CN105944120B - A kind of folic acid liposome and its preparation method and application being loaded with ten diborane maleimide propionyl piperazines, seven methine cyanines thioether salt - Google Patents
A kind of folic acid liposome and its preparation method and application being loaded with ten diborane maleimide propionyl piperazines, seven methine cyanines thioether salt Download PDFInfo
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- CN105944120B CN105944120B CN201610423715.7A CN201610423715A CN105944120B CN 105944120 B CN105944120 B CN 105944120B CN 201610423715 A CN201610423715 A CN 201610423715A CN 105944120 B CN105944120 B CN 105944120B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
- A61K51/1217—Dispersions, suspensions, colloids, emulsions, e.g. perfluorinated emulsion, sols
- A61K51/1234—Liposomes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/041—Heterocyclic compounds
- A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
- A61K51/0459—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with two nitrogen atoms as the only ring hetero atoms, e.g. piperazine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/0495—Pretargeting
Abstract
The present invention relates to the technical fields of folic acid liposome, disclose the folic acid liposome and its preparation method and application that one kind is loaded with ten diborane maleimide propionyl piperazines, seven methine cyanines thioether salt (BS-CyP).The folic acid liposome for being loaded with BS-CyP is made by following each component: BS-CyP, phosphatide, cholesterol, surfactant, folic acid arm, injection solvent.The present invention uses composition material of three kinds of amphipathic molecules as folic acid liposome, in the case where guaranteeing the principle with auxiliary material less, prepares the superior in quality folic acid liposome for being loaded with BS-CyP.Meet injection research and development technology as far as possible less with auxiliary material, guideline of the prescription to be simply advisable, provide the IV delivery dosage form solution using folic acid liposome drug-loading system as BS-CyP, the apparent water-soluble and tumor-targeting for improving BS-CyP, lays technical foundation for the patent medicine possibility of BS-CyP.
Description
Technical field
The present invention relates to the technical fields of folic acid liposome, are loaded with ten diborane maleimides more particularly, to one kind
The folic acid liposome and its preparation method and application of seven methine cyanines thioether salt of amine propionyl piperazine.
Background technique
Boron neutron capture therapy (BNCT) is a kind of binary radiotheraping method based on cellular level, by two part groups
At one is10B carries agent, and two be neutron beam.
BSH is that clinically common boron carries agent, and it is female thin to be usually used in pernicious Intracranial Gliomas, melanocytoma and glue
The tumor diseases such as born of the same parents' tumor.Boron is in basis and the key factor that tumor tissues targeting enrichment is BNCT treatment.In addition, if in tumour
There is fluorescent tracing characteristic while tissue enrichment, then be expected to achieve the purpose that precisely to treat simultaneously.
For tracer, the design of this seminar has synthesized the boron with fluorescent marker and has carried ten diborane maleimide of agent
Seven methine cyanines thioether salt (BS-CyP) of propionyl piperazine, sodium salt molecular formula are C45H66B12N5O3SNa, molecular weight 899, structure
Formula is as shown in Equation 3.
Early-stage study shows that being copolymerized Jiaozhuo with two-photon laser is its detection method, and BS-CyP is in vitro in cell experiment
Show good tracer；And BS- is further confirmed by the internal pharmaceutical indications Journal of Sex Research of 4T1 breast cancer tumor-bearing mice
CyP has good tracing in vivo.Meanwhile being studied according to vitro cytotoxicity, at maximum dosage 25 (10B) mg/L
Normal cell tumour associated fibroblast cell 3T3, human embryonic kidney cells 293 and HepG-2 cell are without overt toxicity, as a result
BS-CyP safety with higher is prompted.
BS-CyP completes the druggabilities such as pharmacokinetics, general pharmacology evaluation main contents, and it is good to show it
Patent medicine potentiality.But tumor-targeting is bad and poorly water-soluble is the biggest problem for hindering its patent medicine.BS-CyP can be dissolved in
The parts such as dimethyl sulfoxide, chloroform, acetonitrile, methanol organic solvent, almost insoluble in water for injection or physiological saline, early period grinds
Drug preparation and administration can only be carried out in studying carefully using dimethyl sulfoxide as cosolvent.Since excessive dimethyl sulfoxide can generate thorn
Swash the side effects such as property and neurotoxicity, significantly limits dosage.Targeting is bad simultaneously makes to be distributed to tumor tissues
BS-CyP content is further reduced, and is limited it and is further developed.
