CN103539799A - Preparation method and application of water-soluble aminopolycarboxylic acid modified phthalocyanine compound - Google Patents
Preparation method and application of water-soluble aminopolycarboxylic acid modified phthalocyanine compound Download PDFInfo
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- CN103539799A CN103539799A CN201310389970.0A CN201310389970A CN103539799A CN 103539799 A CN103539799 A CN 103539799A CN 201310389970 A CN201310389970 A CN 201310389970A CN 103539799 A CN103539799 A CN 103539799A
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- acid
- phthalocyanine compound
- dicyclo
- acid anhydride
- phthalocyanine
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- -1 modified phthalocyanine compound Chemical class 0.000 title claims abstract description 175
- 239000002253 acid Substances 0.000 title claims abstract description 46
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- IEQIEDJGQAUEQZ-UHFFFAOYSA-N phthalocyanine Chemical compound N1C(N=C2C3=CC=CC=C3C(N=C3C4=CC=CC=C4C(=N4)N3)=N2)=C(C=CC=C2)C2=C1N=C1C2=CC=CC=C2C4=N1 IEQIEDJGQAUEQZ-UHFFFAOYSA-N 0.000 claims abstract description 32
- 239000007864 aqueous solution Substances 0.000 claims abstract description 24
- 238000000034 method Methods 0.000 claims abstract description 15
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings
-
- 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
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
- A61K49/0036—Porphyrins
Abstract
The invention discloses a water-soluble aminopolycarboxylic acid modified phthalocyanine compound as well as a preparation method and an application thereof. The water-soluble aminopolycarboxylic acid modified phthalocyanine compound is characterized in that the side chain or the center is connected to aminopolycarboxylic acid, the aminopolycarboxylic acid connected to the side chain is as shown in a structure (I) in the description, and the aminopolycarboxylic acid connected to the center is as shown in a structure (II) in the description. The preparation method of the water-soluble aminopolycarboxylic acid modified phthalocyanine compound is simple and easy to operate. After the phthalocyanines compound is modified by the method, the phthalocyanine compound has stable chemical property and can be completely dissolved in a sodium bicarbonate aqueous solution, the degree of self aggregation of phthalocyanine is reduced, and the phthalocyanine compound is absorbed in a 600-900 nm near-infrared zone and can be applied to the fields of near infrared fluorescence imaging or photodynamic tumor treatment.
Description
Technical field
The invention belongs to organic synthesis and pharmaceutical field, be specifically related to a kind of water soluble amino poly carboxylic acid and modify phthalocyanine compound, Preparation method and use.Particularly relate to by phthalocyanine active intermediate and aminopolycanboxylic acid's anhydride reactant, the aminopolycanboxylic acid who obtains being dissolvable in water sodium bicarbonate aqueous solution modifies phthalocyanine compound, and this aminopolycanboxylic acid modifies phthalocyanine compound aspect optical dynamic treatment of tumor and the application of near-infrared fluorescence imaging aspect.
Background technology
Malignant tumour is one of disease of healing of the refractory in the world today, and the whole world approximately has 7,600,000 people therefore to die every year.At present the clinical treatment method of tumour has chemotherapy, radiotherapy, operation and biological control etc., but there is no a kind for the treatment of means, can accomplish the life quality of not only eradicating tumour but also taking into account patient, the source of being therefore familiar with disease by with explore new methods for the treatment of and seem particularly urgent.
Photodynamic therapy (Photodynamic Therapy, PDT) is a kind of new tumor therapeuticing method that developed recently gets up.It utilizes tumor tissues to take in the selectivity of particular chemicals, and the optical excitation by certain wavelength under the condition existing at oxygen produces the object that photodynamic effect reaches destruction tumor tissues.Because the transformation period of photosensitizers in different tissues is variant, cause the concentration of photosensitizers in tumor tissues apparently higher than healthy tissues, therefore can utilize this difference to carry out magnetic target therapy.The 1993 official approval PhotofrinII of Nian， Her Majesty the Queen in right of Canada as represented by the minister of Healt are for the treatment of bladder cancer.After this, tens countries such as Japan, the U.S., Britain, Germany, Holland, Norway also ratify PDT in succession for the treatment of the malignant tumours such as cancer of the stomach, lung cancer, the esophageal carcinoma, cervical cancer, and the status of photodynamic therapy in clinical application established.
Near-infrared fluorescence imaging (Near-infrared fluorescent, NIRF) is as a kind of non-invasive diagnosing method in optical imaging field, has that energy emission is low, susceptibility is high and the advantage such as tissue penetration is strong.Its ultimate principle is the excitation light source irradiation photosensitizers with specific wavelength, makes photosensitizers produce the photon signal of different spectral response curves, then by signals collecting and data processing, obtains corresponding image.In near infrared spectrum district, photoabsorption or the fluorescence intensity of biological sample matrix are very little, as oxyphorase and water all minimum in the absorption in this region, thereby background interference reduces greatly; And because the biquadratic of scattered light intensity and wavelength is inversely proportional to, along with the increase of wavelength, Raman scattering reduces rapidly, scattering is disturbed and also greatly reduced; Near-infrared fluorescent can penetrate the distance maximum of biological tissue simultaneously.Therefore, adopt near-infrared fluorescence imaging not only highly sensitive, and can to the tissue of deep layer and organ is surveyed and imaging.
