CN108102004A - A kind of dextran polymer, polymer micelle and medicament carrier system - Google Patents
A kind of dextran polymer, polymer micelle and medicament carrier system Download PDFInfo
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- CN108102004A CN108102004A CN201810003817.2A CN201810003817A CN108102004A CN 108102004 A CN108102004 A CN 108102004A CN 201810003817 A CN201810003817 A CN 201810003817A CN 108102004 A CN108102004 A CN 108102004A
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- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
- C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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Abstract
The present invention relates to a kind of dextran polymer, polymer micelle and medicament carrier systems.Dextran polymer of the present invention is by glucan, 4 methylol phenyl boric acid pinacol esters and polyhydric aliphatic acid reaction are prepared, wherein, glucan and polyhydric aliphatic acid provide hydrophilic and hydrophobic units, the polymer is enabled to spontaneously form micella, and glucan, the polymer that 4 methylol phenyl boric acid pinacol esters and polyhydric aliphatic acid are formed after chemical reaction is sensitive to hydrogen peroxide, disease (such as treating myocardial ischemia damage can be expressed in ROS high, atherosclerosis, intestinal inflammatory and tumour etc.) in the environment of response is quickly generated to hydrogen peroxide, micella is triggered to disintegrate, so as to rapidly discharge drug molecule.
Description
Technical field
The present invention relates to pharmaceutical carrier field, in particular to a kind of dextran polymer, polymer micelle and drug
Carrier system.
Background technology
A research report that World Health Organization's International Cancer Research Center is announced recently is said, according to the hair of current cancer
Sick trend, the year two thousand twenty whole world cancer morbidity will increase by 50% than now, and newly-increased cancer patient's number is up to every year in the whole world
15000000 people.Just like, cancer has become one of common morbidity today and cause of death, but lacks and safely and effectively treat hand
Section.
At present, the main method for the treatment of cancer has operation, chemotherapy, radiotherapy, targeted therapy, immunotherapy etc..Being of chemotherapy
The abbreviation of drug therapy is learned, killing cancer cell by using chemotherapeutic agent reaches therapeutic purposes.But the choosing of chemotherapy
Selecting property is low, and side effect is big, but also can generate drug resistance, causes chemotherapy invalid.
In order to improve drug effect, high molecular material is often used in the carrier as drug conveying.It develops rapidly in the recent period
It is the macromolecule carrier of micron and nanoscale, such as：Micella, vesica and nano particle etc., this kind of macromolecule carrier can be effectively
Drug molecule is distributed to wherein, using the various response modes of carrier, realizes the conveying of drug and control release.
Using polymeric micelle as pharmaceutical carrier be 1984 by Bader, H.etal.,
Angew.Makromol.Chem.123/124 (1984) 457-485 proposes that polymeric micelle increasingly becomes scientific circles first
Research hotspot, and as potential weak water soluble drug carrier.Microvascular endothelial gap densification in normal structure, structure
Completely, macromolecular and lipid granule are not easy through vascular wall, and solid tumor mass medium vessels enriches, and vascular wall gap is wider, knot
Structure integrality is poor, lymphatic return missing, and macromolecular and lipid granule is caused to have high selectivity permeability and anelasticity, this existing
High-permeability and retention effect as being referred to as solid tumor mass, referred to as " infiltration enhancing reserve effects " (Permeability
And retention effect, EPR).Polymeric micellar is usually made of macromolecular substances, and grain size is nanoscale in addition, because
This can effectively assemble and be stranded in tumor tissues, realize the passive target of tumor tissues.
But existing polymeric micelle, there are the defects of targeting is poor, stability is insufficient, is limited when preparing tumour medicine carrier
Application of the polymeric micelle in tumour medicine is made.
In view of this, it is special to propose the present invention.
The content of the invention
The first object of the present invention is to provide a kind of dextran polymer, the micella tool of the dextran polymer formation
Have with hydrogen peroxide response it is good, can be in ROS high expression disease (such as treating myocardial ischemia damage, atherosclerosis, enteron aisle
Inflammation and tumour etc.) in the environment of rapid disruption and release drug and the advantages that high storage-stable.
The second object of the present invention is to provide a kind of polymer micelle, and micella has that hydrogen peroxide response is good, energy
It is enough quickly to be broken in the environment of ROS high expression diseases (such as treating myocardial ischemia damage, atherosclerosis, intestinal inflammatory and tumour)
The advantages that splitting and discharge drug and high storage-stable.
