WO2010126179A1 - 클로린 e6-엽산 결합 화합물 및 키토산을 함유하는 암 치료용 약학적 조성물 - Google Patents
클로린 e6-엽산 결합 화합물 및 키토산을 함유하는 암 치료용 약학적 조성물 Download PDFInfo
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- WO2010126179A1 WO2010126179A1 PCT/KR2009/002277 KR2009002277W WO2010126179A1 WO 2010126179 A1 WO2010126179 A1 WO 2010126179A1 KR 2009002277 W KR2009002277 W KR 2009002277W WO 2010126179 A1 WO2010126179 A1 WO 2010126179A1
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- cancer
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- chlorine
- folic acid
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- 0 CCC(C(C=C(C(C)[C@@]1C(O)=O)NC1=C(CC(*)=O)C(C(CCC(NCCOCCOCNC(CCC(C(O)=O)NC(c(cc1)ccc1NCc(cn1)nc2c1N=C(*)NC2=O)=O)=O)=O)[C@]1C)=NC1=C1)=N2)=C(C)C2=C[C@@]2NC1=C(C)C2C=C Chemical compound CCC(C(C=C(C(C)[C@@]1C(O)=O)NC1=C(CC(*)=O)C(C(CCC(NCCOCCOCNC(CCC(C(O)=O)NC(c(cc1)ccc1NCc(cn1)nc2c1N=C(*)NC2=O)=O)=O)=O)[C@]1C)=NC1=C1)=N2)=C(C)C2=C[C@@]2NC1=C(C)C2C=C 0.000 description 1
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- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/716—Glucans
- A61K31/722—Chitin, chitosan
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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
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
- A61K47/551—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds one of the codrug's components being a vitamin, e.g. niacinamide, vitamin B3, cobalamin, vitamin B12, folate, vitamin A or retinoic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- Targeted delivery of photosensitizers may solve these problems. This may be possible by enhancing phototoxicity by improving the degree of selective accumulation of tumor cells. Targeting means binding the photoactivating material directly to a tumor tracking (specific) molecule or using a carrier.
- Several photosensitizers have already been combined with antibodies to tumor-associated antigens. Ligands such as low density lipoproteins, insulin, steroids, transferrins, epidermal growth factor (EGF), all have been discussed for the targeting of ligand-based photosensitizers to cells that overexpress receptors of these ligands.
- folic acid receptors are also useful targets for tumor specific drug delivery for the following reasons.
- Folic acid consists of three components and belongs to the vitamin group.
- folates such as dihydrofolic acid, tetrahydrofolic acid and 5-metil-tetrahydrofolic acid, which are cofactors of enzymes that catalyze the transport of single carbon fragments.
- Folic acid-dependent enzymes participate in the biosynthesis of purine and pyrimidine nucleotides and the metabolism of amino acids of methionine, histidine, serine and glycine. Because of this, folic acid is an essential ingredient for cell division and growth.
- Folic acid is difficult to pass through the plasma membrane of a cell with simple diffusion, as long as it is a divalent anion that exhibits distinct hydrophilic specific characteristics. Only at high pharmacological concentrations can folic acid be transported by passive diffusion.
- folic acid is found in nanomolar concentrations in tissues and serum, which is why cells that absorb and transport these vitamins have a highly effective specific membrane system.
- Chlorine e6 quickly reaches tumor sites from blood and organs, and then accumulates in high concentrations in tumor cells.
- chitosan is a linear polysaccharide composed of ⁇ - (1-4) -linked D-glucosamine (deacetylated unit) and N-acetyl-D-glucosamine (acetylated unit) which are irregularly dispersed. Chitosan is commercially available and can be used in various ways in the biomedical field.
- the present inventors have developed a compound in which chlorine e6 and folic acid are combined to effectively generate singlet oxygen in various media and have significantly superior tumor selectivity compared to conventional porphyrin-based photosensitizers.
- a pharmaceutical composition for treating photodynamically solid cancer containing a novel compound chlorine e6-folate binding compound, or a pharmaceutically acceptable salt thereof, and chitosan as an active ingredient, having a characteristic useful for photodynamic therapy for The present invention has been completed.
- the present invention provides a novel ⁇ - (6-aminohexyl) folic acid] -chlorine e6 or ⁇ - ⁇ N- ⁇ 2, which is a novel chlorine e6-folate binding compound represented by the following general formula (1) or (2). -[2- (2-aminoethoxy) ethoxy] ethyl ⁇ folic acid ⁇ -chlorine e6, or a pharmaceutically acceptable salt thereof and chitosan as an active ingredient, a pharmaceutical composition for treating photodynamically solid cancer to provide.