The core of optical dynamic therapy and near-infrared fluorescence imaging research is photosensitizers.The defect such as long, easily gathering of residence time, long wave direction absorption difference because the photosensitizers using clinically at present exists that effective constituent is uncertain, in body, so people start to seek novel photosensitive drug one after another.Wherein, phthalocyanine is considered to photosensitive dose of most promising a new generation.First Israel chemist Ben-Hur in 1985 etc. have reported the photoinactivation of aluminum oxide phthalocyanine to cancer cells, have caused medicine scholar's broad interest.Phthalocyanine is the macrocylc compound with 18 conjugated electrons systems that a class is comprised of four isoindole unit, as a kind of, completely by the photosensitizers of synthetic, its structure and composition is clear and definite, quality controllable, and can carry out structural modification to it, obtain the photosensitive drug with good physicochemical property.Compare with the photosensitizers of other types such as porphyrin, phthalocyanine has the following advantages: as single in compound composition, good photo and thermal stability and biological activity, higher molar extinction coefficient, singlet oxygen and fluorescence quantum yield etc., thereby phthalocyanine-like compound is suitable for imaging in biological tissues and optical dynamic therapy.But due to the water-soluble and organic solvent hardly of the phthalocyanine without replacing, greatly limited its application.Improving the water miscible method of phthalocyanine, is generally on phenyl ring, to introduce the hydrophilic radicals such as sulfonic acid, amino acid, carboxylic acid, sugar or PEG.Some PDT effect of compound that aforesaid method is modified is not high, and some synthesis technique is complicated, and separated redundant and complicated, is unfavorable for suitability for industrialized production.Because aminopolycanboxylic acid's system is if Gd-DTPA modified porphyrin is as magnetic imaging probe molecule, for clinical, there is good biocompatibility and distinct pathways metabolism, and synthetic method is relatively easy, can directly by ester bond or amido linkage, connect.Thereby we introduce aminopolycanboxylic acid's class polar group by this system at phthalocyanine periphery, a series of new photosensitizerss have been synthesized.Those photosensitizerss have water-soluble and histocompatibility preferably, not only be easy to make up a prescription, the more important thing is that having increased photosensitizers takes in distribution and the selectivity of the target tissues such as tumour, is strengthened light power effect, and reduced side effects, and the phototoxicity of skin is far smaller than to porphyrin.Aminopolycanboxylic acid modifies the maximum absorption wavelength of phthalocyanine compound at 650nm, fluorescent emission wavelength is at 690nm, just in time in the best transmitted wave segment limit of tissue (660-900nm), fluorescence quantum efficiency in the aqueous solution is 0.27-0.5, far above ICG (optical imaging probe of U.S. FDA approval listing, fluorescence quantum efficiency is less than 0.1).Therefore, aminopolycanboxylic acid modifies that phthalocyanine compound not only can be used as efficiently, the new type water-solubility photosensitizers of low toxicity is for oncotherapy, also be suitable as near-infrared fluorescence imaging probe for the early diagnosis of tumour, aspect optical dynamic therapy and near-infrared fluorescence imaging, all having significant application value.
Summary of the invention
The object of the invention is to overcome existing photosensitizers poorly water-soluble, curative effect is weak, side effect is large, synthesis technique is complicated and the deficiency of optical imaging probe poorly water-soluble, the technology such as low near infrared region fluorescence quantum yield, optical stabilization is poor, provide a kind of and there is water miscible aminopolycanboxylic acid and modify phthalocyanine compound.
Second object of the present invention is to provide the preparation method that a kind of water soluble amino poly carboxylic acid is modified phthalocyanine compound.
The 3rd object of the present invention is to provide a kind of water soluble amino poly carboxylic acid and modifies phthalocyanine compound as the purposes of light power antitumor drug.
The 4th object of the present invention is to provide a kind of water soluble amino poly carboxylic acid and modifies phthalocyanine compound as the purposes of near-infrared fluorescent molecular probe.
Technical scheme of the present invention is summarized as follows:
A kind of water soluble amino poly carboxylic acid is modified phthalocyanine compound and is had following structure:
M
1=H, Fe, Cu, Mg or Zn; M
2=Si (O (CH
2)
noR)
2or AlO (CH
2)
noR; N=2,3,4,5,6,7,8;
Water soluble amino poly carboxylic acid is modified a preparation method for phthalocyanine compound, it is characterized in that by phthalocyanine active intermediate and aminopolycanboxylic acid's anhydride reactant, and the aminopolycanboxylic acid who obtains being dissolvable in water sodium bicarbonate aqueous solution modifies phthalocyanine compound.
Aforesaid method is preferably: the N that 0.3-0.7g phthalocyanine active intermediate and 0.1-0.6g polyamino carboxylic acid anhydride is dissolved in to 40-200mL, in dinethylformamide or dimethyl sulfoxide (DMSO), under basic catalyst catalysis, stirring at room reaction 3-48h, react complete 160-300mL anhydrous diethyl ether or acetone or ethyl acetate or methylene dichloride or the water of adding, standing until Precipitation completely after, the aminopolycanboxylic acid that purifies and separates obtains being dissolvable in water sodium bicarbonate aqueous solution modifies phthalocyanine compound.
Described aminopolycanboxylic acid's acid anhydride is amine triacetic acid dicyclo acid anhydride or ethylenediamine tetraacetic acid (EDTA) dicyclo acid anhydride, or diethylene triamine pentacetic acid (DTPA) dicyclo acid anhydride, or triethylenetetramine hexaacetic acid dicyclo acid anhydride.
Described basic catalyst is triethylamine, or DMAP, or sodium carbonate, or sodium bicarbonate.