The third object of the present invention is to provide a kind of medicament carrier system, and the medicament carrier system has hydrogen peroxide
Response is good, can express disease (such as treating myocardial ischemia damage, atherosclerosis, intestinal inflammatory and tumour) in ROS high
In the environment of rapid disruption and release drug and the advantages that high storage-stable.
In order to realize the above-mentioned purpose of the present invention, spy uses following technical scheme：
A kind of dextran polymer, the general formula of the dextran polymer are as follows：AmBn；
Wherein, the structural formula of the A is as follows：
The structural formula of the B is as follows：
The m represents the molar fractions of A in the polymer, 0≤m ＜ 1；The n represent B in the polymer mole point
Number, wherein, 0 ＜ n≤1；1 expression-the C2H4The number of-group, described 1 is selected from 5,6 or 7.
Dextran polymer of the present invention is by glucan, 4- methylol phenyl boric acid pinacol esters and polyhydric aliphatic acid reaction
It is prepared, wherein, glucan and polyacid provide hydrophilic and hydrophobic units so that the polymer can spontaneously form glue
Beam, and the polymer that glucan, 4- methylol phenyl boric acid pinacol esters and polyhydric aliphatic acid are formed after chemical reaction is to peroxide
Change hydrogen sensitive, it can be ROS high expresses disease (such as treating myocardial ischemia damage, atherosclerosis, intestinal inflammatory and tumour etc.)
Response is quickly generated under environment to hydrogen peroxide, micella is triggered to disintegrate, so as to rapidly discharge drug molecule.
In some specific embodiments, 0≤m ＜ 0.7, and 0.3 ＜ n≤1.
In some specific embodiments, 0≤m ＜ 0.5, and 0.5 ＜ n≤1.
In some specific embodiments, 0≤m ＜ 0.3, and 0.7 ＜ n ＜ 1.
In some specific embodiments, m=0, and n=1.
The present invention also further limits m and n, i.e. the grafting rate of glucan is optimized, in above-mentioned polymer
In, compared with m, the accounting of n gradually increases, and the grafting rate of glucan increases, and the accounting of 4- hydroxyl borate esters rises so that institute
It is more sensitive to the response of hydrogen peroxide to state polymer.
The invention further relates to a kind of polymer micelle, the polymer micelle is prepared by foregoing dextran polymer.
Micella of the present invention is prepared using foregoing dextran polymer, has that hydrogen peroxide response is good, energy
It is enough quickly to be broken in the environment of ROS high expression diseases (such as treating myocardial ischemia damage, atherosclerosis, intestinal inflammatory and tumour)
The advantages that splitting and discharge drug and high storage-stable.
In some specific embodiments, the polymer micelle is prepared by the following method：Before water dissolution
Dextran polymer is stated, is dialysed in water 36~60h with the bag filter of 3000~4000KD, obtains dialyzate, is polymer
Micella.
In some specific embodiments, the method further include by dialyzate freeze for powder the step of, the powder
End is polymer micelle.
In some specific embodiments, the bag filter be 3500KD bag filters, dialysis time 48h, freeze when
Between for for 24 hours.
In some specific embodiments, the polymer micelle is prepared by the following method：By aforementioned polymeric
Object is dissolved in DMSO solution, is added dropwise under stirring in PBS buffer solution, continues stirring until that form transparent opalescence molten
Liquid is to get polymer micelle.
In some specific embodiments, the pH value of the PBS buffer solution is 7.2~7.6.
In some specific embodiments, amount ratio between the polymer, DMSO and PBS buffer solution for 50~
150mg: 7~12mL: 50~150mL.
In some specific embodiments, the amount ratio between the polymer, DMSO and PBS buffer solution is 100mg:
10mL∶100mL。
The method of the invention is also defined the specific preparation process of micella, the glue being prepared according to above-mentioned technique
Beam particle size is about 90nm, small, good to the responsiveness of hydrogen peroxide, while has preferable stability, is being stored
Do not allow in journey degradable.
The invention further relates to a kind of medicament carrier system, the pharmaceutical carrier is included by the glucan of claim 1 or 2
The polymer micelle and be wrapped in inside the polymer micelle or be covalently bond to the glucan polymerization that polymer is formed
Drug molecule on object.
