CN102416178B - Water-soluble non-aggregated alkoxy-substituted phthalocyanine-silica nanometer particle - Google Patents
Water-soluble non-aggregated alkoxy-substituted phthalocyanine-silica nanometer particle Download PDFInfo
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- CN102416178B CN102416178B CN 201110373525 CN201110373525A CN102416178B CN 102416178 B CN102416178 B CN 102416178B CN 201110373525 CN201110373525 CN 201110373525 CN 201110373525 A CN201110373525 A CN 201110373525A CN 102416178 B CN102416178 B CN 102416178B
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- alkoxy
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Abstract
The invention provides a water-soluble non-aggregated alkoxy-substituted phthalocyanine-silica nanometer particle and a preparation method thereof. The water-soluble non-aggregated alkoxy-substituted phthalocyanine-silica nanometer particle is a photosensitizer nanometer particle for photodynamic therapy (PDT) and photodynamic diagnosis (PDD). Common phthalocyanine has the characteristics of poor water solubility and easiness of aggregation and thus use of the common phthalocyanine in the PDT and the PDD is influenced by the characteristics. The water-soluble non-aggregated alkoxy-substituted phthalocyanine-silica nanometer particle is characterized in that non-aggregated alkoxy-substituted phthalocyanine (MPc(OR)4) is coated with a SiO2 nanometer particle and the SiO2 nanometer particle with the non-aggregated alkoxy-substituted phthalocyanine (MPc(OR)4) is prepared into the water-soluble non-aggregated alkoxy-substituted phthalocyanine-silica (MPc(OR)4-SiO2) nanometer particle. The water-soluble non-aggregated alkoxy-substituted phthalocyanine-silica nanometer particle partly solves the problem of the common phthalocyanine, and is conducive to development of phthalocyanine as a photodynamic diagnosis and treatment reagent.
Description
Technical field
The invention belongs to the photodynamic therapy field, relate to a kind of photosensitizer for photodynamic therapy, more specifically say a kind of preparation method of water-soluble non-aggregated alkoxy-substituted phthalocyanine-silica nanometer particle.
Background technology
Photodynamic therapy (PDT) is a kind of method that can be used for treating various tumors, cardiovascular, skin and ophthalmic diseases; Light power diagnosis (PDD) is based on fluorescence, utilizes photodynamic reaction to carry out the technology of medical diagnosis on disease.The principle of the photodynamic therapy of cancer is: photosensitizer (PS) but relative rich combines in tumor tissues behind the administration certain hour, this moment, visible light or the near infrared light (NIR) with suitable wavelength shone tumor tissues, the photosensitizer molecule of enrichment is activated in the tumor tissues, and the oxygen molecule around energy conduction given, cause reactive oxygen species (ROS), such as singlet oxygen (
1O
2) or the generation of free radical.Life-span of ROS is short, and it can be confined to very little scope to the disorganization effect, so PDT can destroy illing tissue effectively, selectively, and does not damage surrounding health tissue.
Phthalocyanines photosensitizer stable in properties, and absorption maximum is positioned at the high red light district of tissue transmitance, become the study hotspot of PDT photosensitizer, also is expected to the technology for PDD.But, because the poorly water-soluble of phthalocyanine own is difficult for administration, the easy gathering causes that the degradation characteristics have affected its application in clinical greatly under fluorescent quenching and the ROS productive rate.
In the nano-medicament carrier field, nano SiO 2 particle is the important research object.Nano SiO 2 particle is a kind of nontoxic, tasteless, free of contamination inorganic material, has good hydrophilic and stability; Also have simultaneously the excellent character such as light transmission, chemical inertness, bio-compatibility, these characteristics all make it have broad application prospects at aspects such as cell marking, medicament transport, DNA transfection and Selective Separation.
Summary of the invention
The object of the present invention is to provide a kind of preparation method that can be used for the water-soluble non-aggregated alkoxy-substituted phthalocyanine-silica nanometer particle of optical dynamic therapy.