- chitosan preferably has a molecular weight range of 1000 to 8000 Da and can be easily obtained and used commercially.
- the compounds of formula 1 or formula 2 of the present invention may be prepared with pharmaceutically acceptable salts and solvates according to methods conventional in the art.
- salts are acid addition salts formed with pharmaceutically acceptable free acids.
- Acid addition salts are prepared by conventional methods, for example by dissolving a compound in an excess of aqueous acid solution and precipitating the salt using a water miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. Equivalent molar amounts of the compound and acid or alcohol (eg, glycol monomethyl ether) in water can be heated and the mixture can then be evaporated to dryness or the precipitated salts can be suction filtered.
- a water miscible organic solvent such as methanol, ethanol, acetone or acetonitrile.
- Equivalent molar amounts of the compound and acid or alcohol (eg, glycol monomethyl ether) in water can be heated and the mixture can then be evaporated to dryness or the precipitated salts can be suction filtered.
- organic acids and inorganic acids may be used as the free acid
- hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, and the like may be used as the inorganic acid
- methanesulfonic acid, p -toluenesulfonic acid, acetic acid, trifluoroacetic acid, and maleic acid may be used as the organic acid.
- Bases can also be used to make pharmaceutically acceptable metal salts.
- Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving a compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and then evaporating and drying the filtrate.
- the metal salt it is particularly suitable to prepare sodium, potassium or calcium salt, but is not limited thereto.
- Corresponding silver salts may also be obtained by reacting alkali or alkaline earth metal salts with a suitable silver salt (eg, silver nitrate).
- hexane-1,6-diamine or 2,2 '-(ethylenedioxy) -bis-ethylamine is used for bonding between the two linkers.
- Chlorine e6 of formula 3 13-carboxy-17- [2-carboxyethyl] -15-carboxymethyl-17,18-trans-dihydro-3-vinyl-8-ethyl-2,7,12,18-tetramethylporphyrin
- Folic acid ( N- [4 (2-Amino-4-hydroxy pteridin-6-ylmethylamino) benzoyl] -L (+)-glutamic acid) of formula 4 is hexane-1,6-diamine )
- ⁇ - ⁇ N- ⁇ 2- [2- (2-aminoethoxy) ethoxy] ethyl ⁇ folic acid ⁇ which is a novel chlorine E6-folate binding compound having the structure of Chemical Formula 2 of the present invention -Chlorine e6 or a pharmaceutically acceptable salt thereof can be prepared by a method comprising the following steps:
- the step of obtaining ⁇ - ⁇ [ tert -butyl- N- (6-aminohexyl)] carbamate ⁇ folic acid may be performed as follows.
- the step of obtaining ⁇ - (6-aminohexyl) folic acid or ⁇ - ⁇ N- ⁇ 2- [2- (2-aminoethoxy) ethoxy] ethyl ⁇ folic acid may be performed as follows.
- obtaining the chlorine e6 succinidyl ester may be performed as follows.
- N -hydroxysuccinimide and dicyclohexylcarbodiimide are added to a solution of chlorine e6 in anhydrous DMSO and the mixture is stirred at room temperature for 2-6 hours.
- the solvent is then evaporated and then purified by column chromatography using a 1: 9 (v / v) mixed solvent of acetone: CH 2 Cl 2 as the eluent. Fractions are tested by TLC to collect only those with only one spot and concentrate.
- the step of preparing [ ⁇ - (6-aminohexyl) folic acid] -chlorine e6 or ⁇ - ⁇ N- ⁇ 2- [2- (2-aminoethoxy) ethoxy] ethyl ⁇ folic acid ⁇ -chlorine e6 It may be performed as follows.
- the amino group in the chino acid has a pKa value of ⁇ 6.5.
- chitosan is positively charged and dissolved in acidic to neutral solutions at a charge density with pH. That is, chitosan is bioadhesive and easily adheres to negatively charged surfaces such as mucous membranes. Chitosan enhances the transport of polar drugs across the epithelial surface and is biocompatible and biodegradable. The purified quality chitosan is applicable for biomedical use.
- composition of the present invention can be administered orally or parenterally (eg, applied intravenously, subcutaneously, intraperitoneally or topically) according to the desired method, and the dosage is based on the weight, age, sex, health status, The range varies depending on the diet, the time of administration, the method of administration, the rate of excretion and the severity of the disease.
- the daily dose of the [ ⁇ - (6-aminohexyl) folic acid] -chlorine e6 is about 5 to 1,000 mg / kg, preferably 10 to 500 mg / kg, and is administered once to several times a day. desirable.