Described phthalocyanine active intermediate has following structure:
M
1=H, Fe, Cu, Mg or Zn; M
2=Si (O (CH
2) nOH)
2or AlO (CH
2) nOH; N=2,3,4,5,6,7,8
A kind of water soluble amino poly carboxylic acid of the present invention is modified the optical dynamic therapy that phthalocyanine compound can be used for tumour, malignant tumour particularly, such as liver cancer, cancer of the stomach, lung cancer, mammary cancer, cervical cancer, colorectal carcinoma, prostate cancer, melanoma and neuroblastoma etc.
A kind of water soluble amino poly carboxylic acid of the present invention is modified phthalocyanine compound has higher fluorescence quantum yield and optical stability near infrared region, good biocompatibility and certain ability that penetrates biological barrier, gather around and have broad application prospects in near-infrared fluorescence imaging field.
A kind of water-soluble polyamino carboxylic acid of the present invention is modified the simple easy handling of phthalocyanine compound preparation method, phthalocyanine-like compound is after this method is modified, stable chemical nature, water-soluble improving a lot, and 600-900nm has absorption near infrared region, can be applicable to near-infrared fluorescence imaging and optical dynamic treatment of tumor field.
Accompanying drawing explanation
Fig. 1 is the mass spectrum that the embodiment of the present invention 1 water soluble amino poly carboxylic acid is modified phthalocyanine compound.
Fig. 2 is the UV spectrum that the embodiment of the present invention 1 water soluble amino poly carboxylic acid is modified phthalocyanine compound.
Fig. 3 is the infrared spectra that the embodiment of the present invention 1 water soluble amino poly carboxylic acid is modified phthalocyanine compound.
Fig. 4 is the proton nmr spectra that the embodiment of the present invention 1 water soluble amino poly carboxylic acid is modified phthalocyanine compound.
Fig. 5 is the fluorescence spectrum that the embodiment of the present invention 1 water soluble amino poly carboxylic acid is modified phthalocyanine compound.
Fig. 6 is the size distribution that the embodiment of the present invention 1 water soluble amino poly carboxylic acid is modified phthalocyanine compound.
Fig. 7 is the mass spectrum that the embodiment of the present invention 2 water soluble amino poly carboxylic acids are modified phthalocyanine compound.
Fig. 8 is the UV spectrum that the embodiment of the present invention 2 water soluble amino poly carboxylic acids are modified phthalocyanine compound.
Fig. 9 is the mass spectrum that the embodiment of the present invention 3 water soluble amino poly carboxylic acids are modified phthalocyanine compound.
Figure 10 is the UV spectrum that the embodiment of the present invention 3 water soluble amino poly carboxylic acids are modified phthalocyanine compound.
Figure 11 is the mass spectrum that the embodiment of the present invention 4 water soluble amino poly carboxylic acids are modified phthalocyanine compound.
Figure 12 is the UV spectrum that the embodiment of the present invention 4 water soluble amino poly carboxylic acids are modified phthalocyanine compound.
Figure 13 is the mass spectrum that the embodiment of the present invention 5 water soluble amino poly carboxylic acids are modified phthalocyanine compound.
Figure 14 is the UV spectrum that the embodiment of the present invention 5 water soluble amino poly carboxylic acids are modified phthalocyanine compound.
Figure 15 is the mass spectrum that the embodiment of the present invention 6 water soluble amino poly carboxylic acids are modified phthalocyanine compound.
Figure 16 is the UV spectrum that the embodiment of the present invention 6 water soluble amino poly carboxylic acids are modified phthalocyanine compound.
Figure 17 is the mass spectrum that the embodiment of the present invention 7 water soluble amino poly carboxylic acids are modified phthalocyanine compound.
Figure 18 is the UV spectrum that the embodiment of the present invention 7 water soluble amino poly carboxylic acids are modified phthalocyanine compound.
Figure 19 is the mass spectrum that the embodiment of the present invention 8 water soluble amino poly carboxylic acids are modified phthalocyanine compound.
Figure 20 is the UV spectrum that the embodiment of the present invention 8 water soluble amino poly carboxylic acids are modified phthalocyanine compound.
Figure 21 is the mass spectrum that the embodiment of the present invention 10 water soluble amino poly carboxylic acids are modified phthalocyanine compound.
Figure 22 is the UV spectrum that the embodiment of the present invention 10 water soluble amino poly carboxylic acids are modified phthalocyanine compound.
Figure 23 is the mass spectrum that the embodiment of the present invention 13 water soluble amino poly carboxylic acids are modified phthalocyanine compound.
Figure 24 is the UV spectrum that the embodiment of the present invention 13 water soluble amino poly carboxylic acids are modified phthalocyanine compound.
Figure 25 is the mass spectrum that the embodiment of the present invention 15 water soluble amino poly carboxylic acids are modified phthalocyanine compound.
Figure 26 is the UV spectrum that the embodiment of the present invention 15 water soluble amino poly carboxylic acids are modified phthalocyanine compound.
Figure 27 is the mass spectrum that the embodiment of the present invention 16 water soluble amino poly carboxylic acids are modified phthalocyanine compound.
Figure 28 is the UV spectrum that the embodiment of the present invention 16 water soluble amino poly carboxylic acids are modified phthalocyanine compound.
Figure 29 is that the embodiment of the present invention 1 water soluble amino poly carboxylic acid is modified phthalocyanine compound to mouse H in body
22the antitumor action experimental result picture of liver cancer.