Accordingly, this seminar, which is explored, changes BS-CyP dosage form to improve its apparent water solubility to be suitable for intravenous injection, together
Its tumor-targeting of Shi Shixian.Folic acid liposome (Folic acid liposomes) is by being used in mixed way two kinds or more no
There is drug-loading system made of same surfactant (such as phosphatide, cholesterol etc.) thermodynamic stability and good nanometer to imitate
It answers, is becoming a kind of for delivering the effective means of insoluble drug in recent years.For liposome, phosphatide/cholate is one
A typical using combination, it is Roche Holding Ag (F.Hoffmann-La respectively that the product of existing liposome, which successfully lists, at present
Roche Ltd.) production liposomal doxorubicin formula epirubicin.
Summary of the invention
The technical problem to be solved by the present invention is to overcome existing ten diboranes maleimide propionyl piperazine, seven methine cyanines sulphur
Ether salt application technology is insufficient, provides a kind of folic acid rouge for being loaded with ten diborane maleimide propionyl piperazines, seven methine cyanines thioether salt
Plastid is realized using folic acid liposome drug-loading system as the quiet of ten diborane maleimide propionyl piperazines, seven methine cyanines thioether salt
Arteries and veins delivers dosage form solution, improves the apparent water-soluble, tumor-targeting of BS-CyP, increases its patent medicine possibility.
Another technical problem to be solved by the present invention is that the preparation method of the folic acid liposome of BS-CyP is provided described in providing,
Partial size qualification, even particle size distribution, the stable folic acid liposome of physical property can be prepared based on preparation method of the present invention.
The invention solves an also technical problem be to solve the problems, such as the slightly solubility of main ingredient BS-CyP and improve its tumor target
Tropism provides a kind of intravenous formulations containing the folic acid liposome for being loaded with BS-CyP.
The purpose of the present invention is achieved by the following technical programs:
A kind of folic acid liposome being loaded with ten diborane maleimide propionyl piperazines, seven methine cyanines thioether salt, by following
The each component of mass percent is made:
0.089%~0.30% ten diborane maleimide propionyl piperazines, seven methine cyanines thioether salt,
5.93%~6.82% phosphatide,
1.78%~2.55% cholesterol,
0.30%~0.60% surfactant,
0.30%~0.60% folic acid arm；
Surplus is injection solvent；
Ten diboranes maleimide propionyl piperazine, the seven methine cyanines thioether salt is structure shown in formula 1:
Wherein, boron described in structure is 10 isotope of boron, X+For pharmaceutically acceptable cation；
The folic acid arm is the mixture for one or more of structures that n is 5~60 in structure such as formula 2,
The folic acid liposome of the present invention for being loaded with BS-CyP is carried with two kinds of amphiphilic phosphatide, surfactant liposomes
Body material, injection solvent and main ingredient BS-CyP composition.
Preferably, the pharmaceutically acceptable cation includes alkali metal ion, organic amine ion.Further preferably
Ground, the pharmaceutically acceptable cation is sodium ion.
Preferably, the phosphatide is egg yolk lecithin, soybean lecithin, hydrogenated yolk lecithin, hydrogenated soya phosphatide, brain phosphorus
One or more of rouge, lipositol, serinephosphatide or Polyene Phosphatidylcholine.It is further preferred that the phosphatidyl
Choline is the egg yolk lecithin that content is greater than 99%.
Preferably, the surfactant be nonionic surfactant, including Pluronic F68,
One of the saturation of chain a length of 8~18 or unsaturated fatty acid salt.Further preferably, the surfactant is pool Lip river
Husky nurse 407, enuatrol, PLURONICS F87.
The injection solvent is in the phosphate buffer of water for injection, injection physiological saline or pH 6.5~6.8
It is a kind of.It is further preferred that the injection solvent is the phosphate buffer of pH 6.5~6.8.
Preferentially, the folic acid arm (F-PEG-SUCA-PE) is the one or more that n is 40~55 in structure such as formula 2
The mixture of structure.
