CN109666087A - A kind of cyclodextrin derivative and the preparation method and application thereof - Google Patents
A kind of cyclodextrin derivative and the preparation method and application thereof Download PDFInfo
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- CN109666087A CN109666087A CN201910033186.3A CN201910033186A CN109666087A CN 109666087 A CN109666087 A CN 109666087A CN 201910033186 A CN201910033186 A CN 201910033186A CN 109666087 A CN109666087 A CN 109666087A
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Abstract
The present invention relates to pharmaceutical carrier technical fields, more particularly to a kind of derivative and the preparation method and application thereof of cyclodextrin, the derivative is made of biotin, amino acid and cyclodextrin substance, for fields such as drug delivery, medical and health, as pharmaceutical carrier, bioactive ingredients are contained, there is good biocompatibility, the feature of cancer target.
Description
Technical field
The present invention relates to pharmaceutical carrier technical fields, and in particular to a kind of derivative of cyclodextrin and preparation method thereof with answer
With, more particularly to by biotin, amino acid modification cyclodextrin derivative and its in drug delivery, health care
Using.
Background technique
Cyclodextrin be it is a kind of by 6-12 D-Glucose molecule with the cyclic annular type oligosaccharide compound of Isosorbide-5-Nitrae-glucosides key connection,
Its structure is hollow cylindrical shape, and outer surface has hydrophilic characteristic due to there are hydroxyl, and hydrophobic cavity is then to a variety of visitors
Body molecule has Binding ability.The clathration of cyclodextrin and its derivative can not only change the physicochemical property of drug, increase
The dissolubility of drug weakens stimulation of the drug to human body, or even can change the behavior of drug in vivo.Further, since
Have many advantages, such as that cheap and easy to get, biocompatibility is good, cyclodextrin and its derivative have become chemical industry, medicine and other fields research
Hot spot has received widespread attention especially as medicine controlled release carrier.
It is related to 20S-ppD Benexate Hydrochloride as patent No. CN201110100573.8 is disclosed, can be used for
Antitumor, liver protection, lipid-loweringing, hypoglycemic, promotion gastric secretion, raising appetite, improvement digestive function, Immune-enhancing effect, antioxygen are turned into
With, anti-aging medicine and food applications and its preparation process and composition.For another example patent No. CN201410746604.0 is disclosed
A kind of folic acid-cyclodextrin conjugate, folic acid-cyclodextrin-fullerene drug delivery vehicle, Preparation method and use.Specifically, institute
Folic acid-cyclodextrin conjugate is stated, can connect to be formed with 6 hydroxyls of γ cyclodextrin by the γ carboxyl of folic acid.The invention also relates to
And conjugate embedding Fullerene C20 is formed by drug delivery vehicle.In addition, the invention further relates to folic acid-cyclodextrin-richness
Strangle alkene-platinum medicine composition, Preparation method and use.Folic acid-cyclodextrin-fullerene-platinum medicine composition of the invention
There is height targeting to tumour cell, can be used in inhibiting tumor cell proliferation.For another example patent No. CN201810304175.X
Disclose amphipathic cyclodextrin polymers pharmaceutical carrier, it is characterised in that: using cyclodextrin as core, cyclodextrin core is extremely
The position the 6- modification of a few saccharide ring is grafted with hydrophilic segment；The position 2- of at least one saccharide ring and/or 3- are modified with hydrophobicity
Segment.And with the chemistry key connection water-wet side and cyclodextrin to the irritating responsiveness of tumor microenvironment, reach targeted release
Purpose, the invention also disclose the preparation method and application of the carrier.The amphipathic cyclodextrin of this method preparation carries medicine system
System is suitable for partial size, form is uniform, and drugloading rate is big, and stimulating responsive is good, delays the high advantage of controlled release properties.
Contain a large amount of active hydroxyl groups in cyclodextrin molecular, can be reacted with multiple compounds, form stable chemistry
Grafting, this practicability that cyclodextrin is further enhanced convenient for modified feature.Wherein it is covalently repaired using ligand
Decorations then assign the characteristic of its cancer target to realize the identification for forming specificity with tumor cell surface receptor, can be by medicine
Object orientation is transmitted to target area, and increases the ingestion of medicines of tumour cell by receptor-mediated encytosis, to reach
The effect of Synergy and attenuation is safer effective administration mode.