- the daily dose of chitosan is about 5 to 1,000 mg / kg, preferably 10 to 500 mg / kg, more preferably administered once to several times a day.
- composition of the present invention may be used alone or in combination with methods using surgery, hormone therapy, drug therapy and biological response modifiers for the treatment of solid cancers.
- the present invention is a novel compound in the form of a combination of chlorine e6 and folic acid, which effectively produces singlet oxygen in various media and has significantly superior tumor selectivity compared to conventional porphyrin-based photosensitizers, and thus is highly effective in photodynamic therapy for malignant tumors.
- a therapeutic agent for photodynamic treatment of solid cancer can be provided.
- A is a positive mode
- B is a negative mode measurement results.
- Figure 3 is the mass spectrometry results of Chlorin e 6 succinidyl ester.
- A is a positive mode
- B is a negative mode measurement results.
- FIG. 10 is a graph comparing the accumulation of free chlorine E6 and chlorine E6 conjugates in HeLa cells over time when exogenous folic acid was added.
- FIG. 13 is a graph showing photophotodynamic activity of free chlorine E6 and chlorine E6 conjugates in HeLa cells when irradiated at a dose of 3.3 J / cm 2.
- FIG. 14 is a graph showing the results of measuring chlorine E6 accumulation kinetics in Sacoma M-1 in rats and normal tissues when chlorine E6 was administered at doses of 2.5, 5.0 and 10.0 mg / kg.
- Example 1-1 (Compound I): Synthesis of ⁇ - ⁇ [ tert- butyl- N- (6-aminohexyl)] carbamate ⁇ folic acid (I)
- N -hydroxysuccinimide (8.7 mg, 7.6 ⁇ 10 -2 mmol) and dicyclohex in a solution of Chlorin e6 (45.37 mg, 7.6 ⁇ 10 -2 mmol) in anhydrous DMSO Silkcarbodiimide (DCC) (8.7 mg, 7.6 ⁇ 10 ⁇ 2 mmol) was added. The mixture was stirred at room temperature for 4 hours. The solvent was evaporated and then purified by column chromatography using a 1: 9 (v / v) mixed solvent of acetone: CH 2 Cl 2 as eluent. Fractions were tested by TLC to collect only those with only one spot and then concentrated. 42 mg were obtained, yielding 79.7%.
- Chlorin e6 can accumulate in tumor cells and tissues and destroy tumor cells. It is known that a major role in this process is the abnormal operation of the cell membrane. This abnormal behavior is due to the oxidation of protein and lipid components by highly reactive oxidants such as singlet oxygen. This singlet oxygen is formed during the interaction between the oxygen molecules in the body and the photosensitizer molecules under an activated triplet condition. 1 efficiency of 0 2 produced is determined by the following a number of factors, such as: absorption of the photosensitizer, the intensity and emission of triplet quantum conditions, the life of the above conditions, the present solubility and O 2 diffusion under the environment and the like.
- HAS human serum albumin
- Chlorin e6 conjugates in all systems are in the monomeric state, and that spectral changes are mainly caused by orientational effects.
- the role of distinctive and oriented interactions in this experiment was small. Chlorin e6 conjugates in all complexes have a hydrophobic environment with the same polarity as pyridine.
- A is a coefficient depending on the initial concentration of the interacting reagent
- k 1 and k 2 represent the increasing and extinction constants of the luminescent signal, respectively.
- the Chlorin e6 complex has the optimal properties for effectively generating singlet oxygen in various media.
- the photodynamic activity of the Chlorin e6 conjugates of the present invention is significantly higher than that of other porphyrine-based photosensitive agents. It can be seen that.
- Chlorin e6 Chlorin e6 binder One 0,86 0,40 5 1,45 1,80 10 1,72 2,50 15 0,81 12,5 24 0,40 15,0
- Chlorin e6 conjugates After 24 hours of exposure, the accumulation of Chlorin e6 conjugates was on average 8-10 times higher than that of free Chlorin e6. Accumulation levels of chlorin e6 conjugates increased continuously over 24 hours, suggesting that active transport through receptor-mediated endocytosis occurs rather than nonspecific cell uptake.
- folic acid was added to the cell suspension at a concentration of 4 ⁇ M / l before the addition of free Chlorin e6 and Chlorin e6 conjugates. Incubated with free Chlorin e6 and Chlorin e6 combination for 24 hours. The sample was then centrifuged, the supernatant was collected and the precipitate was washed again in cold Hank's solution. The second precipitate obtained was put back into Hank's solution.