A kind of preparation method of the folic acid liposome being loaded with BS-CyP, comprising the following steps:
S1. ten diborane maleimide propionyl piperazines, seven methine cyanines thioether salt, phosphatide and cholesterol are dissolved in organic
In solvent, solution A is formed；
S2. S1 acquired solution A is evaporated under reduced pressure and removes remaining organic solvent and shape on the wall in S1 acquired solution A
At film；
S3. film obtained by S2 is added in injection solvent, film is made to be dispersed in formation lipid system in injection solvent
Agent B；
S4. folic acid arm and surfactant is added in the resulting Lipidosome B of S3, uniform stirring reaction 12 in room temperature
~for 24 hours, the folic acid liposome of ten diborane maleimide propionyl piperazines, seven methine cyanines thioether salt must be loaded with.
The preparation method of the folic acid liposome of the present invention for being loaded with BS-CyP is prepared using film dispersion method, with phosphatide and
BS-CyP is embedded in bimolecular lipid membrane by cholesterol collectively as liposome vectors material.
Further, the preparation method of the folic acid liposome for being loaded with BS-CyP, comprising the following steps:
S1. BS-CyP, phosphatide, cholesterol are completely dissolved in organic solvent, form solution A；
S2. S1 acquired solution A is set in a round bottom flask, vacuum rotary steam, which removes organic solvent, in Rotary Evaporators makes it
The film of homogeneous transparent is formed in flask walls；
S3. it will be added in injection solvent in film obtained by S2, ultrasound is dispersed in film in injection solvent, must carry
The Liposomal formulation B of BS-CYP.
S4. the resulting Liposomal formulation B of S3 is placed in the cillin bottle of 10ml, folic acid arm (F-PEG-SUCA-is added
PE) and surfactant, uniform stirring reaction for 24 hours, must be loaded with BS-CYP folic acid liposome in room temperature.
Preferably, organic solvent described in S1 includes but is not limited to one in methanol, ethyl alcohol, ethyl acetate, acetone or chloroform
Kind, it is further preferred that the organic solvent is chloroform or methanol.
Preferably, reduction vaporization described in S3 is to be carried out using Rotary Evaporators.
The present invention provides a kind of folic acid lipid for being loaded with ten diborane maleimide propionyl piperazines, seven methine cyanines thioether salt
Body is in the application for preparing ejection preparation.The ejection preparation solves the slightly solubility of main ingredient BS-CyP and increase tumor-targeting is asked
Topic.
Compared with prior art, the invention has the following beneficial effects:
1. the present invention provides a kind of simple folic acid liposomes of composition for being loaded with BS-CyP.Main ingredient is removed in the present invention
Except BS-CyP, by determining the component and ratio of science, realize using only two kinds of amphipathic molecules as the group of liposome
Superior in quality load BS-CyP folic acid Liposomal formulation is prepared, is complied fully in the case where guaranteeing the principle with auxiliary material less at material
The guideline of injection research and development technology: injection prescription uses auxiliary material, prescription under conditions of guaranteeing injection quality less as far as possible
To be simply advisable.The present invention provides the IV delivery dosage form solution using folic acid liposome drug-loading system as BS-CyP,
The apparent water-soluble and tumor-targeting for improving BS-CyP, lays technical foundation for patent medicine possibility.
2. being based on prescription of the present invention, the present invention provides reasonable preparation step and technique, the folic acid lipid that is prepared
Body partial size is smaller, about 102nm, even particle size distribution, PDI 0.172, and ξ potential is -31.4mV, and mode of appearance is that blue is clear and bright
Suspension has apparent Tyndall phenomenon, effect stability.
3. the present invention carries the folic acid Liposomal formulation of BS-CyP using poloxamer188 as additive preparation altogether, relatively
In the common stabilizer of the prior art, the toxicity of poloxamer188 is smaller, therefore, successfully provides and makees using stabilizer and phosphatide
The technical solution that the folic acid liposome of injectable administration is prepared for total additive, to the wide of the folic acid liposome for carrying BS-CyP
Application prospect provides technical guarantee.
Detailed description of the invention
Fig. 1 is the grain size distribution (Malvern laser particle analyzer) of BS-CyP folic acid liposome；
Fig. 2 is the internal targeting and tracer of BS-CyP folic acid liposome.
Specific embodiment
The present invention is further illustrated combined with specific embodiments below.Following embodiment is only illustrative examples, not structure
At inappropriate limitation of the present invention, the multitude of different ways that the present invention can be limited and be covered by summary of the invention is implemented.Unless special
Do not mentionlet alone bright, reagent, compound and the equipment that the present invention uses is the art conventional reagent, compound and equipment.
