CN116574394A - Sensitive fluorescent dye and preparation method thereof - Google Patents
Sensitive fluorescent dye and preparation method thereof Download PDFInfo
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- CN116574394A CN116574394A CN202310420235.5A CN202310420235A CN116574394A CN 116574394 A CN116574394 A CN 116574394A CN 202310420235 A CN202310420235 A CN 202310420235A CN 116574394 A CN116574394 A CN 116574394A
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- phospholipid
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- dye
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- 239000007850 fluorescent dye Substances 0.000 title claims abstract description 97
- 238000002360 preparation method Methods 0.000 title abstract description 12
- 150000003904 phospholipids Chemical class 0.000 claims abstract description 34
- 239000006185 dispersion Substances 0.000 claims abstract description 23
- 150000001841 cholesterols Chemical class 0.000 claims abstract description 15
- 239000007788 liquid Substances 0.000 claims abstract description 10
- 239000008055 phosphate buffer solution Substances 0.000 claims abstract description 8
- 239000002994 raw material Substances 0.000 claims abstract description 3
- 238000009210 therapy by ultrasound Methods 0.000 claims description 34
- 238000010008 shearing Methods 0.000 claims description 28
- 239000000975 dye Substances 0.000 claims description 22
- ANRHNWWPFJCPAZ-UHFFFAOYSA-M thionine Chemical compound [Cl-].C1=CC(N)=CC2=[S+]C3=CC(N)=CC=C3N=C21 ANRHNWWPFJCPAZ-UHFFFAOYSA-M 0.000 claims description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 20
- 239000012528 membrane Substances 0.000 claims description 17
- 239000004698 Polyethylene Substances 0.000 claims description 16
- 229920000573 polyethylene Polymers 0.000 claims description 16
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 14
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 claims description 14
- 238000002156 mixing Methods 0.000 claims description 12
- TZCPCKNHXULUIY-RGULYWFUSA-N 1,2-distearoyl-sn-glycero-3-phosphoserine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCCCC TZCPCKNHXULUIY-RGULYWFUSA-N 0.000 claims description 11
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 claims description 11
- ZWZWYGMENQVNFU-UHFFFAOYSA-N Glycerophosphorylserin Natural products OC(=O)C(N)COP(O)(=O)OCC(O)CO ZWZWYGMENQVNFU-UHFFFAOYSA-N 0.000 claims description 11
- 150000008104 phosphatidylethanolamines Chemical class 0.000 claims description 11
- PYWVYCXTNDRMGF-UHFFFAOYSA-N rhodamine B Chemical compound [Cl-].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=CC=C1C(O)=O PYWVYCXTNDRMGF-UHFFFAOYSA-N 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 238000002390 rotary evaporation Methods 0.000 claims description 8
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 7
- 239000007853 buffer solution Substances 0.000 claims description 7
- 238000004945 emulsification Methods 0.000 claims description 7
- 238000010438 heat treatment Methods 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- 230000001954 sterilising effect Effects 0.000 claims description 7
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 claims description 5
- 229940043267 rhodamine b Drugs 0.000 claims description 4
- VYXSBFYARXAAKO-WTKGSRSZSA-N chembl402140 Chemical compound Cl.C1=2C=C(C)C(NCC)=CC=2OC2=C\C(=N/CC)C(C)=CC2=C1C1=CC=CC=C1C(=O)OCC VYXSBFYARXAAKO-WTKGSRSZSA-N 0.000 claims description 3
- TUFFYSFVSYUHPA-UHFFFAOYSA-M rhodamine 123 Chemical compound [Cl-].COC(=O)C1=CC=CC=C1C1=C(C=CC(N)=C2)C2=[O+]C2=C1C=CC(N)=C2 TUFFYSFVSYUHPA-UHFFFAOYSA-M 0.000 claims description 2
- 239000000243 solution Substances 0.000 abstract description 3
- 230000001804 emulsifying effect Effects 0.000 abstract description 2
- 229910019142 PO4 Inorganic materials 0.000 abstract 1
- 230000003139 buffering effect Effects 0.000 abstract 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 abstract 1
- 239000010452 phosphate Substances 0.000 abstract 1
- 230000000052 comparative effect Effects 0.000 description 24
- 239000002502 liposome Substances 0.000 description 23
- 238000005538 encapsulation Methods 0.000 description 14
- 238000003384 imaging method Methods 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 8
- 230000000694 effects Effects 0.000 description 5
- 239000002245 particle Substances 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 230000035945 sensitivity Effects 0.000 description 3