On the other hand, it is reported according to the global tumour of World Health Organization's publication, the existing malignant tumor patient in the whole world is more than
22000000 people newly examine patient up to 10,100,000 people every year, and dying of tumour number is more than 6,200,000.Operation, radiotherapy, chemotherapy are tumours
The basic skills for the treatment of, wherein chemotherapy is current most important treatment means.However developed some chemotherapeutics are deposited at present
Solubility is low, stability is poor, be easy to cause multidrug resistance, lacks tumor-targeting, to health tissues and cell generation part
Or the problems such as whole body toxic side effect, its application in clinic is greatly limited, therefore develop novel, less toxic, efficient drug
Transmission system is particularly important.
Nano medication transmission system, such as liposome, micella, nanoparticle, increasingly draw as multi-medicine tolerant reversal strategy
Play concern.It can make drug passive target in tumor locus by the infiltration enhanced and retention effect, increase drug in tumour cell
Concentration, Drug controlled release, and by ligand modified corresponding to specific receptors on target cell, reach active targeting effect.Often
The targeting ligand seen includes antibody, folic acid, biotin, peptidyl, glycosyl etc..In recent years, also studies have found that, cyclodextrin have suppression
P- P-glycoprotein expression processed, the ability for influencing cell membrane fluidity, to realize multi-medicine tolerant reversal.
Summary of the invention
In order to solve the above technical problems, the present invention provides a kind of derivative and the preparation method and application thereof of cyclodextrin, this
The preparation method simple process of invention, it is easy to accomplish industrialization, obtained cyclodextrine derivatives have good bio-compatible
Property.
It is realized particular by following technical scheme:
Present invention firstly provides a kind of derivatives of cyclodextrin, and the derivative is by biotin, amino acid to cyclodextrin object
Matter is modified to obtain.
Wherein, the cyclodextrin includes but is not limited to alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, hydroxy propyl-Beta-ring paste
Essence；The cyclodextrin molecular amount is 973-1900Da.
Wherein, amino acid includes but is not limited to arginine, lysine, histidine, the arginine of pbf protection.
Preferably, amino acid include but is not limited to fmoc-protected arginine, it is fmoc-protected lysine, fmoc-protected
The arginine of histidine, Fmoc and the bis- protections of pbf.
Cyclodextrin derivative provided by the invention be first by amino acid, biotin be configured to respectively amino acid active ester,
After biotin Acibenzolar, amino acid active ester, biotin Acibenzolar modification cyclodextrin are successively utilized.
Meanwhile the present invention also provides the preparation method of above-mentioned cyclodextrin derivative, specifically comprise the following steps:
(1) it prepares cyclodextrin solution: by cyclodextrin in solvent, obtaining cyclodextrin solution；
(2) it prepares amino acid active ester: Fmoc- amino acid-OH is dissolved in solvent, catalyst is added, after mixing, control
20-60 DEG C of temperature processed, it is stirred to react 0.5-24h, obtains amino acid active ester；
(3) it prepares biotin Acibenzolar: biotin is dissolved in a solvent, after catalyst mixing is added, control temperature 20-
60 DEG C, 4-96h is reacted with stirring, obtains biotin Acibenzolar；
(4) under agitation, activation of amino acid ester solution is added in cyclodextrin solution, controls 20-60 DEG C of temperature,
React 12-96h；After reaction, reaction dissolvent is removed, acetone stirring 12-48h is added, is filtered to remove acetone, obtains white powder
Last shape crude product；Crude product is recrystallized in water, the ring that obtained product is Fmoc- amino acid modification is isolated and purified and pastes
Essence；
(5) by the cyclodextrin of Fmoc- amino acid modification in reaction dissolvent, 20-60 DEG C of temperature is controlled, with stirring
0.5-24h is reacted, to remove Fmoc blocking group；
(6) by the cyclodextrin of amino acid modification in reaction dissolvent, biotin activated ester solution is slowly added dropwise, controls
20-70 DEG C of temperature, the reaction was continued under stirring condition, and 12-48h after removing reaction dissolvent, is added acetone, stirs after reaction
0.5-12h is mixed, light-yellow precipitate is obtained, is filtered to remove acetone, yellow powder is dissolved in methanol, is removed by filtration unreacted
Biotin obtains biotin-amino acid modification cyclodextrin.
In the above method, the step (1) prepares cyclodextrin solution solvent and is selected from water, methylene chloride, hexamethylene, formyl
One or more of amine, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, DMSO, tetrahydrofuran, piperidines.