Ten diborane maleimide propionyl piperazines, seven methine cyanines thioether sodium salt (BS-CyP) in following embodiment by with
Lower section method is prepared.
(1) 2- (- 2- (- 2- (4- (3- (2,5- dioxy -2,5- dihydro -1H- pyrroles -1- base) propiono) piperazine -1- base) -
3- (- 2- (1- ethyl -3,3- dimethyl indole -2- fork) ethylidene) hexamethylene -1- alkene -1- base) vinyl) -1- ethyl -3,3 two
The synthesis of methyl -3H- indoles iodide, i.e. the synthesis of seven methine cyanines iodide (CyP) of maleimide propionyl piperazine include with
Lower step:
S1: being added single neck bottle for the piperazine of 327.01mg (3.80mM), and suitable acetonitrile dissolution is added, is warming up to 40 DEG C and stirs
It mixes, then weighs the seven methine cyanines iodide of chloro of 240.40mg (0.38mM), be slowly added dropwise after being dissolved with appropriate acetonitrile in piperazine
In piperazine solution, thin layer chromatography monitors reaction process, and reaction solution gradually becomes blue from emerald green, after 2~3h fully reacting, rotation
Turn evaporation of solvent, extracted with methylene chloride/water system, merge organic layer, be spin-dried for methylene chloride, extra moisture uses second
Alcohol azeotropic steams, and obtains 2 crude product 301mg of intermediate, yield 93.11%.Product is 561.1 through Low Resolution Mass Spectra confirmation, with reason
It is consistent by calculated value.Crude product is kept in dark place, and also can be directly used for reacting in next step.
S2: weighing the 3- maleimidopropionic acid of 115.9mg (0.68mM), devotes single neck bottle of 100mL, is added appropriate
Acetonitrile dissolution takes the N of 96.6mg (0.77mM), and N- diisopropylcarbodiimide is added in single neck bottle, and 1h is stirred at room temperature.It takes
The intermediate 2 of 120mg is slowly added into single neck bottle after being dissolved with acetonitrile, is stirred at room temperature 3h, thin layer chromatography monitoring react into
Journey, after completion of the reaction, rotary evaporation remove solvent, use methylene chloride/methanol system to purify as mobile phase silica gel column chromatography, obtain
To the final product CyP of 113mg, yield 78.51%.Verified mass spectrum is 712.1, is consistent with calculated value.Hydrogen nuclear magnetic resonance
Spectrum:1H NMR(400MHz,CDCL3) δ 7.76 (d, J=13.6Hz, 2H), 7.35 (t, J=7.4Hz, 4H), 7.18 (t, J=
7.5Hz, 2H), 7.02 (d, J=7.8Hz, 2H), 6.74 (s, 2H), 5.93 (d, J=13.5Hz, 2H), 4.07 (q, J=
7.1Hz,4H),3.96(t,2H),3.89-3.82(m,4H),3.81-3.75(m,2H),3.63-3.54(m,2H),2.87(t,J
=7.3Hz, 2H), 2.54 (t, J=6.4Hz, 4H), 1.87 (m, J=12.8,6.4Hz, 2H), 1.69 (s, 12H), 1.42 (t, J
=7.2Hz, 6H).
The preparation method of seven methine cyanines thioether sodium salt (BS-CyP) of (2) ten diborane maleimide propionyl piperazine include with
Lower step:
The ten diborane disodium salt (BSH) of sulfydryl of 25.2mg (0.12mM) is accurately weighed in single neck bottle of 10mL, is added
Then plus the n,N-diisopropylethylamine of 42 μ L (0.24mM) water of 2mL dissolves, and, stirs 5 minutes.Weigh CyP 35.4mg
(0.042mM), with being added in above-mentioned ten diborane disodium salting liquid of sulfydryl after the dissolution of 2mL acetonitrile, nitrogen protection is protected from light, often
Temperature stirring, thin-layer chromatography chromatography (TLC) monitor reaction process, reaction are shut down after 3 hours, is spin-dried for solvent, methylene chloride/methanol body
Bitt Chromatographic purification obtains the sterling of 20mg, yield 52.23%.Mass spectroscopy data are 876.6, are consistent with calculated value.