- 230000005540 biological transmission Effects 0.000 description 2
- 210000000170 cell membrane Anatomy 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 238000012921 fluorescence analysis Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000005056 cell body Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011503 in vivo imaging Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 238000006862 quantum yield reaction Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
- C09K11/02—Use of particular materials as binders, particle coatings or suspension media therefor
- C09K11/025—Use of particular materials as binders, particle coatings or suspension media therefor non-luminescent particle coatings or suspension media
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
- C09B1/00—Dyes with anthracene nucleus not condensed with any other ring
- C09B1/16—Amino-anthraquinones
- C09B1/20—Preparation from starting materials already containing the anthracene nucleus
- C09B1/48—Anthrimides
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
- C09B23/00—Methine or polymethine dyes, e.g. cyanine dyes
- C09B23/0075—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain being part of an heterocyclic ring
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
- C09B23/00—Methine or polymethine dyes, e.g. cyanine dyes
- C09B23/02—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain containing an odd number of >CH- or >C[alkyl]- groups
- C09B23/08—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain containing an odd number of >CH- or >C[alkyl]- groups more than three >CH- groups, e.g. polycarbocyanines
- C09B23/086—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain containing an odd number of >CH- or >C[alkyl]- groups more than three >CH- groups, e.g. polycarbocyanines more than five >CH- groups
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
- C09B67/00—Influencing the physical, e.g. the dyeing or printing properties of dyestuffs without chemical reactions, e.g. by treating with solvents grinding or grinding assistants, coating of pigments or dyes; Process features in the making of dyestuff preparations; Dyestuff preparations of a special physical nature, e.g. tablets, films
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
- C09B67/00—Influencing the physical, e.g. the dyeing or printing properties of dyestuffs without chemical reactions, e.g. by treating with solvents grinding or grinding assistants, coating of pigments or dyes; Process features in the making of dyestuff preparations; Dyestuff preparations of a special physical nature, e.g. tablets, films
- C09B67/0001—Post-treatment of organic pigments or dyes
- C09B67/0004—Coated particulate pigments or dyes
- C09B67/0008—Coated particulate pigments or dyes with organic coatings
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
- C09B67/00—Influencing the physical, e.g. the dyeing or printing properties of dyestuffs without chemical reactions, e.g. by treating with solvents grinding or grinding assistants, coating of pigments or dyes; Process features in the making of dyestuff preparations; Dyestuff preparations of a special physical nature, e.g. tablets, films
- C09B67/0071—Process features in the making of dyestuff preparations; Dehydrating agents; Dispersing agents; Dustfree compositions
- C09B67/0084—Dispersions of dyes
- C09B67/0085—Non common dispersing agents
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
- C09B67/00—Influencing the physical, e.g. the dyeing or printing properties of dyestuffs without chemical reactions, e.g. by treating with solvents grinding or grinding assistants, coating of pigments or dyes; Process features in the making of dyestuff preparations; Dyestuff preparations of a special physical nature, e.g. tablets, films
- C09B67/0071—Process features in the making of dyestuff preparations; Dehydrating agents; Dispersing agents; Dustfree compositions
- C09B67/0084—Dispersions of dyes
- C09B67/0091—Process features in the making of dispersions, e.g. ultrasonics
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
- C09B67/00—Influencing the physical, e.g. the dyeing or printing properties of dyestuffs without chemical reactions, e.g. by treating with solvents grinding or grinding assistants, coating of pigments or dyes; Process features in the making of dyestuff preparations; Dyestuff preparations of a special physical nature, e.g. tablets, films
- C09B67/0097—Dye preparations of special physical nature; Tablets, films, extrusion, microcapsules, sheets, pads, bags with dyes