- Fluorescence intensity was measured to compare the accumulation of free chlorin e6 and chlorin e6 conjugates in HeLa cells.
- Cytotoxicity was investigated in consideration of cell proliferation intensity, photosensitizer concentration, and optical power . Three flasks containing a single layer of cell were used for this.
- a monolayer culture of HeLa tumor cells was used as a cell.
- Cultures of Hela tumor cells were grown in nutrient medium containing nutrient medium 199, or 10% fetal calf serum and 100 mg / ml kanamycin.
- photosensitizers were added at 1, 2.5, 5.0, 10.0, 20.0 and 30.0 mg / ml, respectively.
- Flasks with dark cytotoxicity were incubated at 37.5 ° C. for 1 hour. The cells were washed four times using Hank's solution. Add 2.0 ml of fresh nutrient medium and use a "METALAZ" laser medical instrument (wavelength 627.8 nm, 578.2 or 510.6 nm) or "LD 680-2000" (wavelength 670-690 nm) (the spectroscopic maximum absorption wavelength of the photosensitive agent to be investigated) Irradiated with a light flux of 40 J / cm 2 at an ice melting temperature for 5, 10, 15 or 20 minutes. After 20-24 hours tumor cells were counted in a Goriaev's chamber.
- METALAZ laser medical instrument
- LD 680-2000 wavelength 670-690 nm
- the photosensitizer solution to be examined of the nutrient medium was 0.1, 0.5, 1.0, 5.0 or Add to 10 mcg / ml.
- the flasks were wrapped with a light protective cover and incubated at 37 ° C. for 3.5 hours. It was then washed with Hank's solution and irradiated on ice with a dose of 3.3 joule / cm 2 using a laser medical device "LD 680-2000" (wavelength 670-690 nm). After 20-24 hours effective cell monolayers were dispersed with 0.02% Versene solution and tumor cells were counted in Goriaev's chamber. Three flasks were used for this.
- Table 5 shows incubation with photosensitizer for 3.5 hours, additional light exposure (PhE) at a dose of 3.3 joule / cm 2, and the number of HeLa cells as a percentage of the control.
- Chlorin e6 conjugates completely inhibited the proliferation of HeLa cells at a concentration of 5-10 mcg / ml (FIG. 12).
- Figure 13 shows that Chlorin e6 control photosensitizer showed little phototoxicity under the present experimental conditions.
- survival measurement tests showed that the use of Chlorin e6 conjugates resulted in improved photosensitivity compared to Chlorin e6 mediated photosensitivity.
- Chlorin e6 conjugates accumulated on average 10 times higher than Chlorin e6.
- Tumor cells differ significantly in the number and type of receptors that overexpress compared to normal cells. Overexpression of certain receptors is often used for oncoselective delivery of photosensitizers. In HeLa cells that overexpress folate receptors, folate-targeting ligands are used.
- the experiments were performed on rats 7-9 days after tumor transplantation using 100 two-crossed white rats subcutaneously implanted with Sacoma M-1.
- the photosensitizers were administered once intravenously to each group of rats in amounts of 2.5, 5.0 and 10.0 mg / kg, respectively, in low light rooms.
- Sterile natural isotonic solution of sodium chloride was used as solvent.
- Accumulation kinetics of photosensitizers in tumor and normal tissues was performed over 30 minutes, 1-5 hours, and 1-6 days after photosensitizer administration.
- the catheter tip was placed on tumor tissue and normal tissue every hour after drug administration and the intensity of drug accumulation was recorded at the wavelength corresponding to maximum fluorescence.
- Obtained digital values of the indexes considered were processed using generally accepted statistical techniques using the computer program Origin 6.1.
- the significance level was 0.05.
- FIGS. 14 and 15 Fluorescence intensity data in Sacoma M-1 and normal tissues of rats for the first 5 hours and 1-6 days after administration of Chlorin e6 and Chlorin e6 conjugates are shown in FIGS. 14 and 15. Up to 4-5 hours after administration, the difference in the accumulation of two photosensitizers was 2-3 times higher in tumor tissues than in normal tissues.
- the selectivity (mean accumulation in tumors / average accumulation in normal tissues) measured the highest accumulation of Chlorin e6 in rat tumor tissues the first 5 hours after intravenous administration at a dose of 10.0 mg / kg. Showed. For chlorin e6 conjugates, the maximum accumulation was recorded 2-5 hours after intravenous administration at a dose of 5.0 mg / kg.
- Chlorin e6 conjugates were administered intravenously in amounts of 2.5, 5.0 and 10.0 mg / kg, followed by light exposure at a dose of 100 J / cm 2 followed by measurement of necrotic areas in Sacoma M-1 rats.
