KR20160053082A - Water soluble chlorine derivative with photoactivity and preparation method thereof - Google Patents

Abstract

The present invention relates to a novel photosensitizer for photodynamic diagnosis or treatment, which has improved dispersibility in water as compared to the conventional hardly soluble photosensitzers, absorbs light with a broader wavelength range and longer wavelength as compared to the conventional photosensitizers, is accumulated selectively on cancer cells to show a cytotoxic effect. The present invention also relates to a method for preparing the photosensitizer. According to the present invention, triethylene glycol (TEG) dendron is introduced to a chlorin photosensitizer to improve dispersibility in water as compared to the conventional photosensitizers, chlorin absorbs light in a PBS solvent similar to the in vivo environment, the PBS (containing water) solvent is provided with solvent affinity by TEG dendron, thereby producing active oxygen in vivo. In addition, it is difficult to prepare a TEG-chlorin derivative directly and to obtain structural configuration other than limited structural configuration. To solve such problems, according to the method of the present invention, a desired functional group and TEG dendron are coupled to porphyrin first to obtain a water soluble porphyrin derivative having a novel structure and then porphyrin is converted into chlorin to obtain a chlorin derivative having a desired structure in a simple and cost-efficient manner.

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a water-soluble chlorine derivative having a photo-

The present invention relates to a photosensitizing agent for photodynamic diagnosis or treatment and a method for preparing the same. More particularly, the present invention relates to a method for preparing a water-soluble derivative of chlorine, which absorbs a longer wavelength than a conventional photosensitizer, And then converting the porphyrin to chlorine to synthesize a water-soluble chlorine derivative having photoactive activity, and to a photodynamic agent for photodynamic diagnosis or treatment using the same and a method for producing the same.

Photodynamic therapy (PDT) is a therapy using light, photosensitizer, active oxygen in the body, a method of injecting a photosensitizer into the body and irradiating a laser light having a specific wavelength to a disease site to treat the disease . In 1904, von Tappeiner and Jadlbauer demonstrated the need for oxygen in the photoreceptor response, explaining it as oxygen-dependent light sensitization in 1907, and the terminology of photodynamic therapy was established and academic research began. And has been used for the treatment of various diseases such as cancer diagnosis and treatment, autologous bone marrow transplantation, antibiotic treatment, AIDS treatment, skin graft surgery and arthritis, and its application range is gradually increasing.

More specifically, the photodynamic therapy used in the treatment of cancer is a chemical reaction by oxygen in the body and external light by irradiating a light to a photosensitizer which absorbs light of a specific wavelength, thereby causing singlet oxygen or free radical free radicals are produced and these unicellular oxygen or free radicals are destroyed by inducing apoptosis of various lesion sites or cancer cells while preserving normal cells as they are.

Photodynamic therapy is selectively accumulated in cancer cells, and it can complement the existing cancer treatment methods such as surgical operation, radiation therapy, side effects of drug therapy, and aftereffects after cancer treatment, and can be performed by local anesthesia alone. Even an institution can preserve its function and form, and it does not leave tissue damage or scarring.

Examples of the photosensitizer include porphyrins, chlorins, bacteriochlorins, phthalocyanine, 5-aminolevulinic acid, porphycenes, etc. , There is a problem that it is difficult to form a formulation capable of parenteral administration due to the hydrophobic photosensitizer in the clinical application of the photodynamic therapy, so it is necessary to increase the water solubility. Therefore, most of the photosensitizers currently used in photodynamic cancer treatments have low solubility when administered in vivo, inadequate interaction with biomolecules, mutual entanglement between photosensitizers, And low photoreactivity. Thus, the effect of treatment is low. Ideal photosensitizers can reach tumor maxima in a short time, metabolized and excreted quickly in normal tissues, and should respond to longer wavelengths of light.

However, existing porphyrin-based photosensitizers do not deviate significantly from the absorption wavelength band of 630 nm, such as photofrin or benzoporphyrin, and their use is restricted depending on tumor size. In contrast, photosensitizers based on chlorine and bacteriocin are monomeric compounds that produce singlet oxygen effectively and have long wavelength absorption near 650 nm and long absorption wavelengths, which is effective in treating deeply located tumors [ Zheng, X. et al., J. Med. Chem. 2009, 52: 4306-4318. Chlorine and chlorine derivatives are also generally not toxic to normal cells in the organism. At the same time, however, the hydrophobicity is strong and only a definite structural form such as perofoboid A, chlorine e6 and chlorine e4 is obtained, and it is difficult to form various derivatives by attaching other functional groups.