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
- C09K11/06—Luminescent, e.g. electroluminescent, chemiluminescent materials containing organic luminescent materials
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- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
- C09K2211/10—Non-macromolecular compounds
- C09K2211/1018—Heterocyclic compounds
- C09K2211/1025—Heterocyclic compounds characterised by ligands
- C09K2211/1029—Heterocyclic compounds characterised by ligands containing one nitrogen atom as the heteroatom
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
- C09K2211/10—Non-macromolecular compounds
- C09K2211/1018—Heterocyclic compounds
- C09K2211/1025—Heterocyclic compounds characterised by ligands
- C09K2211/1088—Heterocyclic compounds characterised by ligands containing oxygen as the only heteroatom
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Dispersion Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a sensitive fluorescent dye and a preparation method thereof, wherein the sensitive fluorescent dye is prepared from the following raw materials: the fluorescent dye comprises phospholipid, PEG cholesterol derivative, phosphate buffer solution and organic fluorescent dye, wherein the organic fluorescent dye is wrapped in the phospholipid; the preparation process includes forming homogeneous phospholipid film, forming PEG cholesterol derivative and phosphate buffering solution into dispersion liquid, dispersing and emulsifying the homogeneous phospholipid film and the organic fluorescent dye in the dispersion liquid to obtain the sensitive fluorescent dye. The fluorescent dye has good cell penetrability, compatibility and stability, and the preparation is simple and convenient.
Description
Technical Field
The invention relates to a sensitive fluorescent dye and a preparation method thereof, belonging to the technical field of fluorescent dyes.
Background
The fluorescence analysis method displays microscopic information change in a macroscopic form through a fluorescence signal, is widely applied to identification and marking due to the advantages of high sensitivity, strong selectivity, in-situ real-time response and the like, and simultaneously drives fluorescent molecules to develop to higher brightness and higher stability, and the existing organic micromolecular fluorescent dyes used for fluorescence analysis, such as rhodamine, cyanine dyes, fluorescein and the like, but have charges, so that the marking performance, stability and compatibility of the molecules are seriously affected, the lipophilicity of the rhodamine fluorescent dyes is poor, and the penetration capability of the rhodamine fluorescent dyes on cells is poor; the negative ions of the fluorescein molecules are easily oxidized to be quenched, so that the fluorescein molecules are not easy to penetrate cell membranes; the polymethine chain of the cyanine dye is very vulnerable to attack by singlet oxygen, and the torsion of olefin leads to the reduction of quantum yield and the like. In the era of the vigorous development of super-resolution and fluorescent dye detection technology, most of the current researches are to carry out radical modification or structure on single-molecule small-molecule fluorescent dye, but the penetrability, stability and compatibility of the fluorescent dye are still poor, and the fluorescent dye has certain limitation in certain occasions.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides a sensitive fluorescent dye agent and a preparation method thereof, wherein the fluorescent dye agent has good cell penetrability, compatibility and stability, and the preparation is simple and convenient.
In order to achieve the above purpose, the present invention adopts the following technical scheme: a sensitive fluorescent dye agent is prepared from the following raw materials: the fluorescent dye comprises phospholipid, PEG cholesterol derivative, phosphate buffer solution and organic fluorescent dye, wherein the organic fluorescent dye is wrapped in the phospholipid; wherein the mass of the organic fluorescent dye is 41.3-46.5% of the mass of the phospholipid, the mass of the PEG cholesterol derivative is 23.8-27.3% of the mass of the phospholipid, and the mass of the phosphate buffer solution is 1.6-2 times of the mass of the phospholipid.
Preferably, the phospholipid is formed by mixing two or more of phosphatidylcholine, phosphatidylethanolamine or phosphatidylserine.