In the above method, the step (2) prepares amino acid active ester solvent and is selected from water, formamide, N, N- dimethyl
One or more of formamide (DMF), DMAC N,N' dimethyl acetamide, DMSO, tetrahydrofuran, piperidines, methylene chloride.
In the above method, the step (3) prepares biotin Acibenzolar solvent and is selected from water, formamide, N, N- dimethyl
One or more of formamide (DMF), DMAC N,N' dimethyl acetamide, DMSO, tetrahydrofuran, piperidines, methylene chloride.
In the above method, the step (5) is selected from chloroform, water, formamide, N, N- dimethylformamide, dichloro with solvent
One or more of methane, DMAC N,N' dimethyl acetamide, DMSO, tetrahydrofuran, piperidines.
In the above method, the step (6) is selected from chloroform, water, formamide, N, N- dimethylformamide, dichloro with solvent
One or more of methane, DMAC N,N' dimethyl acetamide, DMSO, tetrahydrofuran, piperidines.
In the above method, catalyst described in step (2) includes but is not limited to EDC, NHS, DMAP, DCC.
In the above method, the mole dosage ratio of cyclodextrin and amino acid is 1:100-100:1；Biotin is repaired with amino acid
The mole dosage ratio of the cyclodextrin of decorations is 1:100-100:1.
The dosage molar ratio of the above method, amino acid and catalyst is 1:10-10:1；The dosage and EDC, NHS of biotin
The molar ratio of total dosage is 1:10-10:1；The molar ratio of EDC and NHS dosage is 1:0.2-1:10.
Cyclodextrin derivative of the present invention is for fields such as drug delivery, medical and health；As pharmaceutical carrier, biology is contained
Active constituent, the drug release characteristic with good biocompatibility, cancer target.
The active constituent includes drug or nutriment.
The active constituent includes anti-tumor drug.
The utility model has the advantages that
Cyclodextrin be it is a kind of by 6-12 D-Glucose molecule with the cyclic annular type oligosaccharide compound of Isosorbide-5-Nitrae-glucosides key connection,
Have many advantages, such as that cheap and easy to get, biocompatibility is good.Cyclodextrin and its derivative are passed as excellent pharmaceutical carrier in drug
It passs, had a wide range of applications in medicine and hygiene fields.
The present invention modifies it with amino acid and biotin, it is excellent to assign its using cyclodextrin substance as parent
Physicochemical properties and good biocompatibility, cancer target etc. release the drug feature, are used as being used for for pharmaceutical carrier
Drug can be achieved in the orientation of tumor locus, efficiently release in the transmitting of anti-tumor drug, achievees the effect that Synergy and attenuation.Ring paste
Smart derivative has broad application prospects.In addition, present invention drug delivery systems relevant to P- glycoprotein other for improvement, such as
Oral small intestine drug absorption, gene drug delivery, central nervous system administration etc., which have, inspires meaning.
Detailed description of the invention
Fig. 1: hydroxypropyl-β-cyclodextrin cyclodextrin (A), the hydroxypropyl-β-cyclodextrin (B) of arginine (pbf) modification, biology
The nuclear magnetic spectrum of the hydroxypropyl-β-cyclodextrin (C) of element-arginine (pbf) modification
Fig. 2: hydroxy propyl-Beta-ring paste of hydroxypropyl-β-cyclodextrin cyclodextrin (A), Fmoc and the bis- protection arginine modifications of pbf
The hydroxy propyl-Beta-that smart (B), hydroxy propyl-Beta-cyclodextrin (C) of arginine (pbf) modification, biotin-arginine (pbf) are modified
The infared spectrum of cyclodextrin (D)
Specific embodiment
Specific embodiments of the present invention will be described in further detail below, but the invention is not limited to these realities
Mode is applied, it is claimed to still fall within the claims in the present invention for any improvement or replacement on the present embodiment essence spirit
Range.