For achieving the above object, the present invention adopts following technical scheme:
A kind of preparation method of water-soluble non-aggregated alkoxy-substituted phthalocyanine-silica nanometer particle may further comprise the steps:
(1) under the room temperature, in 10 mL redistilled waters, adds while stirring 0.18 gram tetrabutyl ammonium bromide and 0.4mL n-butyl alcohol, behind the reaction 5-30 min, obtain the microemulsion of stable and uniform;
(2) continue to stir, in the microemulsion of step (1), add successively four-α-(2,2,4-trimethyl-3-amoxy) N of phthalocyanine metal complex, dinethylformamide solution, ammonia, VTES and 3-aminopropyl triethoxysilane, the green solution that obtains clarifying behind the reaction 15-40 h;
(3) green solution of dialysis step (2) namely gets the aqueous solution of described water-soluble non-aggregated alkoxy-substituted phthalocyanine-silica nanometer particle.
The central metal of the described four-α of step (2)-(2,2,4-trimethyl-3-amoxy) phthalocyanine metal complex is Al.The volume ratio of DMF solution, ammonia, VTES and the 3-aminopropyl triethoxysilane of described four-α-(2,2,4-trimethyl-3-amoxy) phthalocyanine metal complex is 200:500:100～250:30; The concentration of the DMF solution of described four-α-(2,2,4-trimethyl-3-amoxy) phthalocyanine metal complex is 4 * 10
-3Mol/L.
The described dialysis time of step (3) is 48-80h.
Remarkable advantage of the present invention is:
Non-aggregation alkoxyl substituted phthalocyanine is wrapped up with nano SiO 2 particle, effectively solved and used limitation.At first, SiO is advanced in the phthalocyanine embedding
2In the nanostructured, can avoid the impact of the internal milieu factor of complexity, improve the stability of phthalocyanine.Secondly, single SiO
2Can a large amount of highly active non-gathering Phthalocyanines of embedding in the nanoparticle.SiO
2Nanoparticle not only becomes the hydrophilic carrier of hydrophobicity photosensitizer, also is the medium that photosensitizer keeps non-coherent condition, so that nanoparticle has the ability than hyperfluorescence and generation singlet oxygen, is suitable for the analysis of high sensitivity fluorescence diagnosis.
Preparation method of the present invention, used the substituted phthalocyanine that has than the large space steric effect, this class phthalocyanine has good anti-ability of aggregation in common organic solvent, but shortcoming is water insoluble, by adopting two kinds of silane combineds effect, behind formation phthalocyanine-nano SiO 2 particle, the system that obtains is not only water-soluble, and phthalocyanine is non-state of aggregation therein, and good generation singlet oxygen and the ability of emitting fluorescence are arranged.This is very beneficial for this application of class phthalocyanine in PDT and PDD.
Description of drawings
Fig. 1 is the AlClPc (OR) that method provided by the invention is prepared
4-SiO
2The transmission electron microscope picture of nano-particle.
Fig. 2 is the AlClPc (OR) that method provided by the invention is prepared
4-SiO
2The electronic figure of nano-particle in water.
Fig. 3 is the AlClPc (OR) that method provided by the invention is prepared
4-SiO
2Nano-particle and the AlClPc of embedding silicon dioxide (OR) not
4Fluorescence spectrum figure in water or DMF: excitation wavelength 645 nm, (a) AlClPc (OR)
4/ DMF; (b) AlClPc (OR)
4-SiO
2Aqueous dispersions; (c) AlClPc (OR)
4/ DMF Solution Dispersion (C in water
AlClPc (OR) 4=4.54 * 10
-5Mol/L; V
DMF/ V
H2O=1/99).
Fig. 4 is the AlClPc (OR) that method provided by the invention is prepared
4-SiO
2Nano-particle is to the extra large firefly fluorescein analog chemiluminescent reinforced effects comparison diagram of photoinduction of (Cypridina Luciferin methoxy-analogue is called for short MCLA, and structure as shown in Figure 5).Use therein is 708nm illumination.
Fig. 5 is the structure chart of MCLA.The chinesization formal name used at school of MCLA: 2-methyl-6-(4-anisyl)-3, the 7-glyoxalidine is [1,2-A] pyrazine-3-keto hydrochloride also.
Fig. 6 is the structural representation of four-α-(2,2,4-trimethyl-3-amoxy) aluminum phthalocyanine.