Preferably, the phospholipid is prepared by mixing phosphatidylcholine, phosphatidylethanolamine and phosphatidylserine according to a weight ratio of 1:0.3:0.45.
Wherein the phospholipid is prepared by mixing phosphatidylcholine and phosphatidylethanolamine according to a weight ratio of 1:0.0.68.
Wherein the phospholipid is formed by mixing phosphatidylcholine and phosphatidylserine according to the weight ratio of 1:0.82.
Preferably, the PEG cholesterol derivative is one of cholesterol-polyethylene glycol-amino, cholesterol-polyethylene glycol-carboxyl or cholesterol-polyethylene glycol-hydroxyl.
Preferably, the organic fluorescent dye is one of rhodamine 6G, rhodamine 123, rhodamine B, fluorescein, cyanine dye Cy3, cyanine dye Cy3.5, cyanine dye Cy5, cyanine dye Cy5.5, cyanine dye Cy7, cyanine dye Cy7.5, cyanine dye sulfo-Cy 3, cyanine dye sulfo-Cy 5, cyanine dye sulfo-Cy 7, and the like.
Preferably, the pH of the phosphate buffer solution is between 6 and 6.5.
The invention also provides a preparation method of the sensitive fluorescent dye, which comprises the following steps:
(1) Adding phospholipid into pure water containing ethanol, shearing at high speed for 30-35 min, performing first ultrasonic treatment at 25-30 ℃, and performing first reduced pressure rotary evaporation at 40-45 ℃ to form a homogeneous membrane;
(2) Dissolving PEG cholesterol derivative in phosphoric acid buffer solution, shearing at high speed for 30-35 min under normal pressure to form dispersion;
(3) Adding dispersion liquid into the homogeneous membrane, carrying out high-speed shearing to carry out dispersion emulsification, adding organic fluorescent dye, continuing high-speed shearing, heating to 30-35 ℃ to hydrate for 45-50 min, carrying out second ultrasonic treatment at 25-30 ℃, and sterilizing by using a microporous filter membrane to obtain the sensitive fluorescent dye.
Preferably, the first and second ultrasonic treatments: the ultrasonic treatment is intermittent ultrasonic with power of 60-65W.
Wherein, the ultrasonic is carried out once every 2s for 3s, and the total ultrasonic time is 21-24 s.
Preferably, the mass fraction of ethanol in the pure water containing ethanol is 60 to 70%.
Preferably, the mass of pure water containing ethanol is 3 to 5 times that of phospholipid.
The invention has the beneficial effects that: the sensitive fluorescent dye agent disclosed by the invention is prepared by wrapping fluorescent dye in liposome, and emulsifying and dispersing by using PEG cholesterol derivative, so that the fluorescent dye has hydrophilic solubility and hydrophobicity, thereby enhancing the sensitivity of the fluorescent dye to cell bodies and improving the penetrability of the fluorescent dye to cell membranes; meanwhile, the liposome wraps the fluorescent dye, so that the release of the fluorescent dye in the imaging transmission process is reduced, and the stability of the fluorescent dye in the imaging transmission process is improved; the liposome molecular particle size in the sensitive fluorescent dye agent has good dispersibility, can avoid aggregation of fluorescent dye, prolongs imaging time and has good imaging effect; the sensitive fluorescent dye agent can effectively realize the transfer of fluorescent dye in vivo, improve the marking performance of fluorescent dye molecules and improve the in vivo imaging effect; the sensitive fluorescent dye provided by the invention can be used without the assistance of an organic solvent, so that the toxicity can be reduced.
Drawings
FIG. 1 shows fluorescence intensities of liposome in the complete state of the sensitive fluorescent dyes of examples 1 to 6 and comparative example 5;
FIG. 2 shows fluorescence intensities after liposome disruption in examples 1 to 6 and comparative example 5.
Detailed Description
The invention will now be more clearly and more fully described by way of the following specific examples, which are not intended to be limiting.