Korean Patent Laid-Open No. 10-2009-0047872 "Novel carbohydrate complex chlorine compound and its preparation method" relate to a novel carbohydrate complex chlorine compound and a preparation method thereof. According to the present invention, The present invention provides novel carbohydrate complex chlorine compounds which can be used for the detection of tumor markers by producing compounds and confirming that the chlorine compounds exhibit an excellent binding force with galectin used as a cancer diagnostic marker and a method for producing the same. However, such chlorine can only be obtained in a limited structural form, and such a production method is not economical and it is not easy to produce a derivative having another water-soluble functional group.

Korean Patent No. 10-0911250 discloses a novel method for producing a choline e6-folic acid binding compound, which comprises reacting chlorin e6 with folic acid in hexane-1,6-diamine or 2, Linking the terminal linker through 2'-ethylenedioxy-bis-ethylamine effectively produces singlet oxygen in various media and has remarkably superior tumor selectivity compared to the conventional porphyrin-based photosensitizing agents, resulting in photodynamic therapy for malignant tumors Lt; RTI ID = 0.0 > e6-folic < / RTI > acid binding compound. However, the structure of chlorine is also limited, and it is difficult to attach a hydrophilic functional group, and such a production method is not economical, and it is not easy to produce a derivative having another water soluble functional group.

In order to overcome the problems inherent in conventional chlorine-based photosensitizers, it is necessary to combine TEG dendron, a water-soluble polymer, with porphyrin, a light-absorbing material for photosensitization, and then convert porphyrin into chlorine TEG dendron - chlorine polymer was prepared and its properties were confirmed. In particular, the present inventors have completed the present invention by confirming a method for producing a chlorine-based polymer by synthesizing a water-soluble porphyrin derivative having a novel structure by binding a desired functional group to porphyrin and then converting the porphyrin to chlorine to synthesize a chlorine derivative having a desired structure.

Disclosure of the Invention An object of the present invention is to provide a novel method for improving the dispersibility in water compared to the conventional poorly soluble photosensitizer and to provide a method of absorbing light of a longer wavelength and longer wavelength than the conventional photosensitizer and accumulating selectively in cancer cells, And to provide a novel photodynamic diagnostic or therapeutic agent and a method for producing the same.

Especially a novel photo-sensitizer which is difficult to synthesize directly.

In order to achieve the above object, the present invention provides a photodynamic agent for photodynamic diagnosis or treatment, which is represented by the following formula (1).

P- (A) n (1)

In the formula (1), P is a molecule having a structure capable of absorbing light of a specific wavelength, A is a polymer which is a polymer of a water-soluble monomer, n is a covalent bond The number of the A connected through the A /

The polymer which is a polymer of the water soluble monomer may be TEG (triethylene glycol) dendron or PEG (polyethylene glycol).

The molecule having a structure capable of absorbing the light of the specific wavelength may be one molecule selected from the group consisting of porphyrin, chlorin, bacteriochlorin, phtalocyanine, naphthalocyanine, Lt; / RTI >

Wherein the polymer that is a polymer of the water soluble monomer is TEG (triethylene glycol) dendron, the molecule having a structure capable of absorbing the light of the specific wavelength is chlorin, the n is 1, 1). ≪ / RTI >

≪ Formula (1) >

The photosensitizer may exhibit photosensitizing activity against light rays of 640 to 660 nm.

The photosensitizer can diagnose or treat solid tumors photodynamically.

The present invention also relates to a method for producing a water-soluble monomer, which comprises: (1) synthesizing a polymer which is a polymer of a water-soluble monomer; (2) synthesizing a precursor of a structural molecule capable of absorbing light of a specific wavelength, and combining the precursor with the polymer of the step (1); And (3) a step of converting a precursor of a structural molecule capable of absorbing light of a specific wavelength into a structural molecule capable of absorbing light of a specific wavelength, in the polymer of the above step (2) There is provided a method for producing a light sensitizer.

In the step (1), the polymer which is a polymer of the water-soluble monomer may be synthesized by polymerizing a TEG (triethylene glycol) monomer to synthesize a TEG dendron.

The structural molecule capable of absorbing light of a specific wavelength in steps (2) and (3) may be a derivative of chlorine or chlorine.