Medicament carrier system of the present invention is prepared using foregoing dextran polymer, has hydrogen peroxide response
Well, the environment of disease (such as treating myocardial ischemia damage, atherosclerosis, intestinal inflammatory and tumour) can be expressed in ROS high
The advantages that lower rapid disruption and release drug and high storage-stable.
In some specific embodiments, the drug molecule by blank micella carry medicine method, dialysis, emulsion process,
Solvent evaporation method or desivac are wrapped in inside the polymer micelle.
In some specific embodiments, the medicament carrier system is prepared by the following method：It will be foregoing poly-
It closes object and drug molecule is dissolved in DMSO solution, be added dropwise under stirring in PBS buffer solution, continue stirring until to be formed
Bright opalescence solution, by the opalescence solution by dialysis to get the medicament carrier system.
In some specific embodiments, the pH value of the PBS buffer solution is 7.2~7.6.
In some specific embodiments, the dosage between the polymer, drug molecule, DMSO and PBS buffer solution
Than for 50~150mg: 5~10mg: 7~12mL: 50~150mL.
In some specific embodiments, the dosage between the polymer, drug molecule, DMSO and PBS buffer solution
Than for 91.5mg: 8.5mg: 10mL: 100mL.
In some specific embodiments, the drug molecule is selected from antitumor drug, cardiovascular drugs and anti-inflammatory agent
Object, it is preferable that the antitumor drug, cardiovascular drugs and anti-inflammatory drug are selected from adriamycin, mustargen, n-formyl sarcolysine, glyciphosphoramide, card
Mo Siting, lomustine, Semustine, Chlorambucil, hemel, dopan, methotrexate (MTX), fluorouracil, Tegafur, Ah
Sugared cytidine, gemcitabine, capecitabine, hydroxycarbamide, actinomycin D, mitomycin, vinorelbine, Teniposide, hydroxyl camplotheca acuminata
Alkali, taxol, docetaxel, tamoxifen, aminoglutethimide, Letrozole, Medroxyprogesterone, megestrol acetate, cis-platinum, carboplatin, sand difficult to understand
Sharp platinum, aspirin, cangrelor, clopidogrel hydrogenesulphate, Pa Sugeer, Fragmin, nifedipine, Nimodipine, dimension
La Pa meter, digoxin, Losartan Potassium, Irbesartan, methoxy benzenpropanoic acid, flurbiprofen, hydrocortisone, dexamethasone, sprinkle
One or more in Buddhist nun pine, Diclofenac or brufen.
The method of the invention is also defined the specific preparation process of medicament carrier system, is prepared according to above-mentioned technique
The particle size of the medicament carrier system formed is about 90nm, small, good to the responsiveness of hydrogen peroxide, while is had preferably
Stability, do not allow in storage degradable.
Compared with prior art, beneficial effects of the present invention are：
(1) micella and medicament carrier system of the present invention have good hydrogen peroxide response, can target dissociation,
It is quickly broken in the environment of ROS high expression diseases (such as treating myocardial ischemia damage, atherosclerosis, intestinal inflammatory and tumour)
Split, discharge drug, and the content of hydrogen peroxide in normal cell is low, drug can not discharge or discharge it is less, so reducing pair
The injury of normal cell.
(2) grain size of micella and medicament carrier system of the present invention is little with the time change of storage, there is preferable storage
Stability is hidden, drug can be protected not degraded by the enzyme in body fluid, prevent drug leakage.
Description of the drawings
It, below will be to specific in order to illustrate more clearly of the specific embodiment of the invention or technical solution of the prior art
Embodiment or attached drawing needed to be used in the description of the prior art are briefly described, it should be apparent that, in describing below
Attached drawing is some embodiments of the present invention, for those of ordinary skill in the art, before not making the creative labor
It puts, can also be obtained according to these attached drawings other attached drawings.
Fig. 1 is the synthetic route schematic diagram of lauric acid/dodecanoic acid-boron ester-glucan；
Fig. 2 is boron ester and the schematic diagram of lauric acid/dodecanoic acid reaction；
Fig. 3 is the schematic diagram of lauric acid/dodecanoic acid-boron ester terminal hydroxylization reaction；
Fig. 4 is lauric acid/dodecanoic acid-boron ester and the schematic diagram of glucan reaction；
Fig. 5 is 1H-NMR collection of illustrative plates, wherein, (A) is DA-B；(B) it is DA-BA；(C) it is DEX；(D) it is DA-B-DEX；
Fig. 6 is the critical micelle concentration value (0.049616 (mg/mL)) of DA-B-DEX polymer；
Fig. 7 is the micellar conformation figure of DA-B-DEX polymer micelles under the tem；
Fig. 8 is for the micella in PBS solution and in H2O2The micella that grain size is destroyed under environment；
Fig. 9 is for PBS solution (pH7.4) and containing H2O2The release of drug in the PBS solution of (100 μM)；
Grain size after Figure 10 is placed 6 months for DOX-P dried frozen aquatic productses in 25 DEG C.