Figure 30 is that the embodiment of the present invention 1 water soluble amino poly carboxylic acid is modified phthalocyanine compound to mouse H in body
22the antitumor action experimental result photo of liver cancer.
Figure 31 embodiment of the present invention 1 water soluble amino poly carboxylic acid is modified phthalocyanine compound application in living imaging field as near infrared fluorescent probe.
Figure 32 embodiment of the present invention 1 water soluble amino poly carboxylic acid is modified phthalocyanine compound application in imaging of tissue field as near infrared fluorescent probe.
Embodiment
By 0.5g phthalocyanine active intermediate (I, M
1=Zn, Y=NH
2) and 0.35g diethylene triamine pentacetic acid (DTPA) dicyclo acid anhydride be dissolved in the N of 120mL, in dinethylformamide, add again 100 μ L triethylamines, stirring at room reaction 26h, reacts the complete 230mL of adding anhydrous diethyl ether, standing after Precipitation is complete, the aminopolycanboxylic acid that purifies and separates obtains being dissolvable in water sodium bicarbonate aqueous solution modifies phthalocyanine compound 0.52g, yield 63.63%, characterizes collection of illustrative plates and sees Fig. 1-6, and structural formula is as follows:
With amine triacetic acid dicyclo acid anhydride or ethylenediamine tetraacetic acid (EDTA) dicyclo acid anhydride or the alternative above-mentioned diethylene triamine pentacetic acid (DTPA) dicyclo acid anhydride of triethylenetetramine hexaacetic acid dicyclo acid anhydride, can prepare corresponding water soluble amino poly carboxylic acid and modify phthalocyanine compound.
By 0.3g phthalocyanine active intermediate (I, M
1=H, Y=NH
2) and 0.1g diethylene triamine pentacetic acid (DTPA) dicyclo acid anhydride be dissolved in the dimethyl sulfoxide (DMSO) of 40mL, add again 10mg4-Dimethylamino pyridine, stirring at room reaction 3h, react the complete 160mL acetone that adds, standing until Precipitation completely after, the aminopolycanboxylic acid that purifies and separates obtains being dissolvable in water sodium bicarbonate aqueous solution modifies phthalocyanine compound 0.31g, yield 62.42%, characterize collection of illustrative plates and see Fig. 7,8, structural formula is as follows:
With amine triacetic acid dicyclo acid anhydride or ethylenediamine tetraacetic acid (EDTA) dicyclo acid anhydride or the alternative above-mentioned diethylene triamine pentacetic acid (DTPA) dicyclo acid anhydride of triethylenetetramine hexaacetic acid dicyclo acid anhydride, can prepare corresponding water soluble amino poly carboxylic acid and modify phthalocyanine compound.
Embodiment 3
By 0.7g phthalocyanine active intermediate (I, M
1=Fe, Y=OH) and 0.6g ethylenediamine tetraacetic acid (EDTA) dicyclo acid anhydride be dissolved in the DMF of 200mL, then add 12mg sodium carbonate, stirring at room reaction 48h, react the complete 300mL ethyl acetate that adds, standing until Precipitation completely after, the aminopolycanboxylic acid that purifies and separates obtains being dissolvable in water sodium bicarbonate aqueous solution modifies phthalocyanine compound 0.66g, yield 64.18%, characterize collection of illustrative plates and see Fig. 9,10, structural formula is as follows:
With amine triacetic acid dicyclo acid anhydride or diethylene triamine pentacetic acid (DTPA) dicyclo acid anhydride or the alternative above-mentioned ethylenediamine tetraacetic acid (EDTA) dicyclo acid anhydride of triethylenetetramine hexaacetic acid dicyclo acid anhydride, can prepare corresponding water soluble amino poly carboxylic acid and modify phthalocyanine compound.
Embodiment 4
By 0.5g phthalocyanine active intermediate (I, M
1=Mg,
n=2) and 0.35g ethylenediamine tetraacetic acid (EDTA) dicyclo acid anhydride be dissolved in the dimethyl sulfoxide (DMSO) of 120mL, add again 10mg sodium bicarbonate, stirring at room reaction 26h, react the complete 230mL methylene dichloride that adds, standing until Precipitation completely after, the aminopolycanboxylic acid that purifies and separates obtains being dissolvable in water sodium bicarbonate aqueous solution modifies phthalocyanine compound 0.47g, yield 63.81%, characterize collection of illustrative plates and see Figure 11,12, structural formula is as follows:
With amine triacetic acid dicyclo acid anhydride or diethylene triamine pentacetic acid (DTPA) dicyclo acid anhydride or the alternative above-mentioned ethylenediamine tetraacetic acid (EDTA) dicyclo acid anhydride of triethylenetetramine hexaacetic acid dicyclo acid anhydride, can prepare corresponding water soluble amino poly carboxylic acid and modify phthalocyanine compound.
Embodiment 5
By 0.3g phthalocyanine active intermediate (I, M
1=Cu,
n=4) and 0.1g ethylenediamine tetraacetic acid (EDTA) dicyclo acid anhydride be dissolved in the N of 40mL, in dinethylformamide, add 100 μ L triethylamines, stirring at room reaction 3h, reacts the complete 160mL of adding water again, it is standing after Precipitation is complete, the aminopolycanboxylic acid that purifies and separates obtains being dissolvable in water sodium bicarbonate aqueous solution modifies phthalocyanine compound 0.27g, and yield 63.32% characterizes collection of illustrative plates and sees Figure 13,14, structural formula is as follows:
With amine triacetic acid dicyclo acid anhydride or diethylene triamine pentacetic acid (DTPA) dicyclo acid anhydride or the alternative above-mentioned ethylenediamine tetraacetic acid (EDTA) dicyclo acid anhydride of triethylenetetramine hexaacetic acid dicyclo acid anhydride, can prepare corresponding water soluble amino poly carboxylic acid and modify phthalocyanine compound.