The specific embodiment
The preparation method of water-soluble non-aggregated phthalocyanine-nano SiO 2 particle of the present invention comprises the following steps:
(1) microemulsion of preparation water, tetrabutyl ammonium bromide (CTAB), n-butyl alcohol;
(2) in above-mentioned microemulsion, add four-α-(2,2,4-trimethyl-3-amoxy) phthalocyanine metal complex (MPc (OR)
4) DMF (DMF) solution, ammonia, VTES (TEVS), 3-aminopropyl triethoxysilane (APTES), the reaction green solution that obtains clarifying;
(3) dialyse the green solution of above-mentioned clarification except desalting with bag filter, obtain phthalocyanine-silicon dioxide (MPc (OR)
4-SiO
2) aqueous solution of nano-particle.
Described bag filter is the specification of 14 kd-44 mm;
A period of time in the described step (1) is approximately 5-30 min;
The response time is about 15-40 h in the described step (2); The volume ratio of TEVS and APTES consumption is about 10:3 to 25:3;
A period of time is about 48-80 h in the described step (3).
Described non-gathering alkoxyl substituted phthalocyanine is four-α-(2,2,4-trimethyl-3-amoxy) phthalocyanine metal complex (MPc (OR)
4), central metal is aluminum.
Embodiment 1
Under the continuous stirring condition of room temperature, in 10 ml redistilled waters, add 0.18 gram CTAB, 400 μ l n-butyl alcohol, mix 20 min after, obtain the microemulsion of stable and uniform.Continue to stir, add successively 200 μ l 4 * 10
-3The AlClPc of mol/L (OR)
4/ DMF, 500 μ l ammonia, 250 μ l TEVS, 30 μ l APTES continue reaction 20 h, the green solution that obtains clarifying.Behind solution 72 h that obtain with bag filter dialysis, obtain AlClPc (OR)
4-SiO
2The nano-particle aqueous solution.
Embodiment 2
Under the continuous stirring condition of room temperature, in 10 ml redistilled waters, add 0.18 gram CTAB, 400 μ l n-butyl alcohol, behind the mixing 5min, obtain the microemulsion of stable and uniform.Continue to stir, add successively 200 μ l 4 * 10
-3The AlClPc of mol/L (OR)
4/ DMF, 500 ul ammonia, 250 μ l TEVS, 30 μ l APTES continue reaction 30 h, the green solution that obtains clarifying.Behind solution 48 h that obtain with bag filter dialysis, obtain AlClPc (OR)
4-SiO
2The nano-particle aqueous solution.
Embodiment 3
Under the continuous stirring condition of room temperature, in 10 ml redistilled waters, add 0.18 gram CTAB, 400 μ l n-butyl alcohol, mix 30 min after, obtain the microemulsion of stable and uniform.Continue to stir, add successively 200 μ l 4 * 10
-3The AlClPc of mol/L (OR)
4/ DMF, 500 μ l ammonia, 100 μ l TEVS, 30 μ l APTES continue reaction 40 h, the green solution that obtains clarifying.Behind solution 56 h that obtain with bag filter dialysis, obtain AlClPc (OR)
4-SiO
2The nano-particle aqueous solution.
Embodiment 4
The AlClPc that method provided by the invention is prepared (OR)
4-SiO
2Nano-particle electronic figure such as Fig. 2 in water, AlClPc (OR)
4-SiO
2The concentration of nanoparticles solution is 4.54 * 10
-5Mol/L, the monomer absworption peak near infrared region 708nm place illustrates that it is in non-coherent condition among the figure.
Embodiment 5
The AlClPc that method provided by the invention is prepared (OR)
4-SiO
2Nano-particle and the AlClPc of embedding silicon dioxide (OR) not
4Fluorescence spectrum figure in water or DMF such as Fig. 3.
AlClPc (OR)
4In water, do not dissolve, so without fluorescence (curve C); And AlClPc (OR)
4-SiO
2Nano-particle is fluorescence strong (curve B) in water, close to the AlClPc (OR) of same concentrations
4Fluorescence intensity in DMF (curve A).This figure illustrates the prepared AlClPc of method provided by the invention (OR)
4-SiO
2Nano-particle has water solublity, and phthalocyanine wherein in organic solvent (such as DMF), similar existence form is arranged, be non-state of aggregation, so the fluorescent emission ability is stronger.
Embodiment 6
The AlClPc that method provided by the invention is prepared (OR)
4-SiO
2Nano-particle is to the chemiluminescent reinforced effects comparison diagram of photoinduction such as Fig. 4 of extra large firefly fluorescein analog MCLA.