Specific embodiment
Embodiment of the present invention is described in detail below in conjunction with embodiment, but those skilled in the art will
Understand, the following example is merely to illustrate the present invention, and is not construed as limiting the scope of the invention.It is not specified in embodiment specific
Condition person, the condition suggested according to normal condition or manufacturer carry out.Reagents or instruments used without specified manufacturer is
The conventional products obtained can be bought by city.
Embodiment 1
A kind of preparation method of dextran polymer and micella with hydrogen peroxide response, synthetic route such as Fig. 1
It is shown, it is as follows shown：
1) first carry out boron ester to react with lauric acid/dodecanoic acid, under nitrogen protection, boron ester raw material A (1eq), lauric acid/dodecanoic acid (1.5eq)
It puts into 25mL round-bottomed bottles, is dissolved with DCM.DMAP (0.2eq) EDCI (1.5eq) is weighed in order, and Et3N (0.5eq) is used respectively
After DCM dissolvings, using with syringe injection system.Reaction solution 18h under room temperature reaction, the tracking of TLC contact plates.Treat that the reaction was complete
Afterwards, water quenching is added to go out.Water layer is extracted 4 times with DCM, is merged organic phase, and is used MgSO4It is dry, it filters, is spin-dried for obtaining crude product,
Purified again with column chromatography, after PE: EA=50: 1 mobile phase crosses impurity removal point, use PE: EA=25: 1 instead and cross product.Product is Huang
Color grease.Reaction process is as shown in Figure 2.
2) lauric acid/dodecanoic acid-boron ester terminal hydroxyl is secondly carried out, raw material (1eq), NaIO4 (2.26eq), NH4Cl
(2.26eq) uses acetone solution, adds in same amount of water, 60 DEG C of reflux, reaction is overnight.After reaction cooling, with DCM, water extraction four
Secondary, organic layer is dried with anhydrous MgSO4, is spin-dried for, and crosses column.It crosses surplus stock with PE: EA=20: 1, crosses with PE: EA=3: 1
Product.Reaction process is as shown in Figure 3.
3) reaction of DA-B and glucan is finally carried out, glucan (monomer 5eq) DMSO ultrasonic dissolutions add in lauric acid/dodecanoic acid
Raw material (1eq) adds in 4A molecular sieves, nitrogen protection, 60 DEG C of reaction 60h.Reaction system, which filters, removes molecular sieve, and filtrate is slow
It instills in ice ethyl alcohol, the precipitation of white occurs, centrifuge 5min in 3000rp, remove supernatant liquid, add in ice ethyl alcohol, centrifuge, weight
It is multiple to operate three times, obtained lower sediment i.e. DA-B-DEX micellas crude product.Reaction process is as shown in Figure 4.
4) DA-B-DEX micellas after completion of the reaction, are prepared.DA-B-DEX micellas crude product is dissolved with ultra-pure water, then is used
The bag filter of 3500KD is dialysed 48h in ultra-pure water, and a water is changed every 4h.Then liquid in bag filter is frozen in freeze dryer
It is dry for 24 hours to get to required DA-B-DEX micellas, the white solid of product.
5) using 1H-NMR spectrum detection DA-B, DA-BA, DEX and DA-B-DEX, on nuclear magnetic resonance chemical analyser, with CDCl3
Making solvent, TMS is internal standard, and (specific testing result is referring to Fig. 5) is composed in the 1HNMR of room temperature measuring sample, and according to diagnostic protons
Peak calculates reactive grafting rate, grafting rate 4.8%.
Embodiment 2
The critical micelle concentration (CMC) of micella described in embodiment 1 is measured using fluorescent probe technique, is as follows：
1) methanol solution of fluorescence probe pyrene is prepared
Pyrene 0.0051g is taken to be dissolved in the methanol of 25ml and obtains concentration as 1.01 × 10-3mol/L pyrene solution, again with methanol dilution
Into the pyrene solution of 1.616 × 10-6mol/L.