- Antitumor effect of PDT using chlorin e6 conjugate was 100 J / cm using LD 680-2000 laser device 2 After photoexposure at the dose of Monitoring was performed by quantitatively assessing the necrotic area formed in tumors by biostaining with 0.6% Ivan Blue for 24 hours (1 ml per 100 g body weight). The necrosis area is 2 hours after biostaining, the mice were killed with chloroform, the tumor was removed, fixed on the 10% -HOM formalin for 1 hour, the cross section of the largest diameter was taken from the tumor mass, and the photograph was taken with a camera connected to a computer. Dipping and measuring.
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Abstract
Description
시스템(System) | l 00 abs Nm | l 00 fl nm | t S ns | B |
H2O, pH 8.1 | 657 | 664 | 4.3 | 0.16 |
Triton X-100, pH 8.1 | 665 | 670 | 5.7 | 0.19 |
HSA, pH 8.1 | 664 | 669 | 5.2 | 0.18 |
리포좀(Liposomes), pH 8.1 | 665 | 670 | 5.4 | 0.21 |
디메틸 설폭사이드 | 661 | 672 | 4.6 | - |
피리딘 | 666 | 673 | 5.0 | 0.18 |
테트라하이드로퓨란 | 667 | 573 | 5.0 | - |
메탄올 | 662 | 667 | 4.8 | - |
상기 식에서, 및 는 각각 Chlorin e6 결합물의 상호결합성 전환 및 표준 물질의 광반응, 및 는 각각 측정 파장에서의 조사대상 용액 및 표준 용액의 삼중항-삼중항 흡수의 최대 편이(deviations), 및 는 각각 CHLORIN과 표준 물질의 일중항 소멸 및 삼중항-삼중항 흡수의 몰비(molar rates) 차이, 및 는 각각 CHLORIN과 표준 물질에 의해 상응하여 흡수된 빛의 점유율(shares)이다.
및 값은 여기된 삼중항 상태에서 조사하고자 하는 모든 분자를 실질적으로 옮긴 후에 측정되었다. 이러한 조건에서, 이다. 여기에서, C는 용액 내 물질의 몰농도를 가리키며, l은 광학 경로(optical way)의 길이를 가리킨다. γ를 측정하기 위한 표준 물질로는 벤졸에서의 γ 값이 1과 동일한 것으로 여겨지는, Pd(II)-octa ethyl porphyn (Pd (II) - OEP)이 선택되었다. 의 파라미터를 측정할 때 여기 파장 상에서의 용액의 흡광도는 γ가 0.5일때 0.2를 초과하지 않았고, Chlorin e6 결합물의 상응하는 농도는 0.7 × 10-6 및 1.75 × 10-5 M을 초과하지 않았다.
시스템(System) | τt 0 μs | τtμs | Tmol-1dm-1cm-1 | γ | φΔ |
H2O, pH 8,1 | 170 | 2.5 | 278 | 0.8 | 0.70 |
Triton X-100 | 230 | 2.6 | 0.80 | ||
HSA,H2O,pH 8,1 | 700 | 14.7 | 798 | 0.82 | 0.63- |
리포좀(Liposomes), H2O, pH 8,1 | 70 | 1.4 | 251 | 078 | - |
피리딘 | 140 | 0.3 | 94 | 0.81 | 0.68 |
이 시스템에서, 값은 버퍼 용액, 피리딘 및 지질 이중층에서 Chlorin e6 결합물에 대하여 각각 1.5 × 109, 4.5 × 109, 및 9 × 109 M-1 c-1이었다. 안료-단백질 및 미셀 복합체에서, Chlorin e6 결합물의 값은 각각 2.5 × 109, 및 1.5 × 109 M-1 c-1이었다. 이러한 값은 만일 단백질 매트릭스 및 Trixon X-100 미셀 내 O2 농도가 수용액에서의 O2 농도와 다르지 않다면 올바른 값이라 할 수 있다. 명백하게, 비극성 매질 내에서의 O2 용해도가 H2O 내에서의 그것의 용해도보다 몇 배 더 높다고 알려져 있는 한, 이는 값의 상한이다. 안료-단백질 복합체 내 산소 분자에 의한 Chlorin e6 결합물의 여기된 삼중항 상태 퀀칭의 특이한 특징을 살펴보았다. 단백질 트립토판일(tryptophaniles)의 형광은 O2에 의해 효과적으로 퀀칭되고, 상응하는 퀀칭의 이분자적 속도상수는 2 × 109 M-1 c-1 ~ 5 × 109 M-1 c-1의 범위라는 점이 알려져 있다. 한편, 구형 단백질의 X-선 구조 분석 데이터는 그들의 아미노산 잔기가 치밀하게 몰려 있음을 나타내었다. 이는 O2와 같은 분자의 확산에 대해 상당한 입체적 장애를 주는 원인이 되었다.