Embodiment 6
By 0.7g phthalocyanine active intermediate (I, M
1=H,
n=2) and 0.6g triethylenetetramine hexaacetic acid dicyclo acid anhydride be dissolved in the dimethyl sulfoxide (DMSO) of 200mL, add again 10mg4-Dimethylamino pyridine, stirring at room reaction 48h, react the complete 300mL anhydrous diethyl ether that adds, standing until Precipitation completely after, the aminopolycanboxylic acid that purifies and separates obtains being dissolvable in water sodium bicarbonate aqueous solution modifies phthalocyanine compound 0.82g, yield 63.94%, characterize collection of illustrative plates and see Figure 15,16, structural formula is as follows:
With amine triacetic acid dicyclo acid anhydride or ethylenediamine tetraacetic acid (EDTA) dicyclo acid anhydride or the alternative above-mentioned triethylenetetramine hexaacetic acid dicyclo acid anhydride of diethylene triamine pentacetic acid (DTPA) dicyclo acid anhydride, can prepare corresponding water soluble amino poly carboxylic acid and modify phthalocyanine compound.
Embodiment 7
By 0.5g phthalocyanine active intermediate (I, M
1=Zn,
n=7) and 0.35g triethylenetetramine hexaacetic acid dicyclo acid anhydride be dissolved in the N of 120mL, in dinethylformamide, add 12mg sodium carbonate, stirring at room reaction 26h, reacts the complete 230mL of adding acetone again, it is standing after Precipitation is complete, the aminopolycanboxylic acid that purifies and separates obtains being dissolvable in water sodium bicarbonate aqueous solution modifies phthalocyanine compound 0.53g, and yield 63.28% characterizes collection of illustrative plates and sees Figure 17,18, structural formula is as follows:
With amine triacetic acid dicyclo acid anhydride or ethylenediamine tetraacetic acid (EDTA) dicyclo acid anhydride or the alternative above-mentioned triethylenetetramine hexaacetic acid dicyclo acid anhydride of diethylene triamine pentacetic acid (DTPA) dicyclo acid anhydride, can prepare corresponding water soluble amino poly carboxylic acid and modify phthalocyanine compound.
Embodiment 8
By 0.3g phthalocyanine active intermediate (I, M
1=Mg,
n=5) and 0.1g triethylenetetramine hexaacetic acid dicyclo acid anhydride be dissolved in the dimethyl sulfoxide (DMSO) of 40mL, add again 10mg sodium bicarbonate, stirring at room reaction 3h, react the complete 160mL ethyl acetate that adds, standing until Precipitation completely after, the aminopolycanboxylic acid that purifies and separates obtains being dissolvable in water sodium bicarbonate aqueous solution modifies phthalocyanine compound 0.33g, yield 62.96%, characterize collection of illustrative plates and see Figure 19,20, structural formula is as follows:
With amine triacetic acid dicyclo acid anhydride or ethylenediamine tetraacetic acid (EDTA) dicyclo acid anhydride or the alternative above-mentioned triethylenetetramine hexaacetic acid dicyclo acid anhydride of diethylene triamine pentacetic acid (DTPA) dicyclo acid anhydride, can prepare corresponding water soluble amino poly carboxylic acid and modify phthalocyanine compound.
Embodiment 9
By 0.7g phthalocyanine active intermediate (I, M
1=Fe,
n=8) and 0.6g triethylenetetramine hexaacetic acid dicyclo acid anhydride be dissolved in the N of 200mL, in dinethylformamide, add again 100 μ L triethylamines, stirring at room reaction 48h, react the complete 300mL methylene dichloride that adds, standing until Precipitation completely after, the aminopolycanboxylic acid that purifies and separates obtains being dissolvable in water sodium bicarbonate aqueous solution modifies phthalocyanine compound 0.74g, yield 63.36%, structural formula is as follows:
With amine triacetic acid dicyclo acid anhydride or ethylenediamine tetraacetic acid (EDTA) dicyclo acid anhydride or the alternative above-mentioned triethylenetetramine hexaacetic acid dicyclo acid anhydride of diethylene triamine pentacetic acid (DTPA) dicyclo acid anhydride, can prepare corresponding water soluble amino poly carboxylic acid and modify phthalocyanine compound.
By 0.5g phthalocyanine active intermediate (I, M
1=H,
n=2) and 0.35g ethylenediamine tetraacetic acid (EDTA) dicyclo acid anhydride be dissolved in the dimethyl sulfoxide (DMSO) of 120mL, add again 10mg4-Dimethylamino pyridine, stirring at room reaction 26h, react the complete 230mL water that adds, standing until Precipitation completely after, the aminopolycanboxylic acid that purifies and separates obtains being dissolvable in water sodium bicarbonate aqueous solution modifies phthalocyanine compound 0.46g, yield 63.12%, characterize collection of illustrative plates and see Figure 21,22, structural formula is as follows:
With amine triacetic acid dicyclo acid anhydride or diethylene triamine pentacetic acid (DTPA) dicyclo acid anhydride or the alternative above-mentioned ethylenediamine tetraacetic acid (EDTA) dicyclo acid anhydride of triethylenetetramine hexaacetic acid dicyclo acid anhydride, can prepare corresponding water soluble amino poly carboxylic acid and modify phthalocyanine compound.