2) preparation of the DA-B-DEX aqueous solutions of various concentration
Compound concentration is respectively 1 × 10-4、1×10-3、1×10-2、1×10-1, 1,10,100, the DA-B- of 1000mg/ml
DEX solution.
3) prepared by the micella containing pyrene
Prepared 150 μ l of pyrene solution are taken, into the volumetric flask of several 10ml, volatilize methanol.Then, containing micro pyrene
10ml volumetric flasks in be separately added into the DA-B-DEX solution 10ml of each concentration.Ultrasound 30min, is placed afterwards under 50 DEG C of water-baths
2h takes out placement room temperature, prepares to measure the fluorescence spectrum of each solution.
4) fluorescent spectrophotometer measuring
The slit that excitation and transmitting are set in fluophotometer is 5nm, scanning range 300-360nm, launch wavelength
372nm measures emitted luminescence intensity I333 and I339 under 333nm and 339nm excitation wavelengths, and calculates I339/I333.Specific detection
As a result referring to Fig. 6.
Embodiment 3
A kind of to prepare the method with hydrogen peroxide responsive polymer Micellar drug carrier, step is as follows：
1) DA-B-DEX (100mg) is dissolved in DMSO (10ml), be added drop-wise under stirring PBS buffer solution (100ml,
PH7.4 in), stirring maintains 30min.Confirm spontaneously forming for micella by observing transparent opalescence solution.
2) while the DA-B-DEX micellas that physics contains adriamycin are prepared, DA-B-DEX (91.5mg) and DOX (8.5mg) are altogether
With 10mL dimethyl sulfoxide (DMSO)s (DMSO) are dissolved in, 100mLPBS buffer solutions are added drop-wise under stirring, stirring maintains 30min.Pass through
Bag filter (molecular cut off=3.5KD) is dialysed for 24 hours, removes organic solvent and free drug, and finally freeze-drying preserves.
3) particle diameter distribution is to utilize Malvern laser particle analyzer (Zetasized Nano, ZS, Malvern, United
Kingdom) measure.The assessment of the form and size of micella be by transmission electron microscope (TEM, Hitachi, H-7500,
Japan) observation obtains, and each sample is used further to observe after carrying out negative staining with 2% acetic acid uranium aqueous solution on copper mesh.It will bag
The micelle freeze-drying of adriamycin is carried, is re-dissolved in dimethyl sulfoxide (DMSO) (DMSO), last ultraviolet determination method (uses UV-Vis spectrophotometry
Degree meter measure light absorption value, substitute into standard curve C=0.018 7A+0.010 3 (r=0.999 8, n=9)) measure micella in Ah
The content of mycin.Drugloading rate is according to DOX useful loads and the calculating of the weight ratio of micella, and envelop rate is the amount that adriamycin is loaded into micella
It is calculated with the percentage of adriamycin initial input.Result of calculation shows, drugloading rate 4.1%, envelop rate 47%.
4) take micellar solution appropriate, be added dropwise on the copper mesh of covering carbon film, 2.0% phosphotungstic acid negative staining, drying at room temperature 0.5h,
Observation micella formalness under transmission electron microscope is placed in, specific form is referring to Fig. 7.
Embodiment 4
The drug release patterns of pharmaceutical carrier described in embodiment 3 are detected, specific detection method is as follows：
(1) measure of DOX standard curves：The DA-B-DEX micellas of the DOX of the 20mg physical encapsulations freezed are dissolved respectively
In PBS buffer solution (20ml) and contain 100 μM of concentration H2O2PBS solution, and be sealed in bag filter, 30ml used at 37 DEG C
PBS buffer solution is dialysed.Collect the external buffer solution of the DOX containing release at predetermined time point, and with 10mL fresh buffers
Solution is replaced.The amount of the DOX of release is measured under 480nm wavelength using UV-Vis spectrum, and is used in various concentration in PBS
Free DOX calculate standard curve.Experiment is repeated 3 times.