The precursor of the structural molecule capable of absorbing the light of the specific wavelength may be a derivative of porphyrin or porphyrin.

The conversion may be performed by sequentially treating p-toluenesulphonyl hydrazide dissolved in a pyridine solvent and ρ-chloranil dissolved in an organic solvent.

According to the present invention, by introducing a triethylene glycol dendron into the chlorine photosensitizer, the dispersibility of the photo-sensitizer is improved compared to the conventional photosensitizer. In the PBS solvent similar to the in-vivo environment, And adsorbed to the PBS (including water) solvent by the TEG dendron to give active oxygen in vivo.

In addition, it is difficult to directly synthesize a TEG-choline derivative, and it is difficult to obtain only a limited structural form. To overcome this problem, a water-soluble porphyrin derivative having a novel structure is synthesized by bonding a desired functional group to porphyrin with TEG dendron, A method of easily synthesizing a chlorine derivative of a desired structure by converting porphyrin into chlorine has been established.

FIG. 1 is a schematic diagram illustrating the synthesis of TEG (3) -G (O) -CH ₂ Br.
FIG. 2 shows the molecular structure analysis by ¹ H NMR to confirm whether TEG (3) -G (O) -CH ₂ Br is synthesized
FIG. 3 is a schematic diagram illustrating a porphyrin ring synthesis process. FIG.
FIG. 4 shows a molecular weight measurement analysis by MALDI-TOF for confirming the synthesis of a porphyrin ring
FIG. 5 is a schematic diagram showing a process of synthesizing TEG-porphyrin-CO ₂ CH _3. FIG.
FIG. 6 shows a molecular weight measurement analysis by MALDI-TOF for confirming the synthesis of TEG-porphyrin-CO ₂ CH ₃
FIG. 7 is a schematic diagram illustrating a TEG-porphyrin-COOH synthesis process. FIG.
8 is a molecular weight measurement analysis by MALDI-TOF which confirms the synthesis of TEG-porphyrin-COOH
FIG. 9 is a schematic diagram illustrating a TEG-chlorin synthesis process. FIG.
FIG. 10 is a graph showing the results of molecular weight measurement analysis by MALDI-TOF for confirming the synthesis of TEG-
Fig. 11 shows the UV-Vis absorption spectrum difference of porphyrin, bacteriocin and chlorine. Fig.
Fig. 12 shows fluorescence spectrum difference between porphyrin and chlorine. Fig.
FIG. 13 is a photograph of a state in which TEG-chlorine is dissolved in THF solvent and PBS solvent.
14 shows UV-Vis absorption spectrum of TEG-chlorine dissolved in THF solvent and PBS solvent.
15 shows the fluorescence spectrum of TEG-chlorine dissolved in THF solvent and PBS solvent.
FIG. 16 is a schematic diagram showing the entire synthesis process of TEG-chlorine. FIG.

Hereinafter, the present invention will be described in detail.

The present invention provides a photodynamic agent for photodynamic diagnosis or treatment, which is represented by the following formula (1).

P- (A) n (1)

In the formula (1), P is a molecule having a structure capable of absorbing light of a specific wavelength, A is a polymer which is a polymer of a water-soluble monomer, n is a covalent bond The number of the A connected through the A /

The polymer which is a polymer of the water-soluble monomer is characterized by being TEG (triethylene glycol) dendron or PEG (polyethylene glycol).

The molecule having a structure capable of absorbing the light of the specific wavelength may be one molecule selected from the group consisting of porphyrin, chlorin, bacteriochlorin, phtalocyanine, naphthalocyanine, .

Wherein the polymer that is a polymer of the water soluble monomer is TEG (triethylene glycol) dendron, the molecule having a structure capable of absorbing the light of the specific wavelength is chlorin, the n is 1, 1). ≪ / RTI >

≪ Formula (1) >

Wherein the photosensitizer exhibits a photosensitizing activity against a light beam of 640 to 660 nm. And preferably exhibits a photosensitizing activity against a light beam of 640 to 650 nm.

The photosensitizer is characterized by photodynamic diagnosis or treatment of solid tumors.

In another aspect, the present invention provides a method for producing a water-soluble monomer, comprising: (1) synthesizing a polymer which is a polymer of a water-soluble monomer; (2) synthesizing a precursor of a structural molecule capable of absorbing light of a specific wavelength, and combining the precursor with the polymer of the step (1); And (3) a step of converting a precursor of a structural molecule capable of absorbing light of a specific wavelength into a structural molecule capable of absorbing light of a specific wavelength, in the polymer of the above step (2) There is provided a method for producing a light sensitizer.

