ standard deviation of four determinations. The chart shows no enhanced activation of the caspase-3 in controls. Data further shows that enhanced activation requires that UDCA present before irradiation.
  • UDCA is a very likely agent for clinical trials since this drug is known to be safe for human administration.
  • Studies on primary hepatocytes show no enhanced photodynamic therapy induced apoptosis by UDCA. This is of importance since it suggests that the effect used by UDCA may be confined to neoplastic cell types.

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Abstract

L'invention concerne un procédé de potentialisation de la phototoxicité de la thérapie photodynamique consistant à coadministrer un agent photosensibiliant avec un potentialisateur photodynamique du groupe constitué par des analogues d'acide uridioxicolique et des conjugués de ceux-ci, qui présente un effet de potentialisation de la phototoxicité, et à faire en sorte que l'agent et l'acide coadministrés soient retenus dans le tissu cible. Le tissu cible est ensuite soumis à une irradiation. Un outil permettant de potentialiser l'apoptose est constitué d'un agent photosensibilisant et d'un potentialisateur photodynamique non toxique. L'invention concerne également un procédé de potentialisation de l'apoptose induite par médicaments, qui consiste à administrer un agent photosensibilisant puis à faire abaisser le seuil de réactivité d'un tissu cible à un niveau provoquant l'effet de photodestruction de l'agent photosensibilisant.
PCT/US2001/012813 2000-05-04 2001-04-20 Utilisation d'acide ursodeoxycholique pour la potentialisation de l'effet phototoxique de la therapie photodynamique Ceased WO2001082860A2 (fr)

Priority Applications (2)

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AU2001253707A AU2001253707A1 (en) 2000-05-04 2001-04-20 Use of ursodeoxycholic acid for potentiation of the phototoxic effect of photodynamic therapy
US10/257,742 US20030212052A1 (en) 2001-04-20 2001-04-20 Use of ursdeoxycholic acid for potentiation of the phototoxic effect of photodynamic therapy

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US60/201,894 2000-05-04

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105694851A (zh) * 2016-03-08 2016-06-22 武汉大学 一种肿瘤靶向诊疗荧光探针

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
KESSEL D. ET AL.: 'Potentiation of photodynamic therapy by ursodeoxycholic acid' CANCER RESEARCH vol. 60, no. 24, 15 December 2000, pages 6985 - 6988, XP002947328 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105694851A (zh) * 2016-03-08 2016-06-22 武汉大学 一种肿瘤靶向诊疗荧光探针
CN105694851B (zh) * 2016-03-08 2018-07-27 武汉大学 一种肿瘤靶向诊疗荧光探针

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AU2001253707A1 (en) 2001-11-12

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