(2) carrier micelle drug release patterns in vitro measures：Carrier micellar solution (the 0.844mg/ prepared is taken respectively
Ml) 1ml is encased in the bag filter that 2 molecular cut offs are 3500, by two bag filters respectively marked as a, b.Then into a
Add the PBS buffer solution of 1mL；1ml is added in into b and contains H2O2PBS buffer solution.Bag filter is placed in and is buffered equipped with 6mL PBS
In the 50mL centrifuge tubes of solution, concussion is protected from light with the frequency of 100rev/min in 30 DEG C of constant temperature oscillators；In the time of setting
In interval, 2mL solution is taken out from bag filter a, b respectively, and the fresh PBS buffer solution of 2mL is added in a, 2mL is added in b
It is fresh to contain H2O2PBS buffer solution.Take out a, b bag filter outside solution, with UV spectrophotometer measuring its at 485nm
Absorption value, standard curves of the DOX measured according to front in PBS buffer solution calculate carrier micelle within this time
The specific testing result of release amount of medicine release amount of medicine is referring to Fig. 9.
Embodiment 5
Investigate the storage-stable of medicament carrier system (DOX-P) dried frozen aquatic products described in the embodiment of the present invention 3：DOX-P is frozen
Dry product is placed 6 months in 25 DEG C, 0,1,2,3 and is periodically sampled June, and grain is measured with Malvern grain size potential measurement instrument after redissolution
Footpath, wherein, the droplet measurement result of 6 months is placed referring to Figure 10.
Finally it should be noted that：The above embodiments are only used to illustrate the technical solution of the present invention., rather than its limitations；To the greatest extent
Pipe is described in detail the present invention with reference to foregoing embodiments, but it will be understood by those of ordinary skill in the art that：Its
It can still modify to the technical solution recorded in foregoing embodiments either to which part or all technical characteristic
Carry out equivalent substitution；These modifications are replaced, and the essence of appropriate technical solution is not made to depart from various embodiments of the present invention technology
The scope of scheme.
Claims (10)
1. a kind of dextran polymer, which is characterized in that the general formula of the dextran polymer is as follows：AmBn；
Wherein, the structural formula of the A is as follows：
The structural formula of the B is as follows：
The m represents the molar fractions of A in the polymer, 0≤m ＜ 1；The n represents the molar fractions of B in the polymer,
In, 0 ＜ n≤1；L expressions-the C2H4The number of-group, the l are selected from 5,6 or 7.
2. dextran polymer as described in claim 1, which is characterized in that wherein, 0≤m ＜ 0.7, and 0.3 ＜ n≤1；It is excellent
Selection of land, 0≤m ＜ 0.5, and 0.5 ＜ n≤1；It is highly preferred that 0≤m ＜ 0.3, and 0.7 ＜ n≤1；Most preferably, m=0, and n=
1。
3. a kind of polymer micelle, which is characterized in that the polymer micelle is by the dextran polymer of claim 1 or 2
It is prepared.
4. polymer micelle as claimed in claim 3, which is characterized in that the polymer micelle be prepared by the following method and
Into：
With 1 or 2 dextran polymer of water dissolution claim, 36 are dialysed in water with the bag filter of 3000~4000KD~
60h obtains dialyzate, is polymer micelle；
Preferably, the method further include by dialyzate freeze for powder the step of, the powder is polymer micelle；
It is highly preferred that the bag filter is 3500KD bag filters, dialysis time 48h, freeze-drying time is for 24 hours.
5. polymer micelle as claimed in claim 3, which is characterized in that the polymer micelle be prepared by the following method and
Into：
The polymer of claim 1 or 2 is dissolved in DMSO solution, is added dropwise in PBS buffer solution, holds under stirring
Continuous stirring is to forming transparent opalescence solution to get polymer micelle；
Preferably, the pH value of the PBS buffer solution is 7.2~7.6, the dosage between the polymer, DMSO and PBS buffer solution
Than for 50~150mg: 7~12mL: 50~150mL；
It is highly preferred that the pH value of the PBS buffer solution is 7.4, the amount ratio between the polymer, DMSO and PBS buffer solution
For 100mg: 10mL: 100mL.
6. a kind of medicament carrier system, which is characterized in that the pharmaceutical carrier includes being gathered by the glucan of claim 1 or 2
It closes the polymer micelle of object formation and is wrapped in inside the polymer micelle or is covalently bond to the dextran polymer
On drug molecule.
7. medicament carrier system as claimed in claim 6, which is characterized in that the drug molecule carries medicine by blank micella
Method, dialysis, emulsion process, solvent evaporation method or desivac are wrapped in inside the polymer micelle.
8. medicament carrier system as claimed in claim 6, which is characterized in that the medicament carrier system is made by the following method
It is standby to form：
The polymer of claim 1 or 2 and drug molecule are dissolved in DMSO solution, PBS is added dropwise under stirring
It in buffer solution, continues stirring until to form transparent opalescence solution, by the opalescence solution by dialysis to get the pharmaceutical carrier
System.