The synthesis of the polymer as the polymer of the water-soluble monomer in the step (1) is characterized by synthesizing a TEG dendron by polymerizing a TEG (triethylene glycol) monomer.

The structural molecules capable of absorbing light of a specific wavelength in steps (2) and (3) are derivatives of chlorine or chlorine.

And the precursor of the structural molecule capable of absorbing the light of the specific wavelength is a derivative of porphyrin or porphyrin.

The conversion process is characterized by sequentially treating p-toluenesulphonyl hydrazide dissolved in a pyridine solvent and ρ-chloranil dissolved in an organic solvent.

The central chlorin of the photosensitizer for photodynamic diagnosis or treatment according to the present invention has a light absorption wavelength band exceeding 640 nm and can not be widely deviated from the absorption wavelength band of 630 nm conventionally such as photofrin or benzoporphyrin, The present invention has the merit of complementing the disadvantages of the existing photosensitizer which can not treat tumors of terminal cancer patients lacking oxygen molecules in the cells by supplementing the disadvantages of the existing photosensitizer and relying only on activation of oxygen molecules present in the cells. However, in order to overcome these disadvantages, chlorin has only a limited structural form such as perofoboid A, chlorine e6 and chlorine e4, and it is difficult to attach other functional groups. In order to overcome this disadvantage, A water-soluble porphyrin derivative was synthesized, and porphyrin was converted to chlorine to synthesize a chlorine derivative having a desired structure.

Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are merely illustrative of the present invention and that the scope of the present invention is not construed as being limited by these embodiments.

Example 1. TEG (3) -G (O) -CH ₂ Formation of Br

Overall, the formation of TEG (3) -G (O) -CH ₂ Br was synthesized using known methods as shown in FIG. First, Tosylation was performed using Tosyl chloride in triethylene glycol monomethyl ether, followed by Williamson ester synthesis. TEG (3) -G (O) -CH ₂ OH was synthesized by the reduction reaction using LiAlH ₄ and the -CH ₂ OH group was converted into the Bromination with -CH ₂ Br group for the subsequent coupling reaction.

The formation of intermediates in each step was confirmed by analyzing the molecular structure by ¹ H NMR. ^{1 H NMR (600 MHz; TMS} ) of the measuring solvent was used as the CDCl _3.

(1) TEG Tosylation

More specifically, add a mixture of triethylene glycol monomethyl ether (TEG) and NaOH to a 1000 ml flask and mix well. Add 4-Toluenesulfonyl chloride to the dropping funnel and dissolve in THF. Dropping slowly over 1 hour while maintaining the temperature at 5 [deg.] C. After dropping, stir at room temperature for 18 hours. Add water, MC, hydrochloric acid, MC, water and MC to the mixture in order to wash. Finally, a silica column (8 cm x 14 cm, EA: Hexane was used in a ratio of 5: 5 to 9: 1) was separated and the result was confirmed by NMR. This process corresponds to the step (a) of FIG.

(2) Williamson reaction of TEG-OTs and metyl 3,4,5-trihydroxybenzoate

Add metyl 3,4,5-dihydroxybenzylalcohol, TEG-OTs, 18-crown-6 and K ₂ CO ₃ to a 2-neck round flask with a capacity of 1000 ml. After three times of vacuum treatment and nitrogen treatment, THF is added with nitrogen only. After the vacuum treatment is performed once, the nitrogen is filled for 5 minutes. The solution was monitored while proceeding with reflux for 12 hours while maintaining the temperature at 90 ° C, and then separated using a silica column. The results were confirmed by NMR. This process corresponds to step (b) of FIG.

(3) TEG-G (O) -CO ₂ CH ₃ Reduction reaction of

Add LiAlH ₄ to a 2-neck round flask with a capacity of 1000 ml, add TEG-G (0) -CO ₂ CH ₃ to the dropping funnel, perform a vacuum treatment for 20 minutes, and dry the tube for 1 minute with nitrogen. 100 ml of THF in a 1000 ml flask and 100 ml of THF in a dropping funnel are added to each flask, and the flask is agitated for 5 minutes so that THF and LiAlH ₄ are mixed well in the flask. Dropwise is performed in an ice bath. Work-up with a drop of water using a micropipette (with stirring) and then add 15% NaOH if no more H ₂ is present. After removing THF solvent by evaporating, the remaining material was confirmed by NMR. This process corresponds to the step (c) of FIG.