Embodiment 1
(1) preparation of arginine active ester:
220mgEDC, 8mgDMAP, 300mgFmoc-Arg (pbf)-OH is weighed respectively, is mixed in three-necked bottle, in room temperature
Under the conditions of be protected from light stir-activating 2-4h, obtain the arginine active ester solution of Fmoc Yu the bis- protections of pbf；
(2) preparation of biotin activity ester:
30mg biotin is taken, 50mgEDC and 60mgNHS are dissolved in 5mlDMF simultaneously, are protected from light stir-activating at room temperature
12-14h obtains biotin activity ester solution；
(3) preparation of the hydroxypropyl-β-cyclodextrin of the bis- protection arginine modifications of Fmoc and pbf:
150mg hydroxypropyl-β-cyclodextrin is taken, is dissolved in 10mlDMF, hydroxypropyl-β-cyclodextrin solution is obtained, is added
The arginine active ester solution of Fmoc and the bis- protections of pbf, are protected from light are stirred to react 48h at room temperature, after reaction, remove dereaction
Solvent adds acetone stirring 12-48h, is filtered to remove acetone, obtains white powder crude product；Crude product is tied again in water
Crystalline substance isolates and purifies the hydroxypropyl-β-cyclodextrin that obtained product is the bis- protection arginine modifications of Fmoc and pbf；
(4) removal of Fmoc blocking group:
The hydroxypropyl-β-cyclodextrin of the arginine modification of the bis- protections of Fmoc and pbf is dissolved in the piperidine solution of 10 ml,
It is stirred to react 2h, at room temperature to remove Fmoc blocking group.After reaction, reaction dissolvent is removed, the smart ammonia of pbf protection is obtained
Hydroxy propyl-Beta-cyclodextrin of acid modification；
(5) preparation of the hydroxypropyl-β-cyclodextrin of biotin-arginine (pbf) modification:
Arg (pbf)-hydroxypropyl-β-cyclodextrin is dissolved in DMF, biotin activity ester solution is slowly added dropwise, in 50 DEG C
Under, it is stirred to react 24-32h；After reaction, reaction dissolvent is removed, later, acetone is added, stirs 2h, it is light yellow heavy to obtain
It forms sediment, is filtered to remove acetone, yellow powder is dissolved in methanol, be removed by filtration unreacted biotin, obtain biotin-essence
The hydroxypropyl-β-cyclodextrin of propylhomoserin (pbf) modification；
(6) hydroxypropyl-β-cyclodextrin of biotin-arginine (pbf) modification contains the system of taxol (PTX) nanoparticle
It is standby:
It takes 1.5mgPTX to be dissolved in 0.5ml acetone, PTX solution is made；Biotin-arginine (pbf) is separately taken to modify
Hydroxypropyl-β-cyclodextrin 10mg is dissolved in 10ml distilled water, and under stirring condition, PTX solution is added dropwise, continues to stir
12h makes PTX well into the hydrophobic cavity to cyclodextrin.Later, at 35 DEG C, rotary evaporation removes acetone, is carried
The nanoparticle aqueous solution of medicine taxol, and with 0.45 μm of filtering with microporous membrane, to remove free drug and vector aggregation body.Through surveying
Fixed, the partial size of drug-carrying nanometer particle is 121.9nm, encapsulation rate 83.9%, drugloading rate 11.2%.
Embodiment 2
(1) it prepares cyclodextrin solution: by cyclodextrin in solvent, obtaining cyclodextrin solution；
(2) it prepares amino acid active ester: Fmoc- arginine (pbf)-OH is dissolved in solvent, catalyst, mixing is added
Afterwards, temperature 60 C is controlled, is stirred to react for 24 hours, obtains arginine Acibenzolar；
(3) it prepares biotin Acibenzolar: biotin is dissolved in a solvent, after catalyst mixing is added, control temperature 60
DEG C, 96h is reacted with stirring, obtains biotin Acibenzolar；
(4) under agitation, arginine activated ester solution is added in cyclodextrin solution, controls temperature 60 C, instead
Answer 96h；With after reaction, reaction dissolvent is removed, acetone stirring 48h is added, is filtered to remove acetone, it is thick to obtain white powder
Product；Crude product is recrystallized in water, obtains the cyclodextrin of Fmoc- arginine (pbf) modification；
(5) cyclodextrin of Fmoc- arginine (pbf) modification is controlled into temperature 60 C, in stirring in reaction dissolvent
It is lower to react for 24 hours, to remove Fmoc blocking group；
(6) it is molten that biotin Acibenzolar is slowly added dropwise in reaction dissolvent in the cyclodextrin of arginine (pbf) modification
Liquid, controls temperature 70 C, after the reaction was continued under stirring condition 48h, after removing reaction dissolvent, acetone is added, stirs 12h, obtains