Example 1
A specific preparation method of the sensitive fluorescent dye comprises the following steps:
(1) Adding 10g of phospholipid formed by mixing phosphatidylcholine and phosphatidylethanolamine according to a weight ratio of 1:0.0.68 into 30g of pure water with the mass fraction of 70% of ethanol, shearing at a high speed for 30-35 min, performing first ultrasonic treatment at 25-30 ℃, performing ultrasonic treatment once every 2s under the power of 60-65W, performing first ultrasonic treatment for 3s, performing ultrasonic total time for 21s, and performing first reduced pressure rotary evaporation at 40-45 ℃ to form a homogeneous film;
(2) Dissolving 2.38g of cholesterol-polyethylene glycol-amino in 16g of phosphoric acid buffer solution with pH of 6-6.5, and shearing at high speed for 30-35 min under normal pressure to form a dispersion;
(3) Adding dispersion liquid into a homogeneous membrane, carrying out high-speed shearing to carry out dispersion emulsification, adding rhodamine B4.13g, continuing high-speed shearing, heating to 30-35 ℃ to hydrate for 45-50 min, carrying out second ultrasonic treatment at 25-30 ℃, carrying out ultrasonic once every 2s under the power of 60-65W, carrying out ultrasonic once for 3s, carrying out total ultrasonic time of 21s, and sterilizing by a microporous filter membrane to obtain the sensitive fluorescent dye.
Example 2
10g of phospholipid formed by mixing phosphatidylcholine and phosphatidylserine according to a weight ratio of 1:0.82 is added into 40g of pure water with the mass fraction of 65% of ethanol, after high-speed shearing for 30-35 min, first ultrasonic treatment is carried out at 25-30 ℃, ultrasonic treatment is carried out once every 2s under the power of 60-65W, ultrasonic treatment is carried out once for 3s, the total ultrasonic time is 24s, and then first reduced pressure rotary evaporation is carried out at 40-45 ℃ to form a homogeneous film;
(2) Dissolving 2.38g of cholesterol-polyethylene glycol-amino in 16g of phosphoric acid buffer solution with pH of 6-6.5, and shearing at high speed for 30-35 min under normal pressure to form a dispersion;
(3) Adding dispersion liquid into a homogeneous membrane, carrying out high-speed shearing to carry out dispersion emulsification, adding rhodamine B4.13g, continuing high-speed shearing, heating to 30-35 ℃ to hydrate for 45-50 min, carrying out second ultrasonic treatment at 25-30 ℃, carrying out ultrasonic once every 2s under the power of 60-65W, carrying out ultrasonic once for 3s, carrying out total ultrasonic time for 24s, and sterilizing by a microporous filter membrane to obtain the sensitive fluorescent dye.
Example 3
A specific preparation method of the sensitive fluorescent dye comprises the following steps:
(1) 10g of phospholipid formed by mixing phosphatidylcholine, phosphatidylethanolamine and phosphatidylserine according to a weight ratio of 1:0.25:0.45 is added into 30g of pure water with the mass fraction of 65% of ethanol, after shearing for 30-35 min at high speed, first ultrasonic treatment is carried out at 25-30 ℃, ultrasonic treatment is carried out once every 2s under the power of 60-65W, ultrasonic treatment is carried out for 3s, the total ultrasonic time is 21s, and then first decompression rotary evaporation is carried out at 40-45 ℃ to form a homogeneous membrane;
(2) Dissolving 2.38g of cholesterol-polyethylene glycol-amino in 16g of phosphoric acid buffer solution with pH of 6-6.5, and shearing at high speed for 30-35 min under normal pressure to form a dispersion;
(3) Adding dispersion liquid into a homogeneous membrane, carrying out high-speed shearing to carry out dispersion emulsification, adding rhodamine B4.13g, continuing high-speed shearing, heating to 30-35 ℃ to hydrate for 45-50 min, carrying out second ultrasonic treatment at 25-30 ℃, carrying out ultrasonic once every 2s under the power of 60-65W, carrying out ultrasonic once for 3s, carrying out total ultrasonic time of 21s, and sterilizing by a microporous filter membrane to obtain the sensitive fluorescent dye.