상기 표 2에서 분명하게 볼 수 있듯이, 피리딘과 버퍼 용액 내에서 Chlorin 결합물의 분자들은 1O를 매우 효율적으로 생성하였다. 용액 내 단백질의 존재는 τΔ를대략 1.1까지 감소시키는데, 이는 이분자적 퀀칭 상수, = 1.5 × 108 M-1c-1에 상응하는 것이다. 용액 내 안료 농도(3.1×10-6 M) 및 단백질의 농도(Cσ= 9.3×10-6M), 상수값(κCB=1.2×106M-1) 및 Chlorin e6 결합물(n = 1)과 결합하는 위치의 수를 알고 있으므로, 다음 수학식 3을 사용하여 안료-단백질 복합체에 포함된 민감제 분자의 점유율을 측정할 수 있다.
상기 식에서, r 및 C는 각각 결합된 단백질 안료의 농도 및 비결합된 단백질 안료의 농도이며, 이다. 본 실험에서는 90%와 동일하다. 이는 해당 F 값을 단백질 구체 내에 결합되어있는 Chlorin e6 결합물 분자들의 생성 효율성으로서 간주할 수 있는 이유이다. 이는 또한 Triton Х-100의 미셀 내에 포함되어 있는 안료 분자들에도 적용가능하다. 그러나 안타깝게도 단일층 막과 Chlorin e6 결합물의 복합체 형성을 다루는데 있어서는 몇 가지 방법상의 문제로 인해 F값을 측정할 수 없었다. 그러나, 지질 이중-층 내 Chlorin e6 결합물의 광물리학적 파라미터들을 고려하면, 1O2 생성 효율성이 다른 연구된 복합체 내에서 보다도 최소한 더 낮지는 않아야 할 것이라고 주장할 수 있을 것이다.
세포를 3일간 배지 199에서 배양하여 Hank's 용액/배지 199 (9/1)에 이식했다. 3시간 후에 트립신을 이용하여 기질로부터 세포를 수집하여 Hank's 용액에 옮겼다(105 . 세포 현탁액에 Chlorin e6 결합물을 2×10-7 M/l의 농도로 첨가하고, 37℃에서 배양하였다. 1 시간, 그리고 5, 10, 15, 24 시간 후에, 시료를 원심분리하고, 침전물을 차가운 Hank's 용액 내에서 세척한 후, 상기 침전물을 Hank's 용액에 초기 현탁액 내 세포 농도까지 넣었다. 얻어진 시료 내의 Chlorin e6과 Chlorin e6 결합물의 상대적 농도는 에서의 현탁액의 형광 세기로 측정하였다.
배양시간(hours) | Chlorin e6 | Chlorin e6 결합물 |
1 | 0,86 | 0,40 |
5 | 1,45 | 1,80 |
10 | 1,72 | 2,50 |
15 | 0,81 | 12,5 |
24 | 0,40 | 15,0 |
광민감제 농도(μm) | Chlorin e6 | Chlorin e6 결합물 |
1 | 101.3 | 102.1 |
2.5 | 99.1 | 95.6 |
5.0 | 98.4 | 94.1 |
10.0 | 95.5 | 95.9 |
20.0 | 90.0 | 89.0 |
30.0 | 89.7 | 86.6 |
광민감제 농도(mcg/ml) | Chlorin e6 | Chlorin e6 결합물 |
0,1 | 87,1 | 65,1 |
0,5 | 83,6 | 42,3 |
1,0 | 64,7 | 12,6 |
5,0 | 19 | 0,1 |
10,0 | 3,8 | - |
슬라이드 번호 | 사코마 M-1 슬라이드 면적, ㎠ | 괴사면적, ㎠ | 전체 면적 대비 괴사면적 비율, % |
1 | 2.409 | 0.568 | 24 |
2 | 2.209 | 0.378 | 17 |
3 | 2.457 | 0.460 | 19 |
4 | 2.735 | 0.409 | 15 |
5 | 2.687 | 0.488 | 18 |
6 | 2.761 | 0.864 | 31 |
7 | 2.635 | 0.832 | 32 |
8 | 2.611 | 0.858 | 33 |
9 | 2.394 | 1.038 | 43 |
10 | 2.519 | 0.899 | 36 |
11 | 2.190 | 0.498 | 23 |
12 | 2.348 | 0.579 | 25 |
13 | 2.394 | 0.754 | 32 |
14 | 2.571 | 0.778 | 30 |
15 | 2.780 | 0.996 | 36 |
16 | 2.363 | 0.661 | 28 |
17 | 2.093 | 0.565 | 27 |
18 | 2.212 | 0.795 | 36 |
19 | 2.636 | 0.627 | 24 |
20 | 2.805 | 0.808 | 29 |
21 | 2.587 | 0.414 | 16 |
22 | 2.504 | 0.357 | 14 |
23 | 2.942 | 0.394 | 13 |
24 | 2.471 | 0.369 | 15 |
25 | 2.377 | 0.547 | 23 |
X± | 2.508 | 0.637 | 25.56 |