To light-yellow precipitate, it is filtered to remove acetone, yellow powder is dissolved in methanol, is removed by filtration unreacted biotin, it will be molten
Agent, which is evaporated, to be isolated and purified, and the cyclodextrin of biotin-arginine (pbf) modification is obtained；
In the above method, the step (1) prepares cyclodextrin solution solvent and is selected from water；
In the above method, the step (2) prepares amino acid active ester solvent and is selected from DMF；
In the above method, the step (3) prepares biotin Acibenzolar solvent and is selected from formamide, N, N- dimethylacetamide
Amine, DMSO；
In the above method, the step (5) is selected from piperidines with solvent；
In the above method, the step (6) is selected from DMF with solvent；
In the above method, catalyst described in step (2) is DCC；
In the above method, catalyst described in step (3) is EDC and NHS；
In the above method, cyclodextrin and arginic mole dosage ratio are 1:10；Biotin and the ring of arginine modification are pasted
The mole dosage ratio of essence is 1:10；
The dosage molar ratio of the above method, arginine and catalyst is 1:10；The dosage and the total dosage of EDC, NHS of biotin
Molar ratio be 1:10；The dosage molar ratio of EDC and NHS is 1:1；
Cyclodextrin derivative of the present invention is for fields such as drug delivery, medical and health；As pharmaceutical carrier, biology is contained
Active constituent, the drug release characteristic with cancer target, high transmittance film；
The active constituent includes drug or nutriment；
The active constituent includes anti-tumor drug.
Embodiment 3
(1) it prepares cyclodextrin solution: by cyclodextrin in solvent, obtaining cyclodextrin solution；
(2) it prepares amino acid active ester: Fmoc- lysine-OH is dissolved in solvent, catalyst is added, after mixing, control
40 DEG C of temperature processed, it is stirred to react 18h, obtains amino acid active ester；
(3) it prepares biotin Acibenzolar: biotin is dissolved in a solvent, after catalyst mixing is added, control temperature 40
DEG C, 58h is reacted with stirring, obtains biotin Acibenzolar；
(4) under agitation, lysine activated ester solution is added in cyclodextrin solution, controls 40 DEG C of temperature, instead
Answer 48h；After reaction, mixed liquor rotary evaporation is removed into reaction dissolvent, adds acetone stirring 36h, is filtered to remove acetone,
Obtain white powder crude product；Crude product is recrystallized in water, to remove cyclodextrin, obtains the ring of Fmoc- polylysine modification
Dextrin；
(5) by the cyclodextrin of Fmoc- polylysine modification in reaction dissolvent, 40 DEG C of temperature are controlled, with stirring instead
18h is answered, to remove Fmoc blocking group；
(6) by the cyclodextrin of polylysine modification in reaction dissolvent, biotin activated ester solution is slowly added dropwise, controls
60-70 DEG C of temperature, the reaction was continued under stirring condition, and it is molten to be removed dereaction after reaction by 12-48h for mixed liquor rotary evaporation
After agent, 300ml acetone is added, stirs 6h, obtains light-yellow precipitate, be filtered to remove acetone, yellow powder is dissolved in methanol,
It is removed by filtration unreacted biotin, solvent is evaporated and is isolated and purified, obtains biotin-polylysine modification cyclodextrin；
In the above method, the step (1) prepares cyclodextrin solution solvent and is selected from tetrahydrofuran；
In the above method, the step (2) prepares amino acid active ester solvent and is selected from DMF；
In the above method, the step (3) prepares biotin Acibenzolar solvent and is selected from DMSO；
In the above method, the step (5) is selected from piperidines with solvent；
In the above method, the step (6) is selected from DMSO with solvent；
In the above method, catalyst described in step (2) is EDC and NHS；
In the above method, catalyst described in step (3) is DCC；
In the above method, the mole dosage ratio of cyclodextrin and lysine is 100:1；The ring of biotin and polylysine modification paste
The mole dosage ratio of essence is 1:10；
The dosage molar ratio of the above method, biotin and catalyst is 10:1；The dosage and the total dosage of EDC, NHS of lysine
Molar ratio be 1:10；The dosage molar ratio of EDC and NHS is 1:2；
Cyclodextrin derivative of the present invention is for fields such as drug delivery, medical and health；As pharmaceutical carrier, biology is contained
Active constituent has good biocompatibility, cancer target feature；
The active constituent includes drug or nutriment.
The active constituent includes anti-tumor drug.