1H NMR (400MHz, DMSO) δ 7.70 (d, J=13.6Hz, 2H), 7.57 (d, J=7.3Hz, 2H), 7.35 (t, J
=7.7Hz, 2H), 7.27 (d, J=7.9Hz, 2H), 7.16 (t, J=7.4Hz, 2H), 5.99 (d, J=13.6Hz, 2H), 4.11
(q, J=12.9,5.9Hz, 4H), 3.81-3.69 (m, 4H), 3.69-3.60 (m, 4H), 3.62-3.53 (m, J=8.1,
3.1Hz, 4H), 3.01 (dd, J=18.5,8.1Hz, 1H), 2.90 (d, J=4.9Hz, 2H), 2.72 (d, 2H), 2.68 (dt, J
=15.7,7.7Hz, 2H), 1.80-1.73 (m, 2H), 1.26 (t, J=7.1Hz, 6H) 0.5-1.2 (m, 11H).
Embodiment 1
The present embodiment provides a kind of folic acid liposomes for being loaded with BS-CyP, with amphiphilic egg yolk lecithin, cholesterol
For two kinds of liposome vectors materials, injection solvent and main ingredient BS-CyP composition.Concrete composition is as follows:
| BS-CyP | 3mg |
| Egg yolk lecithin | 2270.0mg |
| Cholesterol | 85.0mg |
| Chloroform | 10.0mL |
| Methanol | 1.0mL |
| Folic acid arm (F-PEG-SUCA-PE) | 10mg |
| Poloxamer188 | 10.0mg |
| 6.5~6.8 phosphate buffer of PH | 3.0mL |
Preparation step is as follows:
S1.BS-CyP, egg yolk lecithin, cholesterol are completely dissolved in chloroform, in methanol, form solution A；
S2. S1 acquired solution A is set in a round bottom flask, vacuum rotary steam, which removes organic solvent, in Rotary Evaporators makes it
The film of homogeneous transparent is formed in flask walls；
S3. being added in 6.5~6.8 phosphate buffer of 3ml pH in film obtained by S2, ultrasound makes BS-CyP liposome
It is dispersed in phosphate buffer, the Liposomal formulation B of BS-CyP must be carried.
S4. Liposomal formulation B is placed in the cillin bottle of 10ml, addition folic acid arm and poloxamer188, in room temperature slowly
Stirring for 24 hours, must be loaded with the folic acid liposome of BS-CyP.
The product appearance for the folic acid liposome for being loaded with BS-CyP: blue-tinted transparent suspension is obtained, has apparent dindar existing
As.Partial size: average grain diameter 102.6nm, ξ potential as shown in Figure 1: -31.4mv.
2 stability test of embodiment
The long-time stability experimental result such as table carried out for being loaded with the folic acid liposome of BS-CyP made from embodiment 1
Shown in 1:
1 stability experiment result of table
Embodiment 3~7
Preparation method of the present embodiment based on embodiment 1, the ratio of drug and phosphatide, gallbladder are solid in 3~7 pairs of embodiment compositions
The ratio of the ratio of alcohol and phosphatide, outer aqueous phase and organic phase carries out many experiments, and the composition of each embodiment is as shown in table 2:
Table 2
The load BS-CyP folic acid Liposomal formulation being prepared according to prescription in table 2 is the clear and bright suspension of blue, carries BS-
Average Particle Diameters, ξ potential and the 12 months stability experiments of CyP folic acid liposome the results are shown in Table shown in 3:
Table 3
By 3 experimental result of table it is found that the size distribution ratio of the load BS-CyP folic acid liposome using the method for the present invention preparation
It is more uniform, it is the clear and bright suspension of blue, shows effect stability of the invention by 12 months stability test results, can grasp
The property made is stronger, and prescription and technique are controllable, ensure that the reliability of the quality of the pharmaceutical preparations and the safety of clinical application.
Embodiment 8
The present embodiment is based on 1 the method for embodiment and prepares BS-CyP folic acid liposome, is given by mouse tail vein injection
Medicine breast cancer transplantable tumor mouse, Fig. 2 are experimental result.
By Fig. 2 experimental result it is found that passing through petty action using the folic acid liposome for being loaded with BS-CyP prepared by the method for the present invention
Object living imaging is observed to be enriched in the tumour of breast cancer transplantable tumor mouse, realizes the targeting of tumour.