Singlet oxygen can be induced the chemiluminescence of MCLA, among Fig. 4, when AlClPc (OR) is arranged
4-SiO
2In the time of the nano-particle coexistence, chemiluminescent intensity and the luminous speed of MCLA all significantly improve, and the AlClPc (OR) that the present invention prepares is described
4-SiO
2Nano-particle has the ability of stronger generation singlet oxygen.
The above only is preferred embodiment of the present invention, and all equalizations of doing according to the present patent application claim change and modify, and all should belong to covering scope of the present invention.
Claims (1)
1. the preparation method of a water-soluble non-aggregated alkoxy-substituted phthalocyanine-silica nanometer particle, it is characterized in that: described preparation method may further comprise the steps:
(1) under the room temperature, in 10 mL redistilled waters, adds while stirring 0.18 gram tetrabutyl ammonium bromide and 0.4mL n-butyl alcohol, behind the reaction 5-30 min, obtain the microemulsion of stable and uniform;
(2) continue to stir, in the microemulsion of step (1), add successively four-α-(2,2,4-trimethyl-3-amoxy) N of phthalocyanine metal complex, dinethylformamide solution, ammonia, VTES and 3-aminopropyl triethoxysilane, the green solution that obtains clarifying behind the reaction 15-40 h;
(3) green solution of dialysis step (2) namely gets the aqueous solution of described water-soluble non-aggregated alkoxy-substituted phthalocyanine-silica nanometer particle;
The central metal of the described four-α of step (2)-(2,2,4-trimethyl-3-amoxy) phthalocyanine metal complex is Al;
Step (2) described four-α-(2,2,4-trimethyl-3-amoxy) volume ratio of the DMF solution of phthalocyanine metal complex, ammonia, VTES and 3-aminopropyl triethoxysilane is 200:500:100～250:30; The concentration of the DMF solution of described four-α-(2,2,4-trimethyl-3-amoxy) phthalocyanine metal complex is 4 * 10
-3Mol/L;
The described dialysis time of step (3) is 48-80h.
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|---|---|---|---|
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|---|---|---|---|
| CN 201110373525 CN102416178B (en) | 2011-11-22 | 2011-11-22 | Water-soluble non-aggregated alkoxy-substituted phthalocyanine-silica nanometer particle |
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| CN102416178A CN102416178A (en) | 2012-04-18 |
| CN102416178B true CN102416178B (en) | 2013-04-17 |
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| CN103864833B (en) * | 2014-03-24 | 2016-09-07 | 福州大学 | A kind of axial end hydroxyl replaces silicon phthalocyanine and self-assembly thereof |
| EP3213779A1 (en) * | 2016-03-01 | 2017-09-06 | Chemical Intelligence Limited | Medical examination gloves |
| JP7371476B2 (en) | 2018-12-13 | 2023-10-31 | 東洋インキＳｃホールディングス株式会社 | Near-infrared fluorescent composition and near-infrared fluorescent labeling agent |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101456880A (en) * | 2008-12-30 | 2009-06-17 | 南京师范大学 | Phosphamidon amphipathic phthalocyanine derivates, preparation method and application thereof in phototherapy medicament preparation |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101456880A (en) * | 2008-12-30 | 2009-06-17 | 南京师范大学 | Phosphamidon amphipathic phthalocyanine derivates, preparation method and application thereof in phototherapy medicament preparation |
Non-Patent Citations (4)
| Title |
|---|
| p-HPcZn-SiO2纳米粒的制备与表征;戴冬萍等;《南京师大学报(自然科学版)》;20090331;第32卷(第1期);87-90页 * |
| 四-α-(2,2,4-三甲基-3-戊氧基)酞菁金属配合物(M=Co,Ni,Cu,Zn)的合成与光谱性质;江舟等;《无机化学学报》;20051231;第21卷(第12期);1891-1896页 * |
| 戴冬萍等.p-HPcZn-SiO2纳米粒的制备与表征.《南京师大学报(自然科学版)》.2009,第32卷(第1期), |
| 江舟等.四-α-(2,2,4-三甲基-3-戊氧基)酞菁金属配合物(M=Co,Ni,Cu,Zn)的合成与光谱性质.《无机化学学报》.2005,第21卷(第12期), |
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