Embodiment 11
By 0.3g phthalocyanine active intermediate (I, M
1=Fe,
n=4) and 0.1g diethylene triamine pentacetic acid (DTPA) acid anhydride be dissolved in the N of 40mL, in dinethylformamide, add again 12mg sodium carbonate, stirring at room reaction 3h, react the complete 160mL anhydrous diethyl ether that adds, standing until Precipitation completely after, the aminopolycanboxylic acid that purifies and separates obtains being dissolvable in water sodium bicarbonate aqueous solution modifies phthalocyanine compound 0.29g, yield 62.40%, structural formula is as follows:
With amine triacetic acid dicyclo acid anhydride or ethylenediamine tetraacetic acid (EDTA) dicyclo acid anhydride or the alternative above-mentioned diethylene triamine pentacetic acid (DTPA) dicyclo acid anhydride of triethylenetetramine hexaacetic acid dicyclo acid anhydride, can prepare corresponding water soluble amino poly carboxylic acid and modify phthalocyanine compound.
By 0.7g phthalocyanine active intermediate (I, M
1=Cu,
n=6) and 0.6g triethylenetetramine hexaacetic acid dicyclo acid anhydride be dissolved in the dimethyl sulfoxide (DMSO) of 200mL, add again 10mg sodium bicarbonate, stirring at room reaction 48h, react the complete 300mL acetone that adds, it is standing after Precipitation is complete, the aminopolycanboxylic acid that purifies and separates obtains being dissolvable in water sodium bicarbonate aqueous solution modifies phthalocyanine compound 0.75g, yield 64.18%, and structural formula is as follows:
With amine triacetic acid dicyclo acid anhydride or ethylenediamine tetraacetic acid (EDTA) dicyclo acid anhydride or the alternative above-mentioned triethylenetetramine hexaacetic acid dicyclo acid anhydride of diethylene triamine pentacetic acid (DTPA) dicyclo acid anhydride, can prepare corresponding water soluble amino poly carboxylic acid and modify phthalocyanine compound.
By 0.5g phthalocyanine active intermediate (I, M
1=Zn,
n=8) and 0.35g diethylene triamine pentacetic acid (DTPA) acid anhydride be dissolved in the N of 120mL, in dinethylformamide, add 100 μ L triethylamines, stirring at room reaction 26h, reacts the complete 230mL of adding ethyl acetate again, it is standing after Precipitation is complete, the aminopolycanboxylic acid that purifies and separates obtains being dissolvable in water sodium bicarbonate aqueous solution modifies phthalocyanine compound 0.48g, and yield 63.51% characterizes collection of illustrative plates and sees Figure 23,24, structural formula is as follows:
With amine triacetic acid dicyclo acid anhydride or ethylenediamine tetraacetic acid (EDTA) dicyclo acid anhydride or the alternative above-mentioned diethylene triamine pentacetic acid (DTPA) dicyclo acid anhydride of triethylenetetramine hexaacetic acid dicyclo acid anhydride, can prepare corresponding water soluble amino poly carboxylic acid and modify phthalocyanine compound.
By 0.3g phthalocyanine active intermediate (II, M
2=Si (O (CH
2)
noH)
2n=2) and 0.1g diethylene triamine pentacetic acid (DTPA) acid anhydride be dissolved in the dimethyl sulfoxide (DMSO) of 40mL, add again 10mg4-Dimethylamino pyridine, stirring at room reaction 3h, react the complete 160mL methylene dichloride that adds, standing until Precipitation completely after, the aminopolycanboxylic acid that purifies and separates obtains being dissolvable in water sodium bicarbonate aqueous solution modifies phthalocyanine compound 0.4g, yield 62.51%, structural formula is as follows:
With amine triacetic acid dicyclo acid anhydride or ethylenediamine tetraacetic acid (EDTA) dicyclo acid anhydride or the alternative above-mentioned diethylene triamine pentacetic acid (DTPA) dicyclo acid anhydride of triethylenetetramine hexaacetic acid dicyclo acid anhydride, can prepare corresponding water soluble amino poly carboxylic acid and modify phthalocyanine compound.
By 0.7g phthalocyanine active intermediate (II, M
2=Si (O (CH
2)
noH)
2n=6) and 0.6g ethylenediamine tetraacetic acid (EDTA) dicyclo acid anhydride be dissolved in the DMF of 200mL, then add 12mg sodium carbonate, stirring at room reaction 48h, react the complete 300mL water that adds, standing until Precipitation completely after, the aminopolycanboxylic acid that purifies and separates obtains being dissolvable in water sodium bicarbonate aqueous solution modifies phthalocyanine compound 0.77g, yield 63.57%, characterize collection of illustrative plates and see Figure 25,26, structural formula is as follows:
With amine triacetic acid dicyclo acid anhydride or diethylene triamine pentacetic acid (DTPA) dicyclo acid anhydride or the alternative above-mentioned ethylenediamine tetraacetic acid (EDTA) dicyclo acid anhydride of triethylenetetramine hexaacetic acid dicyclo acid anhydride, can prepare corresponding water soluble amino poly carboxylic acid and modify phthalocyanine compound.