Sd | 0.042 | 0.041 | 1.651 |
슬라이드 번호 | 사코마 M-1 슬라이드 면적, ㎠ | 괴사면적, ㎠ | 전체 면적 대비 괴사면적 비율, % |
1 | 2.149 | 0.433 | 20 |
2 | 2.412 | 0.668 | 28 |
3 | 2.640 | 0.691 | 26 |
4 | 1.886 | 0.521 | 28 |
5 | 2.664 | 0.792 | 30 |
6 | 2.450 | 0.732 | 30 |
7 | 2.913 | 0.837 | 29 |
8 | 2.845 | 0.994 | 35 |
9 | 2.409 | 0.931 | 39 |
10 | 2.510 | 0.998 | 40 |
11 | 1.937 | 0.474 | 24 |
12 | 1.374 | 0.602 | 44 |
13 | 1.598 | 0.901 | 56 |
14 | 1.412 | 0.642 | 46 |
15 | 1.663 | 0.947 | 57 |
16 | 1.814 | 0.978 | 54 |
17 | 2.226 | 0.548 | 25 |
18 | 1.813 | 0.531 | 29 |
19 | 2.292 | 0.489 | 21 |
20 | 3.105 | 0.927 | 30 |
21 | 2.227 | 0.647 | 29 |
22 | 3.117 | 0.841 | 27 |
23 | 2.835 | 0.810 | 29 |
24 | 2.172 | 0.662 | 30 |
25 | 1.924 | 0.932 | 48 |
X± | 2,255 | 0.741 | 34.16 |
Sd | 0.100 | 0.036 | 2.163 |
슬라이드 번호 | 사코마 M-1 슬라이드 면적, ㎠ | 괴사면적, ㎠ | 전체 면적 대비 괴사면적 비율, % |
1 | 1.399 | 0.913 | 65 |
2 | 1.368 | 0.908 | 66 |
3 | 1.422 | 1.026 | 72 |
4 | 1.533 | 1.196 | 78 |
5 | 1.734 | 1.606 | 93 |
6 | 1.672 | 1.539 | 92 |
7 | 1.724 | 1.473 | 85 |
8 | 1.574 | 1.423 | 90 |
9 | 2.207 | 0.720 | 33 |
10 | 2.503 | 0.860 | 32 |
11 | 1.961 | 1.009 | 51 |
12 | 2.105 | 1.231 | 58 |
13 | 1.891 | 1.690 | 89 |
14 | 2.007 | 1.803 | 90 |
15 | 1.719 | 1.346 | 78 |
16 | 1.460 | 0.988 | 68 |
17 | 2.613 | 0.762 | 29 |
18 | 1.655 | 1.313 | 79 |
19 | 2.124 | 1.075 | 51 |
20 | 2.414 | 1.279 | 53 |
21 | 2.034 | 1.405 | 69 |
22 | 2.357 | 1.165 | 49 |
23 | 2.451 | 1.297 | 53 |
24 | 1.668 | 1.199 | 72 |
25 | 1.557 | 0.919 | 59 |
X± | 1.886 | 1.205 | 66.16 |
Sd | 0.075 | 0.058 | 3.828 |
7 | 10 | 12 | 14 | 17 | 19 | 21 | 24 | |
대조구 | 0.46±0.03 | 1.36±0.09 | 2.75±0.34 | 4.03±0.43 | 8.87±0.66 | 11.53±0.6 | 16.61±0.59 | 18.61±0.78 |
2,5 mg/kg + 100 J/㎠ for 1 h | 0.25±0.03 | 0.28±0.03 | 0.34±0.06 | 0.41±0.09 | 0.46±0.11 | 0.69±0.27 | 0.96±0.38 | 1.19±0.48 |
5 mg/kg + 100 J/㎠ for 1 h | 0.29±0.02 | 0.300±.03 | 0.30±0.03 | 0.30±0.03 | 0.37±0.05 | 0.47±0.11 | 0.50±0.14 | 0.54±0.17 |
10 mg/kg + 100 J/㎠ for 1 h | 0.20±0.03 | 0.19±0.04 | 0.17±0.03 | 0.17±0.03 | 0.17±0.03 | 0.17±0.03 | 0.20±0.03 | 0.20±0.03 |
투여량 | 시간(일)에 따른 래트의 사코마 M-1의 부피 성장 억제율 | |||||||
7 | 10 | 12 | 14 | 17 | 19 | 21 | 24 | |
2,5 mg/100 g +100 J/㎠ for 1 h | 47,5 | 79,4 | 87,6 | 89,8 | 94,8 | 94,1 | 94,2 | 93,6 |