Example 4
The sensitive fluorescent dye of this example 4 is the same as that of example 3, except that: the phospholipid of example 4 was prepared by mixing phosphatidylcholine, phosphatidylethanolamine and phosphatidylserine in a weight ratio of 1:0.3:0.45.
Example 5
The sensitive fluorescent dye of this example 5 is the same as that of example 1, except that: the PEG cholesterol derivative of this example 6 is cholesterol-polyethylene glycol-carboxyl.
Example 6
The sensitive fluorescent dye of this example 6 is the same as in example 1, except that: the PEG cholesterol derivative of this example 6 is cholesterol-polyethylene glycol-hydroxy.
Example 7
A specific preparation method of the sensitive fluorescent dye comprises the following steps:
(1) Adding 10g of phospholipid formed by mixing phosphatidylcholine and phosphatidylethanolamine according to a weight ratio of 1:0.0.68 into 50g of pure water with the mass fraction of 60% of ethanol, performing first ultrasonic treatment at 25-30 ℃ after shearing at high speed for 30-35 min, performing ultrasonic treatment once every 2s under the power of 60-65W, performing ultrasonic treatment for 3s for 24s for the total ultrasonic time, and performing first reduced pressure rotary evaporation at 40-45 ℃ to form a homogeneous film;
(2) Dissolving 2.58g of cholesterol-polyethylene glycol-carboxyl into 20g of phosphoric acid buffer solution with pH of 6-6.5, and shearing at high speed for 30-35 min under normal pressure to form dispersion liquid;
(3) Adding dispersion liquid into a homogeneous membrane, performing high-speed shearing to perform dispersion emulsification, adding rhodamine 6G4.35g, continuing high-speed shearing, heating to 30-35 ℃ to hydrate for 45-50 min, performing second ultrasonic treatment at 25-30 ℃, performing ultrasonic treatment once every 2s under the power of 60-65W, performing ultrasonic treatment once for 3s, performing total ultrasonic treatment for 24s, and performing sterilization through a microporous filter membrane to obtain the sensitive fluorescent dye.
Example 8
10g of phospholipid formed by mixing phosphatidylcholine and phosphatidylserine according to a weight ratio of 1:0.82 is added into 30g of pure water with the mass fraction of 65% of ethanol, after high-speed shearing for 30-35 min, first ultrasonic treatment is carried out at 25-30 ℃, ultrasonic treatment is carried out once every 2s under the power of 60-65W, ultrasonic treatment is carried out once for 3s, the total ultrasonic time is 21s, and then first reduced pressure rotary evaporation is carried out at 40-45 ℃ to form a homogeneous film;
(2) Dissolving 2.73g of cholesterol-polyethylene glycol-hydroxyl in 18g of phosphoric acid buffer solution with pH of 6-6.5, and shearing at high speed for 30-35 min under normal pressure to form a dispersion;
(3) Adding dispersion liquid into a homogeneous membrane, performing high-speed shearing to perform dispersion emulsification, adding cyanine dye Cy 7.65 g, continuing high-speed shearing, heating to 30-35 ℃ to hydrate for 45-50 min, performing second ultrasonic treatment at 25-30 ℃, performing ultrasonic once every 2s under the power of 60-65W, performing ultrasonic once for 3s, performing total ultrasonic time of 21s, and performing sterilization by a microporous filter membrane to obtain the sensitive fluorescent dye.
Comparative example 1
The sensitive fluorescent dye of this comparative example 1 is the same as in example 1 except that: the phospholipid of comparative example 1 was phosphatidylcholine.
Comparative example 2
The sensitive fluorescent dye of this comparative example 2 is the same as in example 1, except that: the phospholipid of comparative example 2 was phosphatidylethanolamine.