9. medicament carrier system according to claim 8, which is characterized in that the pH value of the PBS buffer solution for 7.2~
7.6, amount ratio between the polymer, drug molecule, DMSO and PBS buffer solution for 50~150mg: 5~10mg: 7~
12mL: 50~150mL；
Preferably, the pH value of the PBS buffer solution is 7.4, between the polymer, drug molecule, DMSO and PBS buffer solution
Amount ratio is 91.5mg: 8.5mg: 10mL: 100mL.
10. such as claim 6~9 any one of them medicament carrier system, which is characterized in that the drug molecule is selected from anti-swollen
Tumor medicine, cardiovascular drugs and anti-inflammatory drug, it is preferable that the antitumor drug, cardiovascular drugs and anti-inflammatory drug be selected from Ah
Mycin, mustargen, n-formyl sarcolysine, glyciphosphoramide, Carmustine, lomustine, Semustine, Chlorambucil, hemel, dopan,
Methotrexate (MTX), fluorouracil, Tegafur, cytarabine, gemcitabine, capecitabine, hydroxycarbamide, actinomycin D, mitogen are mould
Element, vinorelbine, Teniposide, Hydroxycamptothecin, taxol, docetaxel, tamoxifen, aminoglutethimide, Letrozole, first hydroxyl are pregnant
Ketone, megestrol acetate, cis-platinum, carboplatin oxaliplatin, aspirin, cangrelor, clopidogrel hydrogenesulphate, Pa Sugeer, method
An Ming, nifedipine, Nimodipine, Verapamil, digoxin, Losartan Potassium, Irbesartan, methoxy benzenpropanoic acid, fluorine biphenyl third
One or more in acid, hydrocortisone, dexamethasone, prednisone, Diclofenac or brufen.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109806250A (en) * | 2019-01-23 | 2019-05-28 | 吉林大学 | A kind of application of the pharmaceutical composition of hydroxyl urea |
| CN110478318A (en) * | 2019-09-17 | 2019-11-22 | 齐鲁工业大学 | A kind of Fenton reagent and adriamycin cotransport targeted nano carrier and preparation method thereof |
| CN114983930A (en) * | 2022-05-19 | 2022-09-02 | 沈阳药科大学 | ROS response type brain targeting nanogel double-layer drug release system based on high molecular polymer and preparation method and application thereof |
| CN115364236A (en) * | 2022-08-24 | 2022-11-22 | 安徽工业大学 | Cell membrane anchored ROS (reactive oxygen species) -responsive chitosan gel prodrug system, preparation method and application thereof |
| CN115505047A (en) * | 2022-08-17 | 2022-12-23 | 浙江怡辉生物科技有限公司 | Nitrogen mustard-glucan polymer and preparation method thereof, self-assembled nanoparticles, drug-loaded complex and application thereof |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0424168A1 (en) * | 1989-10-19 | 1991-04-24 | Nippon Oil And Fats Company, Limited | Polymer complexes of a sugar response type |
| EP1504039A1 (en) * | 2002-05-14 | 2005-02-09 | Rhodia Chimie | Polymer obtained by means of controlled radical polymerisation comprising at least one boronate function, association thereof with a ligand compound and uses of same |
| CN103755839A (en) * | 2014-01-21 | 2014-04-30 | 张建祥 | Active oxygen free radical sensitive cyclodextrin material as drug delivery carrier and preparation method thereof |
| CN104857521A (en) * | 2015-05-15 | 2015-08-26 | 江南大学 | Preparation method of bio-based macromolecular vesicles with glucose response |
| CN105012272A (en) * | 2015-07-06 | 2015-11-04 | 中国人民解放军第四军医大学 | Redox sensitive bone-targeting micelle for treating metastatic carcinoma of bone |
| CN106267149A (en) * | 2016-09-08 | 2017-01-04 | 南京医科大学 | A kind of apoplexy intellectual drug carrier of ROS response and preparation method thereof |
| CN106947003A (en) * | 2017-03-23 | 2017-07-14 | 西北师范大学 | Hydroxyl phenyl boric acid glucan high molecular polymer and its preparation and application between a kind of rhodamine |
| CN107082828A (en) * | 2017-05-19 | 2017-08-22 | 暨南大学 | A kind of active oxygen response macromolecule carrier and preparation method thereof |
-
2018