5 mg/100 g +100 J/㎠ for 1 h | 36,9 | 77,9 | 89,1 | 92,6 | 95,8 | 95,9 | 96,9 | 97,1 |
10 mg/100 g +100 J/㎠ for 1 h | 56,5 | 86,0 | 93,8 | 95,8 | 98,1 | 95,2 | 98,8 | 98,9 |
Claims (4)
- 제 1항에 있어서, 상기 키토산은 1000 내지 8000 Da의 분자량 범위를 가지는 것임을 특징으로 하는 광역학적으로 고형암을 치료하기 위한 약학적 조성물.
- 제 1항에 있어서, 상기 클로린 e6-엽산 결합 화합물 또는 이의 약제학적으로 허용 가능한 염과, 키토산의 배합 비율은 75~95 중량부 : 0.5~10 중량부인 것을 특징으로 하는 광역학적으로 고형암을 치료하기 위한 약학적 조성물.
- 제 1항에 있어서, 상기 고형암은 뇌종양, 양성성상세포종, 악성성상세포종, 뇌하수체 선종, 뇌수막종, 뇌림프종, 핍지교종, 두개내인종, 상의세포종, 뇌간종양, 두경부 종양, 후두암, 구인두암, 비강/부비동암, 비인두암, 침샘암, 하인두암, 갑상선암, 구강암, 흉부종양, 소세포성 폐암, 비소세포성 폐암, 흉선암, 종격동 종양, 식도암, 유방암, 남성유방암, 복부종양, 위암, 간암, 담낭암, 담도암, 췌장암, 소장암, 대장암, 항문암, 방광암, 신장암, 전립선암, 자궁경부암, 자궁내막암, 난소암, 자궁육종 및 피부암으로 이루어진 군으로부터 선택되는 어느 하나임을 특징으로 하는 광역학적으로 고형암을 치료하기 위한 약학적 조성물.
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US12/594,180 US20120035180A1 (en) | 2009-04-29 | 2009-04-29 | Pharmaceutical composition for treating cancer comprising chlorin e6-folic acid conjugate compound and chitosan |
JP2011511497A JP2011518891A (ja) | 2009-04-29 | 2009-04-29 | クロリンe6−葉酸結合化合物およびキトサンを含有する癌治療用薬学的組成物 |
EP09844061A EP2431040A1 (en) | 2009-04-29 | 2009-04-29 | Pharmaceutical composition comprising chlorine e6-folic acid conjugated compound and chitosan for treatment of cancer |
BRPI0924296A BRPI0924296A2 (pt) | 2009-04-29 | 2009-04-29 | composição farmacêutica para tratar do câncer compreendendo um composto conjugado de cloro e6-ácido fólico e quitosana |
CN2009800002080A CN101977608A (zh) | 2009-04-29 | 2009-04-29 | 含有二氢卟酚e6-叶酸共轭化合物和壳聚糖的用于癌症治疗的药物组合物 |
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GRAVIER JULIEN ET AL.: "Improvement of meta-tetra(Hydroxyphenyl) chlorin-Like Photosensitizer Selectivity with Folate-Based Targeted Delivery. Synthesis and in Vivo Delivery Studies", J. MED. CHEM., vol. 51, 2008, pages 3867 - 3877, XP008152133 * |
PRIVALOV VALERY A. ET AL.: "Five Years' Experience of Photodynamic Therapy with New Chlorin Photosensitizer", PROCEEDINGS OF SPIE, vol. 5863, 2005, pages 186 - 198, XP008152134 * |
UZDENSKY A.B. ET AL.: "Photodynamic effect of novel chlorin e6 derivatives on a single nerve cell", LIFE SCIENCES, vol. 74, 2004, pages 2185 - 2197, XP008150873 * |
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