Comparative example 3
The sensitive fluorescent dye of this comparative example 3 is the same as in example 1, except that: the phospholipid of comparative example 3 was phosphatidylserine.
Comparative example 4
The sensitive fluorescent dye of this comparative example 4 is the same as in example 1, except that: in step (2) of comparative example 4, 2.38g of cholesterol was dissolved in 16g of a phosphate buffer solution having a pH of 6 to 6.5.
Comparative example 5
The sensitive fluorescent dye of this comparative example 5 is the same as in example 1, except that: the first and second ultrasonic treatments of this comparative example 5 were continuous ultrasonic treatment, and the ultrasonic time was 21.
Comparative example 6
The sensitive fluorescent dye of this comparative example 6 was the same as in example 1, except that: the first and second ultrasonic treatments of this comparative example 6 were intermittent ultrasonic, with ultrasonic once every 2s, ultrasonic once for 2s, and ultrasonic total time for 24s.
Effect examples
1. The sensitive fluorescent dye prepared in examples 1 to 6 and comparative examples 1 to 6 was concentrated by rotary evaporation under reduced pressure at 30 to 35℃and dried, and then tested, and the results are shown in Table 1.
Through the above table 1, compared with comparative examples 1 to 3, the sensitive fluorescent dye of the present invention, after concentrating and drying, has higher encapsulation efficiency of examples 1 to 8, the encapsulation efficiency is more than 91%, the particle size distribution is uniform, and the dispersibility is better; compared with comparative examples 5 and 6, examples 1 to 8 have higher encapsulation efficiency, the encapsulation efficiency is more than 91%, the particle size is smaller, the particle size is about 110, the particle size is basically unchanged after being placed for a period of time, and the dispersibility is better; the sensitive fluorescent dye provided by the invention has good stability.
2. Taking the sensitive fluorescent dye agent coated with rhodamine B prepared in the above examples 1 to 6, and measuring the fluorescence intensity of the sensitive fluorescent dye agent in the complete state of the liposome and the fluorescence intensity after the liposome is ruptured, wherein the fluorescence intensity is shown in the complete state of the liposome in the graph in FIG. 1, and the fluorescence intensity is shown in the graph in FIG. 2;
from fig. 1 and fig. 2, it is found that fluorescence in the complete state of the liposome is quenched, after the liposome is ruptured, fluorescence can be recovered, and the higher the encapsulation efficiency of the liposome encapsulation is, the higher the strength of the fluorescent dye in the later stage of liposome rupture is, which indicates that the liposome encapsulation of the fluorescent dye can effectively avoid quenching the fluorescent dye in the conveying process, and in combination with table 1, the encapsulation efficiency of the liposome is high, which is helpful for reducing release of the fluorescent dye in the imaging conveying process, improving the stability of the fluorescent dye in the imaging conveying process, prolonging the imaging time and improving the imaging effect; example 4 and example 3 are better in the encapsulation efficiency of the fluorescent dye with the phospholipid mixed with phosphatidylcholine, phosphatidylethanolamine and phosphatidylserine in example 4 and example 3 than in example 1 and example 2; in examples 1, 2, 5 and 6, the phospholipid was dispersed and emulsified by using a PEG cholesterol derivative such as cholesterol-polyethylene glycol-amino, cholesterol-polyethylene glycol-carboxyl or cholesterol-polyethylene glycol-hydroxyl, and after the liposome was ruptured, the PEG cholesterol derivative increased the sensitivity of the fluorescent dye and increased the fluorescence intensity, compared with comparative example 5.