Test 1
Safety testing
It is whether safe for being injected intravenously administration for measurement drug-carrying nanometer particle, biotin-arginine (pbf) is repaired respectively
The hydroxypropyl-β-cyclodextrin of decorations is the hydroxyl of the drug-carrying nanometer particle (taxol is model drug) of material preparation, arginine (pbf) modification
Propyl-beta-cyclodextrin is the drug-carrying nanometer particle (taxol is model drug) of material preparation, biotin-polylysine modification hydroxypropyl
Base-β-cyclodextrin is hydroxy propyl-Beta-ring paste of the drug-carrying nanometer particle (taxol is model drug) of material preparation, biotin modification
Essence is hydroxy propyl-Beta-ring paste of the drug-carrying nanometer particle (taxol is model drug) of material preparation, folic acid-arginine (pbf) modification
Essence is hydroxy propyl-Beta-ring paste of the drug-carrying nanometer particle (taxol is model drug) of material preparation, folic acid-lysine (pbf) modification
Essence is the drug-carrying nanometer particle (taxol is model drug) of material preparation, and using unmodified hydroxypropyl-β-cyclodextrin as material
The drug-carrying nanometer particle (taxol is model drug) of preparation carries out hemolysis in vitro experiment.New zealand white rabbit auricular vein blood is taken,
Fibrinogen is removed, brine, centrifugation is added, the suspension of 2% (v/v) is made.2.5ml red blood cell is taken to be suspended
Liquid and 2.5ml drug-carrying nanometer particle are uniformly mixed.After mixed liquor is incubated for 4h at 37 DEG C, under the revolving speed of 3000r/min
It is centrifuged 10min, collects supernatant, the absorbance of each sample is measured under 540nm.Physiological saline and distilled water separately are taken, is grasped with method
Make, respectively as negative and positive control, calculates Percent hemolysis.Percent hemolysis=(sample absorbance-negative control extinction
Degree)/(positive control absorbance-negative control absorbance) × 100%.
The results show that when paclitaxel concentration is in the range of 0-200 μ g/ml, the hydroxyl of biotin-arginine (pbf) modification
Propyl-beta-cyclodextrin is the hydroxypropyl-of the drug-carrying nanometer particle (taxol is model drug) of material preparation, arginine (pbf) modification
Beta-cyclodextrin is the drug-carrying nanometer particle (taxol is model drug) of material preparation, biotin-polylysine modification hydroxy propyl-Beta-ring
Dextrin be material preparation drug-carrying nanometer particle (taxol is model drug), biotin modification hydroxypropyl-β-cyclodextrin be material
The drug-carrying nanometer particle (taxol is model drug) of preparation, the hydroxypropyl-β-cyclodextrin of folic acid-arginine (pbf) modification are material
The drug-carrying nanometer particle (taxol is model drug) of preparation, the hydroxypropyl-β-cyclodextrin of folic acid-lysine (pbf) modification are material
The drug-carrying nanometer particle (taxol is model drug) of preparation, and the load prepared using unmodified hydroxypropyl group-beta-cyclodextrin as material
The haemolysis score of medicine nanoparticle (taxol is model drug) is respectively 4.8%, 5.0%, 4.8%, 5.5%, 5.3%, 5.2% with
And 4.9%, have no significant difference between previous materials, and all material haemocylolysis be it is negligible, illustrate arginine
And still have after biotin modification hydroxypropyl-β-cyclodextrin, lysine and biotin modification hydroxypropyl group-beta-cyclodextrin
Good haemolysis safety.