Claims (10)
1. a kind of folic acid liposome for being loaded with ten diborane maleimide propionyl piperazines, seven methine cyanines thioether salt, feature exist
In being made by each component of following mass percent:
0.089%~0.30% ten diborane maleimide propionyl piperazines, seven methine cyanines thioether salt,
5.93%~6.82% phosphatide,
1.78%~2.55% cholesterol,
0.30%~0.60% surfactant,
0.30%~0.60% folic acid arm,
Surplus is injection solvent；
Ten diboranes maleimide propionyl piperazine, the seven methine cyanines thioether salt is structure shown in formula 1:
Wherein, boron described in structure is 10 isotope of boron；X+For pharmaceutically acceptable cation；
The folic acid arm is the mixture for one or more of structures that n is 5~60 in structure such as formula 2,
2. being loaded with the folic acid lipid of ten diborane maleimide propionyl piperazines, seven methine cyanines thioether salt according to claim 1
Body, which is characterized in that the pharmaceutically acceptable cation is selected from alkali metal ion and organic amine ion.
3. being loaded with the folic acid lipid of ten diborane maleimide propionyl piperazines, seven methine cyanines thioether salt according to claim 1
Body, which is characterized in that the phosphatide is egg yolk lecithin, soybean lecithin, hydrogenated yolk lecithin, hydrogenated soya phosphatide, brain phosphorus
Rouge, lipositol, serinephosphatide or Polyene Phosphatidylcholine.
4. being loaded with the folic acid lipid of ten diborane maleimide propionyl piperazines, seven methine cyanines thioether salt according to claim 3
Body, which is characterized in that the Polyene Phosphatidylcholine is the egg yolk lecithin that content is greater than 99%.
5. being loaded with the folic acid lipid of ten diborane maleimide propionyl piperazines, seven methine cyanines thioether salt according to claim 1
Body, which is characterized in that the surfactant is nonionic surfactant, selected from Pluronic F68 and
The saturation or unsaturated fatty acid salt of chain a length of 8~18.
6. being loaded with the folic acid lipid of ten diborane maleimide propionyl piperazines, seven methine cyanines thioether salt according to claim 5
Body, which is characterized in that the surfactant is poloxamer188, enuatrol or PLURONICS F87.
7. being loaded with the folic acid lipid of ten diborane maleimide propionyl piperazines, seven methine cyanines thioether salt according to claim 1
Body, which is characterized in that the injection solvent is the phosphate buffer of water for injection, injection physiological saline or pH6.5~6.8
One of.
8. ten diborane maleimide propionyl piperazines, seven methine cyanines thioether is loaded with described in any one according to claim 1~7
The folic acid liposome of salt is in the application for preparing ejection preparation.
9. being loaded with ten diborane maleimide propionyl piperazines, seven methine cyanines thioether described in a kind of claim 1~7 any one
The preparation method of the folic acid liposome of salt, which comprises the following steps:
S1. ten diborane maleimide propionyl piperazines, seven methine cyanines thioether salt, phosphatide and cholesterol are dissolved in organic solvent
In, form solution A；
S2. S1 acquired solution A is evaporated under reduced pressure and removes remaining organic solvent in S1 acquired solution A and is formed on the wall thin
Film；
S3. film obtained by S2 is added in injection solvent, film is made to be dispersed in formation Liposomal formulation B in injection solvent；
S4. folic acid arm and surfactant is added in the resulting Liposomal formulation B of S3, uniform stirring reaction 12 in room temperature~
For 24 hours, the folic acid liposome of ten diborane maleimide propionyl piperazines, seven methine cyanines thioether salt must be loaded with.
10. being loaded with the folic acid rouge of ten diborane maleimide propionyl piperazines, seven methine cyanines thioether salt according to claim 9
The preparation method of plastid, which is characterized in that organic solvent described in S1 is methanol, ethyl alcohol, ethyl acetate, acetone, acetonitrile or chloroform
One of.
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| CN105647513A (en) * | 2015-12-30 | 2016-06-08 | 中国科学院深圳先进技术研究院 | Dual-mode imaging probe with pH response as well as preparation method and application thereof |
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| 叶酸脂质体对乳腺癌4T1细胞的体内靶向性研究;傅刘鹏等;《山东医药》;20101231;第50卷(第7期);第23-25页 |
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| WO2023196405A1 (en) * | 2022-04-05 | 2023-10-12 | University Of Virginia Patent Foundation | Systems and methods utilizing theranostic agents for bpct and bnct for targeted cancer treatment |
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