Besides the encapsulation of rhodamine B by using liposome, example 7 also provides encapsulation of rhodamine 6G, example 8 also provides encapsulation of cyanine dye Cy7, in addition, a lot of experiments prove that the fluorescence intensity of the fluorescent dye in the complete state of the liposome and the fluorescence intensity of the fluorescent dye in the complete state of the liposome are similar to those of fig. 1 and 2, so that after the liposome is ruptured, the fluorescence can be recovered, and the higher the encapsulation rate of the liposome is, the higher the intensity of the fluorescent dye in the later stage of the liposome is, the more effective the encapsulation of the fluorescent dye by the liposome can be avoided, the more stable the transfer time of the fluorescent dye can be improved, and the imaging effect of the fluorescent dye can be improved; the liposome of the sensitive fluorescent dye provided by the invention has good cell penetrability, compatibility and stability.
Finally, it should be noted that the above-mentioned embodiments are only for illustrating the technical solution of the present invention and not for limiting the technical solution of the present invention, and although the present invention has been described in detail with reference to the above-mentioned embodiments, it should be understood by those skilled in the art that the present invention may be modified or equivalently replaced without departing from the spirit and scope of the present invention, and any modification or partial replacement thereof should be included in the scope of the claims of the present invention.
Claims (9)
1. A sensitive fluorescent dye is characterized by comprising the following raw materials: the fluorescent dye comprises phospholipid, PEG cholesterol derivative, phosphate buffer solution and organic fluorescent dye, wherein the organic fluorescent dye is wrapped in the phospholipid; wherein the mass of the organic fluorescent dye is 41.3-46.5% of the mass of the phospholipid, the mass of the PEG cholesterol derivative is 23.8-27.3% of the mass of the phospholipid, and the mass of the phosphate buffer solution is 1.6-2 times of the mass of the phospholipid.
2. The sensitive fluorescent dye of claim 1, wherein the phospholipid is formed by mixing two or more of phosphatidylcholine, phosphatidylethanolamine or phosphatidylserine.
3. The sensitive fluorescent dye according to claim 2, wherein the phospholipid is prepared by mixing phosphatidylcholine, phosphatidylethanolamine and phosphatidylserine according to a weight ratio of 1:0.3:0.45.
4. A sensitive fluorescent dye according to claim 1, wherein the PEG cholesterol derivative is one of cholesterol-polyethylene glycol-amino, cholesterol-polyethylene glycol-carboxyl or cholesterol-polyethylene glycol-hydroxyl.
5. A sensitive fluorescent dye according to claim 1, characterized in that the organic fluorescent dye is one of rhodamine 6G, rhodamine 123, rhodamine B, fluorescein, cyanine dye Cy3, cyanine dye Cy3.5, cyanine dye Cy5, cyanine dye Cy5.5, cyanine dye Cy7, cyanine dye Cy7.5, cyanine dye sulfo-Cy 3, cyanine dye sulfo-Cy 5 or cyanine dye sulfo-Cy 7.
6. A sensitive fluorescent dye as claimed in claim 1, wherein the pH of the phosphate buffer solution is between 6 and 6.5.
7. A method for preparing a sensitive fluorescent dye according to claim 1, comprising the steps of:
(1) Adding phospholipid into pure water containing ethanol, shearing at high speed for 30-35 min, performing first ultrasonic treatment at 25-30 ℃, and performing first reduced pressure rotary evaporation at 40-45 ℃ to form a homogeneous membrane;
(2) Dissolving PEG cholesterol derivative in phosphoric acid buffer solution, shearing at high speed for 30-35 min under normal pressure to form dispersion;
(3) Adding dispersion liquid into the homogeneous membrane, carrying out high-speed shearing to carry out dispersion emulsification, adding organic fluorescent dye, continuing high-speed shearing, heating to 30-35 ℃ to hydrate for 45-50 min, carrying out second ultrasonic treatment at 25-30 ℃, and sterilizing by using a microporous filter membrane to obtain the sensitive fluorescent dye.
8. The method for preparing a sensitive fluorescent dye according to claim 7, wherein the first and second ultrasonic treatments: the ultrasonic treatment is intermittent ultrasonic with power of 60-65W.
9. The method for preparing a sensitive fluorescent dye according to claim 8, wherein the ultrasonic waves are performed once every 2s for 3s, and the total ultrasonic time is 21-24 s.
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