(4) TEG-G (O) -CH ₂ OH Bromination

Contain TEG-G (O) -CH ₂ OH and CBr ₄ in a 1000-ml 2-neck round flask, add PPh ₃ to the dropping funnel, perform 20 min of vacuum and 1 min of nitrogen dry for 3 times. Add 2 ml of THF in a 1000 ml flask and 50 ml of THF in a dropping funnel. Stir in the ice bath for 5 minutes until the flask is well mixed with THF and CBr4. Slow dropping is carried out for 1 hour while maintaining 0 to 5 ° C in an ice bath. When the reaction is confirmed to be completed, the reaction is terminated, which is extracted several times with MC and Water, and then dried with anhydrous sodium sulfate (Na ₂ SO ₄ ). Removal of impurities by filtration was followed by evaporation to remove the THF solvent. The product was purified by using a silica column (CH ₂ Cl ₂ / Methanol = 10: 1) to obtain a yellow oil-like product, and the result was confirmed by NMR. This process corresponds to the step (d) in FIG.

Finally, TEG (3) -G (0 ) -CH 2 Br was formed.

Example 2. Porphyrin ring synthesis

Overall, the porphyrin rings were synthesized using known methods as shown in FIG. First, dissolve in 3,5-dihydroxybenzaldehyde and MeOH in a 1000 mL round-bottomed flask, and stir to confirm that 3,5-dihydroxybenzaldehyde is dissolved. DPM and Methyl 4-formyl-benzoate are dissolved in CHCl ₃ and nitrogen bubbled for 30 minutes. Add BF ₃ OEt ₂ and stir in the dark for 6 hours. When the reaction is confirmed, P-chloranil is added and stirred for 1 hour. Add TEA and stir for 30 minutes, then evaporate to remove the solvent. After purification by silica column, the results were confirmed by molecular weight measurement by MALDI-TOF. Finally, after washing with water, it was dried with anhydrous sodium sulfate (Na ₂ SO ₄ ).

Example 3. TEG-porphyrin-CO ₂ CH ₃ Formation of

Overall, TEG-porphyrin-CO ₂ CH ₃ was synthesized using known methods as shown in FIG. First, add TEG (3) -G (O) -CH ₂ Br, Porphyrin-CO ₂ CH ₃ , K ₂ CO ₃ , and 18-crown-6 to a 30 ml shrunk. THF is prepared by repeating vacuum and nitrogen three times, removing reaction impurities such as H ₂ O and O ₂ and forming a nitrogen atmosphere. While maintaining the temperature at 90 ° C, stirring is continued while proceeding with reflux. When the reaction is completed, the reaction mixture is cooled to room temperature and filtered under reduced pressure. After filtration, it is extracted several times with CHCl ₃ and water, and then dried with anhydrous sodium sulfate (Na ₂ SO ₄ ). The solvent is removed under reduced pressure and separated by size exclusion chromatography (Open GPC). The results were then confirmed by molecular weight measurements by MALDI-TOF.

Example 4. Formation of TEG-porphyrin-COOH

As a whole, TEG-porphyrin-COOH was synthesized by hydrolyzing TEG-porphyrin-CO ₂ CH ₃ using a method known as NaOH, as shown in FIG. The results were then confirmed by molecular weight measurements by MALDI-TOF.

Example 5. Chlorination of TEG-porphyrin

Overall, the conversion of TEG-porphyrin to TEG-chlorine was synthesized using the method shown in FIG. First, p-toluenesulphonyl hydrazide is vacuum-treated and purged with nitrogen, placed in anhydrous pyridine, and stirred for 20 minutes to prepare solution (1). Subsequently, p-toluenesulphonyl hydrazide (180 mg) was vacuum-treated and replaced with nitrogen, placed in anhydrous pyridine, and stirred for 20 minutes to prepare solution (2). Anhydrous K ₂ CO ₃ is subjected to nitrogen treatment and vacuum substitution at 90-100 ° C. TEG-porphyrin is subjected to nitrogen treatment and vacuum substitution, and the prepared solution (1) is treated. (2) times at 100 to 105 ° C in a nitrogen state for 12 hours is added every 2, 4, 6, and 8 hours. A mixture of EA and DI water in a two-to-one ratio was added and stirred at 100 ° C for one hour. The organic layer was separated with HCl (2M), DI water and NaHCO ₃ solvent and washed. Add ρ-chloranil to the organic solvent several times and stir at room temperature until absorption peak at ~ 735 nm disappears. Finally, wash with NaHSO ₃ (5%), DI water, NaOH (0.01 M) saturated NaHCO ₃ solution, dry with anhydrous sodium sulfate (Na ₂ SO ₄ ) and evaporate the solvent. The results were confirmed by molecular weight measurement by MALDI-TOF.