- 2018-01-03 CN CN201810003817.2A patent/CN108102004B/en not_active Expired - Fee Related
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0424168A1 (en) * | 1989-10-19 | 1991-04-24 | Nippon Oil And Fats Company, Limited | Polymer complexes of a sugar response type |
| EP1504039A1 (en) * | 2002-05-14 | 2005-02-09 | Rhodia Chimie | Polymer obtained by means of controlled radical polymerisation comprising at least one boronate function, association thereof with a ligand compound and uses of same |
| CN103755839A (en) * | 2014-01-21 | 2014-04-30 | 张建祥 | Active oxygen free radical sensitive cyclodextrin material as drug delivery carrier and preparation method thereof |
| CN104857521A (en) * | 2015-05-15 | 2015-08-26 | 江南大学 | Preparation method of bio-based macromolecular vesicles with glucose response |
| CN105012272A (en) * | 2015-07-06 | 2015-11-04 | 中国人民解放军第四军医大学 | Redox sensitive bone-targeting micelle for treating metastatic carcinoma of bone |
| CN106267149A (en) * | 2016-09-08 | 2017-01-04 | 南京医科大学 | A kind of apoplexy intellectual drug carrier of ROS response and preparation method thereof |
| CN106947003A (en) * | 2017-03-23 | 2017-07-14 | 西北师范大学 | Hydroxyl phenyl boric acid glucan high molecular polymer and its preparation and application between a kind of rhodamine |
| CN107082828A (en) * | 2017-05-19 | 2017-08-22 | 暨南大学 | A kind of active oxygen response macromolecule carrier and preparation method thereof |
Non-Patent Citations (2)
| Title |
|---|
| HONGLEI GUO ET AL: "Phenylboronic acid-based ampphiphilic glycopolymeric nanocarriers for in vivo insulin delivery", 《POLYMER CHEMISTRY》 * |
| MATUSZEWSKA A ET AL: "Glucose-responsive hybrid nanoassemblies in aqueous solutions:ordered phenylboronic acid within intermixed poly(4-hydroxystryene)-block-poly(ethylene oxide) block copolymer", 《BIOMACROMOLECULES》 * |
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109806250A (en) * | 2019-01-23 | 2019-05-28 | 吉林大学 | A kind of application of the pharmaceutical composition of hydroxyl urea |
| WO2020200305A1 (en) * | 2019-01-23 | 2020-10-08 | 吉林大学 | Use of pharmaceutical composition containing hydroxyurea |
| CN109806250B (en) * | 2019-01-23 | 2021-09-24 | 吉林大学 | Application of pharmaceutical composition containing hydroxyurea |
| CN110478318A (en) * | 2019-09-17 | 2019-11-22 | 齐鲁工业大学 | A kind of Fenton reagent and adriamycin cotransport targeted nano carrier and preparation method thereof |
| CN110478318B (en) * | 2019-09-17 | 2021-07-30 | 齐鲁工业大学 | Fenton reagent and adriamycin co-transport targeting nano-carrier and preparation method thereof |
| CN114983930A (en) * | 2022-05-19 | 2022-09-02 | 沈阳药科大学 | ROS response type brain targeting nanogel double-layer drug release system based on high molecular polymer and preparation method and application thereof |
| CN114983930B (en) * | 2022-05-19 | 2023-08-29 | 沈阳药科大学 | ROS (reactive oxygen species) response type brain targeting nanogel bilayer drug release system based on high molecular polymer and preparation method and application thereof |
| CN115505047A (en) * | 2022-08-17 | 2022-12-23 | 浙江怡辉生物科技有限公司 | Nitrogen mustard-glucan polymer and preparation method thereof, self-assembled nanoparticles, drug-loaded complex and application thereof |
| CN115505047B (en) * | 2022-08-17 | 2024-03-29 | 浙江怡辉生物科技有限公司 | Polymer of nitrogen mustard-glucan, preparation method of polymer, self-assembled nanoparticle, drug-loaded complex and application of polymer |
| CN115364236A (en) * | 2022-08-24 | 2022-11-22 | 安徽工业大学 | Cell membrane anchored ROS (reactive oxygen species) -responsive chitosan gel prodrug system, preparation method and application thereof |
| CN115364236B (en) * | 2022-08-24 | 2024-05-03 | 安徽工业大学 | Cell membrane anchored ROS (reactive oxygen species) responsive chitosan gel prodrug system, preparation method and application thereof |
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