Test 2
Antineoplastic target effect test compares
U14 bearing mouse model is constructed, tumor-bearing mice is randomly divided into 8 groups, every group 6, every group of animal is carried out respectively
Marker number simultaneously starts to be administered, and gives physiological saline respectively, the hydroxypropyl-β-cyclodextrin of biotin-arginine (pbf) modification is
The drug-carrying nanometer particle (taxol is model drug, dosage 15mg/kg) of material preparation, the hydroxypropyl-β-of arginine (pbf) modification
Cyclodextrin is the drug-carrying nanometer particle (taxol is model drug, 15 mg/kg of dosage) of material preparation, biotin-polylysine modification
Hydroxypropyl-β-cyclodextrin is the drug-carrying nanometer particle (taxol is model drug, dosage 15mg/kg) of material preparation, biotin modification
Hydroxypropyl group-beta-cyclodextrin be material preparation drug-carrying nanometer particle (taxol is model drug, 15 mg/kg of dosage), folic acid-essence
Propylhomoserin (pbf) modification hydroxypropyl-β-cyclodextrin be material prepare drug-carrying nanometer particle (taxol is model drug, dosage 15mg/
Kg), folic acid-lysine (pbf) modification hydroxypropyl-β-cyclodextrin be material prepare drug-carrying nanometer particle (taxol is model
Medicine, dosage 15mg/kg), and (taxol is for the drug-carrying nanometer particle that is prepared using unmodified hydroxypropyl-β-cyclodextrin as material
Model drug, dosage 15mg/kg), which is denoted as administration the 1st day.Each every 3 days tail vein injections of preparation are administered once, and continuously give
Medicine 4 times.Through 4 dosage periods, animal is put to death, removes tumor mass, weighing calculates tumour inhibiting rate；Tumour inhibiting rate=(physiological saline group is flat
Equal knurl weight-treatment group's average knurl weight)/physiological saline group average knurl weight × 100%；
The results show that the hydroxypropyl-β-cyclodextrin of biotin-arginine (pbf) modification is the load taxol of material preparation
Nanoparticle group tumour inhibiting rate is 72.6%, and the hydroxypropyl-β-cyclodextrin of arginine (pbf) modification is that the load taxol of material preparation is received
Grain of rice group tumour inhibiting rate is 66.8%, and biotin-polylysine modification hydroxypropyl-β-cyclodextrin is the drug-carrying nanometer particle of material preparation
Group tumour inhibiting rate is 74.6%, and the hydroxypropyl-β-cyclodextrin of biotin modification is that the drug-carrying nanometer particle group tumour inhibiting rate of material preparation is
63.5%, the hydroxypropyl-β-cyclodextrin of folic acid-arginine (pbf) modification is that the drug-carrying nanometer particle group tumour inhibiting rate of material preparation is
67.9%, the hydroxypropyl-β-cyclodextrin of folic acid-lysine (pbf) modification is that the drug-carrying nanometer particle group tumour inhibiting rate of material preparation is
70.8%, unmodified hydroxypropyl-β-cyclodextrin is that the tumour inhibiting rate of the load effect of nano-paclitaxel group of material preparation is 53.2%, is said
It is to carry that bright hydroxypropyl-β-cyclodextrin, which has through arginine or polylysine modification rear bearing taxol than simple hydroxypropyl-β-cyclodextrin,
Body carries taxol has an obvious preferably antitumous effect in Mice Body, and biotin-amino acid modification hydroxy propyl-Beta-ring
Dextrin is that carrier carries after taxol that have in Mice Body than the corresponding hydroxypropyl-β-cyclodextrin of amino acid modification merely be load
Body load taxol has the effect of obvious more excellent antitumor.The material of biotin modification be carrier carry taxol after than corresponding leaf
The material of acid modification is that the antitumous effect of carrier load taxol becomes apparent from.
Meanwhile this test is also respectively to lewis lung cancer in mice, SCID kidney mouse, H22 liver cancer mouse, lymthoma lotus knurl
Mouse is modeled, and according to the administration of above-mentioned test method part and comparative test, as the result is shown: cyclodextrin of the invention is derivative
Object has inhibitory effect to lung cancer, kidney, liver cancer, lymph cancer etc. as after carrier carried anticancer medicine, and tumour inhibiting rate is about 70-
77%.
Chemotherapeutics may also can kill organism normal cell, institute since selectivity is low while killing tumor cell
With developing, there is tumor-targeting drug to be increasingly valued by people.By with active targeting effect ligand or antibody with
It is that active target preparation designs common means that anti-tumor drug or its carrier, which combine,.As one kind of vitamin, biotin
There is special status, it is the essential nutrient for maintaining human body natural's growth, development and function of human body health.Many research tables
Bright, biotin has booster action, such as carboxylase to many enzymes of human body, it plays the work for carrying CO2 in carboxylation enzyme reaction
With.In addition, biotin also participates in synthesis and decomposition, amino acid and metabolism of carbohydrate of body fat acid etc..Most importantly
The Multivitamin body that biotin can be relied on Na+ is specifically bound, and the biotin acceptor content of tumor cell surface is obvious
Higher than other normal tissues, therefore, using this characteristic of biotin, biotin is connected to anti-tumor drug or other carriers
On, the tumor-targeting of drug can be improved.