Embodiment 16
By 0.5g phthalocyanine active intermediate (II, M
2=AlO (CH
2)
noH, n=4) and 0.35g ethylenediamine tetraacetic acid (EDTA) dicyclo acid anhydride be dissolved in the dimethyl sulfoxide (DMSO) of 120mL, add 10mg sodium bicarbonate, stirring at room reaction 26h, reacts the complete 230mL of adding anhydrous diethyl ether again, it is standing after Precipitation is complete, the aminopolycanboxylic acid that purifies and separates obtains being dissolvable in water sodium bicarbonate aqueous solution modifies phthalocyanine compound 0.5g, and yield 62.66% characterizes collection of illustrative plates and sees Figure 27,28, structural formula is as follows:
With amine triacetic acid dicyclo acid anhydride or diethylene triamine pentacetic acid (DTPA) dicyclo acid anhydride or the alternative above-mentioned ethylenediamine tetraacetic acid (EDTA) dicyclo acid anhydride of triethylenetetramine hexaacetic acid dicyclo acid anhydride, can prepare corresponding water soluble amino poly carboxylic acid and modify phthalocyanine compound.
Embodiment 17
By 0.3g phthalocyanine active intermediate (II, M
2=AlO (CH
2)
noH, n=8) and 0.1g triethylenetetramine hexaacetic acid dicyclo acid anhydride be dissolved in the N of 40mL, in dinethylformamide, add 100 μ L triethylamines, stirring at room reaction 3h, reacts the complete 160mL of adding acetone again, it is standing after Precipitation is complete, the aminopolycanboxylic acid that purifies and separates obtains being dissolvable in water sodium bicarbonate aqueous solution modifies phthalocyanine compound 0.31g, yield 60.93%, and structural formula is as follows:
With amine triacetic acid dicyclo acid anhydride or ethylenediamine tetraacetic acid (EDTA) dicyclo acid anhydride or the alternative above-mentioned triethylenetetramine hexaacetic acid dicyclo acid anhydride of diethylene triamine pentacetic acid (DTPA) dicyclo acid anhydride, can prepare corresponding water soluble amino poly carboxylic acid and modify phthalocyanine compound.
By embodiment 1 gained water soluble amino poly carboxylic acid, modify phthalocyanine compound treatment transplanted hepatoma H
22mouse, at body experimentation, comprises the steps:
(1), under aseptic condition, extract the rat liver cancer H of inoculation after 7 days
22plant the ascites of mouse, by stroke-physiological saline solution, press 1:3 dilution, make tumor cell suspension, with freshly prepared 0.2% Trypan Blue, after mixing, by white blood cell count(WBC) method counting, adjusting cell concn is 2 * 10
7individual/mL, every the 0.2mL of take is inoculated in back that body weight is the healthy Kunming mouse of 18-22g near afterbody (24h plucks at inoculation position with 8% sodium sulphite before inoculation), makes solid tumor animal model.
(2) inoculate after 1 week, treat that tumor growth is 0.5 * 0.5cm
2, mouse is divided into blank group, the high, medium and low dosage group of water soluble amino poly carboxylic acid modification phthalocyanine compound optical dynamic therapy at random, 10 every group, weigh respectively.Blank group tail vein injection saline 0.2mL/ only, modify the high, medium and low dosage group of phthalocyanine compound optical dynamic therapy and press 4mg/kg, 2mg/kg, the administration of 1mg/kg tail vein injection by water soluble amino poly carboxylic acid.Animal lucifuge is raised to 24h, and the laser that the wavelength of take is 650nm carries out irradiation, only irradiates tumor by local, other position lucifuges, illumination density: 0.15W, light application time: 10min, intensity of illumination: 100J/cm
2, in this way respectively at 48h and 72h twice of irradiation again.
(3) observe the situation such as general activity, fur, diet, ight soil of mouse every day.After last irradiation 2 weeks, put to death animal, take Mouse Weight, dissect knurl body, spleen, liver, lung, thymus gland, weigh respectively, calculate tumour inhibiting rate (seeing Figure 29), spleen index, liver index, lung exponential sum thymus index, evaluate tumor killing effect (seeing Figure 30).The average knurl of tumour inhibiting rate (%)=(the average knurl weight of the average knurl weight-administration of blank group group)/blank group is heavy by * 100, organ index (mg/g)=10 * internal organs weight/body weight.
Table 1 water soluble amino poly carboxylic acid is modified phthalocyanine compound to H
22the impact of liver cancer mouse tumor growth
*P<0.001
Table 2 water soluble amino poly carboxylic acid is modified phthalocyanine compound to H
22the impact of liver cancer mouse lung, liver, spleen and thymus index
(4) aminopolycanboxylic acid who obtains in embodiment 1-17 modifies phthalocyanine compound to H
22the tumour inhibiting rate of liver cancer mouse sees the following form:
Table 3 aminopolycanboxylic acid modifies phthalocyanine compound to H
22the tumour inhibiting rate of liver cancer mouse (dosage 4mg/kg)
Result shows, water soluble amino poly carboxylic acid is modified phthalocyanine compound associating optical dynamic therapy to rat liver cancer H
22have extremely significant restraining effect, after optical dynamic therapy, most of tumour is no longer bred, and 4mg/kg dosage group tumor control rate reaches 81%.
By embodiment 1 gained water soluble amino poly carboxylic acid, modify phthalocyanine compound as fluorescent probe, live body and the experimentation of organizing near-infrared fluorescence imaging, comprise the steps:
(1) water soluble amino poly carboxylic acid is modified to phthalocyanine compound and be formulated as 2 * 10 with 0.9% physiological saline
-4mol/L, as near infrared fluorescent probe solution for standby.