The overall procedure from Example 1 to Example 5 is summarized in FIG.

EXPERIMENTAL EXAMPLE 1 Identification of Produced Substances

Whether or not the substance was produced in each step was confirmed by separating the second fraction from the column chromatography and measuring the molecular weight by MALDI-TOF or ¹ H NMR. ^{1 H NMR (300 MHz; TMS} ) solvent for measurement was used as the CDCl _3. The final TEG-Chlorine formation was confirmed by molecular weight determination by MALDI-TOF.

(1) Synthesis of TEG (3) -G (O) -CH ₂ Formation of Br

FIG. 2 shows the molecular structure analysis of TEG (3) -G (O) -CH ₂ Br formed by Example 1 by ¹ H NMR.

The characteristic peaks are the H (6.6 ppm) of the 9 H (3.4 ppm) of the ⓐ portion in the TEG chain and the 2 ⓑ portion of the hydrogen bonded to the G (0) phenyl ring, confirming the presence of these peaks were there in the CH ₂ OH sure that the missing one H (1.65ppm) peaks of the -OH group to TEG (3) -G (0) -CH 2 Br are formed -, TEG (3) -G ( 0) Respectively.

G is an abbreviation of generation and means the number of households of TEG dendron.

(2) Formation of porphyrin according to Example 2

Fig. 4 shows molecular weight measurements of porphyrin formed by Example 2 by MALDI-TOF. It was confirmed that a characteristic peak of molecular weight (553.6) corresponding to porphyrin was formed.

(3) TEG-porphyrin-CO according to Example 3 ₂ CH ₃ Formation of

FIG. 6 shows Molecular weight measurement by MALDI-TOF for TEG-porphyrin-CO ₂ CH ₃ formed by Example 3. FIG. It was confirmed that a characteristic peak of molecular weight (1706) corresponding to TEG-porphyrin-CO ₂ CH ₃ was formed.

(4) Formation of TEG-porphyrin-COOH according to Example 4

FIG. 8 shows the molecular weight measurement by MALDI-TOF for TEG-porphyrin-COOH formed by Example 4. FIG. And a characteristic peak of molecular weight (1692.5) corresponding to TEG-porphyrin-COOH was formed.

(5) Formation of TEG-chlorine according to Example 5

10 shows the molecular weight measurement by MALDI-TOF for TEG-choline formed by Example 5. Fig. Since the change from porphyrin to chlorine resulted in a change of one hydrogen, the expected mass was 1694, which was +1 at 1693, confirming that the corresponding peak appeared.

FIG. 11 is a graph showing changes in UV-Vis absorption spectrum in the course of conversion of TEG-porphyrin to TEG-chlorine according to Example 5. FIG. During the conversion process, the 735 nm peak (see the red arrow in FIG. 11) of the intermediate bacteriochlorin appeared with the 640 nm peak, and after the completion of the reaction, the peak disappeared and the peak at 640 nm (See blue arrow in FIG.

FIG. 12 is a graph showing the conversion of TEG-porphyrin to TEG-chlorine by the fluorescence spectrum (THF solvent / excitation: 410 nm / absorbance: 1.15@403 nm / range: 400-800 nm) The fluorescence properties of porphyrin showing two peaks were changed to show only one peak of fluorescence characteristic of chlorine after conversion.

It was confirmed that TEG-chlorine was formed by the above three methods.

Experimental Example 2 Visual observation of solubility in THF solvent and PBS solvent

Chlorine was dissolved in THF (Tetrahydrofuran) and PBS (Phosphate Buffer Saline, 100: 1). Unlike the case of dissolving in THF (Fig. 13 (a)), when dissolved in PBS (Fig. 13 (b)), TEG shows the formation of a pseudo-micelle structure in a PBS solution.