In our study, the biotin targeting vector for proposing a kind of amino-acid modified cyclodextrin material preparation is answered
Treatment for cancer.Wherein used raw material monomer is amino acid or fmoc-protected amino acid and Fmoc (pbf)
The amino acid of double protections, amino acid are one of the important substance for constituting living organism, and the base for constructing cell, building tissue
Material, biocompatibility are very good.For example, the one kind of arginine as amino acid, containing hydrophilic guanidine radicals and carboxylic group,
Urea, ornithine, proline, polyamines, NO, guanidine can be generated through arginase, NOS, amion acetic acid transaminase, arginine decarboxylase
Butylamine, glutamic acid and glutamate isoreactivity molecule, confrontation neoplastic process play important adjustment effect.Therefore, pass through drug
Carrier is effectively contained to taxol, can be reduced the toxic side effect of taxol, be improved curative effect of medication, to preferably be applied to swollen
In the treatment of tumor.
Claims (10)
1. a kind of cyclodextrin derivative, which is characterized in that the derivative is by biotin, amino acid and cyclodextrin substance structure
At.
2. cyclodextrin derivative according to claim 1, which is characterized in that the cyclodextrin includes but is not limited to α-ring
Dextrin, beta-cyclodextrin, gamma-cyclodextrin, hydroxypropyl-β-cyclodextrin.
3. cyclodextrin derivative according to any one of claim 1 or 2, which is characterized in that the cyclodextrin point
Son amount is 973-1900Da.
4. cyclodextrin derivative according to claim 1, which is characterized in that the amino acid includes but is not limited to smart ammonia
Acid, lysine, histidine, the arginine of pbf protection.
5. the preparation method of cyclodextrin derivative according to claim 1, which comprises the following steps:
(1) it prepares cyclodextrin solution: by cyclodextrin in solvent, obtaining cyclodextrin solution；
(2) it prepares amino acid active ester: Fmoc- amino acid-OH is dissolved in solvent, catalyst is added, after mixing, control temperature
20-60 DEG C of degree, is stirred to react 0.5-24h, obtains amino acid active ester；
(3) it prepares biotin Acibenzolar: biotin is dissolved in a solvent, after catalyst mixing is added, control temperature 20-60
DEG C, 4-96h is reacted with stirring, obtains biotin Acibenzolar；
(4) under agitation, activation of amino acid ester solution is added in cyclodextrin solution, controls 20-60 DEG C of temperature, reaction
12-96h；After reaction, reaction dissolvent is removed, acetone stirring 12-48h is added, is filtered to remove acetone, obtains white powder
Crude product；Crude product is recrystallized in water, isolates and purifies to obtain the cyclodextrin of Fmoc- amino acid modification；
(5) by the cyclodextrin of Fmoc- amino acid modification in reaction dissolvent, 20-60 DEG C of temperature is controlled, is reacted with stirring
0.5-24h, to remove Fmoc blocking group；
(6) by the cyclodextrin of amino acid modification in reaction dissolvent, biotin activated ester solution is added dropwise, controls temperature 20-
70 DEG C, the reaction was continued under stirring condition, and 12-48h after removing reaction dissolvent, is added acetone, stirs 0.5- after reaction
12h obtains light-yellow precipitate, is filtered to remove acetone, and yellow powder is dissolved in methanol, is removed by filtration unreacted biology
Element obtains biotin-amino acid modification cyclodextrin.
6. the preparation method of cyclodextrin derivative according to claim 5 is urged used in amino acid active ester wherein preparing
Agent includes but is not limited to EDC, NHS, DMAP, DCC.
7. the mole dosage of the preparation method of cyclodextrin derivative according to claim 5, cyclodextrin and amino acid
Than for 1:100-100:1；The mole dosage of biotin and the cyclodextrin of amino acid modification ratio is 1:100-100:1.
8. the preparation method of cyclodextrin derivative according to claim 5, the wherein dosage mole of amino acid and catalyst
Than for 1:10-10:1；The dosage of biotin and the molar ratio of the total dosage of catalyst are 1:10-10:1.
9. the cyclodextrin derivative according to claim 1 is for fields such as drug delivery, medical and health.
10. being used as pharmaceutical carrier according to the cyclodextrin derivative in claim 9, bioactive ingredients are contained, there is tumour
It targets, the drug release characteristic of high transmittance film.
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