(2) with transplanted hepatoma H
22mouse is experimental animal model, tail vein injection 0.2mL near infrared fluorescent probe solution, blank group tail vein injection 0.9% physiological saline 0.2mL.At 0h, 4h, 8h, 12h and 24h, anaesthetize mouse by 0.15mL/20g abdominal injection 1% vetanarcol normal saline solution, and blank group and near infrared fluorescent probe group laboratory animal are placed side by side in small animal living body imaging system (Maestro EX), take 635nm as excitation wavelength, 675nm-long wave is emission wavelength, gathers wavelength region and is set as 670-900nm, carries out fluorescence living imaging (seeing Figure 31).
(3) after 24h, put to death above-mentioned laboratory animal, with the perfusion of 60mL physiological saline, dissect knurl body, the heart, liver, spleen, lung, kidney, be placed in small animal living body imaging system, carry out fluorescence living imaging (seeing Figure 32).
(4) the fluorescence intensity ratio that the polyamino carboxylic acid obtaining in embodiment is modified phthalocyanine compound imaging of tissue sees the following form:
Table 4 aminopolycanboxylic acid modifies the fluorescence intensity ratio of phthalocyanine compound imaging of tissue
Claims (7)
1. water soluble amino poly carboxylic acid is modified a phthalocyanine compound, it is characterized in that side chain or center are connected with aminopolycanboxylic acid, and what side chain connected is shown in following structure (I), and what center connected is shown in following structure (II):
M
1=H, Fe, Cu, Mg or Zn; M
2=Si (O (CH
2)
noR)
2or AlO (CH
2)
noR; N=2,3,4,5,6,7,8;
2. water soluble amino poly carboxylic acid is modified a preparation method for phthalocyanine compound, it is characterized in that by phthalocyanine active intermediate and aminopolycanboxylic acid's anhydride reactant, and the aminopolycanboxylic acid who obtains being dissolvable in water sodium bicarbonate aqueous solution modifies phthalocyanine compound.
3. method according to claim 2, it is characterized in that comprising the steps: 0.3-0.7g phthalocyanine active intermediate and 0.1-0.6g polyamino carboxylic acid anhydride are dissolved in the N of 40-200mL, in dinethylformamide or dimethyl sulfoxide (DMSO), under basic catalyst catalysis, stirring at room reaction 3-48h, react complete 160-300mL anhydrous diethyl ether or acetone or ethyl acetate or methylene dichloride or the water of adding, standing until Precipitation completely after, the aminopolycanboxylic acid that purifies and separates obtains being dissolvable in water sodium bicarbonate aqueous solution modifies phthalocyanine compound.
The feature of described phthalocyanine active intermediate is:
M
1=H, Fe, Cu, Mg or Zn; M
2=Si (O (CH
2) nOH)
2or AlO (CH
2) nOH; N=2,3,4,5,6,7,8
4. according to the method in claim 2 or 3, it is characterized in that described aminopolycanboxylic acid's acid anhydride is amine triacetic acid dicyclo acid anhydride or ethylenediamine tetraacetic acid (EDTA) dicyclo acid anhydride, or diethylene triamine pentacetic acid (DTPA) dicyclo acid anhydride, or triethylenetetramine hexaacetic acid dicyclo acid anhydride.
5. according to the method in claim 2 or 3, it is characterized in that basic catalyst is triethylamine, or DMAP, or sodium carbonate, or sodium bicarbonate.
6. aminopolycanboxylic acid claimed in claim 1 modifies the application of phthalocyanine compound in the photosensitive antitumor drug of preparation.
7. aminopolycanboxylic acid claimed in claim 1 modifies phthalocyanine compound in the application in near-infrared fluorescence imaging field.
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| CN109283161A (en) * | 2018-09-19 | 2019-01-29 | 青岛大学 | A kind of method using peroxide value in fluorescent quenching method detection grease |
| CN110960686A (en) * | 2019-12-26 | 2020-04-07 | 中国医学科学院生物医学工程研究所 | Phthalocyanine compound for tumor targeted fluorescence imaging and photodynamic therapy |
| JP2022527672A (en) * | 2020-04-10 | 2022-06-02 | ラクテン・メディカル，インコーポレイテッド | Phthalocyanine pigment compounds, conjugates and how to use them |
| CN115246799A (en) * | 2021-12-15 | 2022-10-28 | 温州医科大学 | Compound, preparation method thereof and nano photothermal reagent containing compound |
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| CN110960686A (en) * | 2019-12-26 | 2020-04-07 | 中国医学科学院生物医学工程研究所 | Phthalocyanine compound for tumor targeted fluorescence imaging and photodynamic therapy |
| JP2022527672A (en) * | 2020-04-10 | 2022-06-02 | ラクテン・メディカル，インコーポレイテッド | Phthalocyanine pigment compounds, conjugates and how to use them |
| JP7125828B2 (en) | 2020-04-10 | 2022-08-25 | ラクテン・メディカル，インコーポレイテッド | Phthalocyanine dye compounds, conjugates and methods of use thereof |
| US11466158B2 (en) | 2020-04-10 | 2022-10-11 | Rakuten Medical, Inc. | Phthalocyanine dye compounds, conjugates and methods of use thereof |
| CN115246799A (en) * | 2021-12-15 | 2022-10-28 | 温州医科大学 | Compound, preparation method thereof and nano photothermal reagent containing compound |
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