Experimental Example 3. UV-Vis absorption spectrum measurement

The UV-Vis absorption spectrum was measured by dissolving TEG-chlorine obtained in the above example in THF (Tetrahydrofuran) solvent and PBS (Phosphate Buffer Saline) solvent (see FIG. 14). .

In the case of TEG-chlorine, both absorption peaks were formed at 410 nm and another peak was formed at 644 nm. However, the absorption peak of PBS solvent was less than half of that of THF solvent, and the peak was broadly changed to absorb light of a broader range of wavelengths.

Experimental Example 4. Fluorescence Spectrum Measurement

TEG-choline obtained in the above example was dissolved in THF (Tetrahydrofuran) solvent and PBS (Phosphate Buffer Saline) solvent and fluorescence spectrum (THF solvent / excitation: 410 nm / absorbance: 1.15@403 nm / range: 400-800 nm) was measured .

As a result, fluorescence was observed at 645.5 nm and fluorescence intensities were significantly reduced when PBS solvent was used (see FIG. 15).

In the PBS solvent, the strength was decreased to 43.8 and 2.2, 20 times. This suggests that the aggregation due to the formation of micelles in PBS causes quenching, resulting in weak fluorescence. These results indicate that the hydrophilicity is enhanced by the introduced TEG dendron to easily form micelles, thereby securing stability in an aqueous solution.

In conclusion, TEG-chlorine The material can be used as a photosensitizer for photodynamic diagnosis and treatment, and the method of synthesizing TEG-chlorine by chlorination after first synthesizing TEG-porphyrin is easier than synthesis by using chlorin as starting material And it can be an economical method.

Having described specific portions of the present invention in detail, it will be apparent to those skilled in the art that this specific description is only a preferred embodiment and that the scope of the present invention is not limited thereby. It will be obvious. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.

Claims (11)

A photosensitizer for photodynamic diagnosis or treatment, represented by the following formula (1);
P- (A) n (1)
In the above formula (1)
P is a molecule having a structure capable of absorbing light of a specific wavelength,
A is a polymer which is a polymer of a water-soluble monomer,
n is an integer of 1 or more as the number of A connected to the P through a covalent bond mediated directly or via a crosslinking agent.
The polymer of claim 1, wherein the polymer of the water-
Wherein the photodynamic agent is TEG (triethylene glycol) dendron or PEG (polyethylene glycol).
The method according to claim 1, wherein the molecule having a structure capable of absorbing the light of the specific wavelength comprises:
Wherein the photosensitizer is a molecule selected from the group consisting of porphyrin, chlorin, bacteriochlorin, phthalocyanine, and naphthalocyanine.
The method according to claim 1,
The polymer which is a polymer of the water-soluble monomer is TEG (triethylene glycol) dendron,
The molecule having a structure capable of absorbing the light of the specific wavelength is chlorin,
Wherein n is 1 and is represented by the following formula (1).
≪ Formula (1) >

5. The method of claim 4,
Wherein the photosensitizer exhibits photosensitizing activity against light rays of 640 to 660 nm.
5. The method of claim 4,
Wherein said photosensitizer is a photodynamic diagnostic or therapeutic agent for photodynamic diagnosis, characterized in that said solid tumor is photodynamically diagnosed or treated.
(1) synthesizing a polymer which is a polymer of a water-soluble monomer;
(2) synthesizing a precursor of a structural molecule capable of absorbing light of a specific wavelength, and combining the precursor with the polymer of the step (1); And
(3) a step of converting the precursor of the structural molecule capable of absorbing light of a specific wavelength into a structural molecule capable of absorbing light of a specific wavelength, in the polymer of the step (2) A method of producing a photosensitizer;
8. The method of claim 7,
The synthesis of the polymer as the polymer of the water-soluble monomer in the step (1)
Wherein the TEG (triethylene glycol) monomer is polymerized to synthesize a TEG dendron.
8. The method of claim 7,
Wherein the structural molecule capable of absorbing light of a specific wavelength in steps (2) and (3) is a derivative of chlorine or chlorine.
10. The method of claim 9,
Wherein the precursor of the structural molecule capable of absorbing light of the specific wavelength is a derivative of porphyrin or porphyrin.
11. The method of claim 10,
The conversion process includes:
wherein the method comprises sequentially treating p-toluenesulphonyl hydrazide dissolved in a pyridine solvent and ρ-chloranil dissolved in an organic solvent.

Images