CN104399085B - The heparin vitamin e succinate polymer of modified with folic acid and its synthetic method - Google Patents
The heparin vitamin e succinate polymer of modified with folic acid and its synthetic method Download PDFInfo
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- CN104399085B CN104399085B CN201410625235.XA CN201410625235A CN104399085B CN 104399085 B CN104399085 B CN 104399085B CN 201410625235 A CN201410625235 A CN 201410625235A CN 104399085 B CN104399085 B CN 104399085B
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Abstract
The present invention relates to the heparin vitamin e succinate polymer and its synthetic method of a kind of modified with folic acid, its repeat unit structure formula is as follows：Wherein R1For vitamin e succinate, R2For Folic Acid.With heparin as hydrophilic back bone, which is carried out with vitamin e succinate hydrophobically modified, obtain amphipathic heparin vitamin e succinate polymer, amphipathic heparin vitamin e succinate polymer is further modified with Folic Acid, the heparin vitamin e succinate polymer of modified with folic acid is obtained, to improving the ability of the target tumor tissue of nanoparticle.Present invention process is easy, mild condition；The nanoparticle that the raw material for being used has good biocompatibility and biodegradability, preparation can serve as a kind of excellent anti-cancer medicament carrier, to increase the dissolubility of medicine and improve its internal distribution.
Description
Technical field
The present invention relates to a kind of synthesis of the heparin-vitamin e succinate of polymer nano material modified with folic acid, this gathers
Compound can be self-assembly of nanoparticle in aqueous, belong to polymerization synthesis and technical field of nano material.
Background technology
In aqueous, the amphipathic nature polyalcohol being made up of hydrophilic polymer backbones and hydrophobic patches, due to hydrophobic
The driving of the noncovalent forces such as effect, can spontaneously form a kind of polymer nanoparticle with nucleocapsid structure.
Heparin (Heparin) is a kind of mucopolysaccharide being present in human body, is clinically used as anticoagulant for a long time.In recent years
Come, heparin causes extensive concern as a kind of nano material delivery cancer therapy drug, and its main advantage is as follows.On the one hand, liver
Element as a kind of endogenous material, with preferable biocompatibility and biodegradability.On the other hand, heparin has in itself
The effect of certain promotion cancer cell-apoptosis.
Vitamin e succinate is the derivant of natural Vitamin E.Which has significant lethal effect to tumor cell, and
There is no obvious toxic action to normal cell.Vitamin e succinate has been reported to enough induction lymphoma cells, prostatitis
The growth of the mankind malignant cell such as adenocarcinoma cell, colon cancer cell, breast cancer cell has certain inhibitory action.Vitamin
E succinates are a kind of good materials of lipotropy, if using it for building nano-carrier, it can become hydrophobic drug
Good bank.
If can merge to get up them, prepare a kind of can displaying one's respective advantages and overcome the material of deficiency then significant.
The content of the invention
It is an object of the invention to provide a kind of heparin of modified with folic acid-vitamin e succinate polymer and its synthesis side
Method.
The present invention is achieved by the following technical solutions：
A kind of heparin of modified with folic acid-vitamin e succinate polymer, its repeat unit structure formula are as follows：
Wherein, R1=
R2=
Polymer its molecular weight is in 4000-10000.
The synthetic method of the heparin of described modified with folic acid-vitamin e succinate polymer, comprises the steps：
(1) heparin is dissolved in into distilled water, after fully dissolving, adds adipic dihydrazide, 1- ethyls-(3- dimethylaminos third
Base) carbodiimide hydrochloride, hydroxy benzo triazole, system pH is adjusted to stir under 6.8 ± 0.2, room temperature with sodium hydroxide solution
Crude product is obtained after mixing 24 ± 5h of reaction, water is dialysed, lyophilized products are dissolved in Methanamide, solution under magnetic stirring for lyophilizing
It is standby；
(2) vitamin e succinate is dissolved in into DMF, adds 1- ethyls-(3- dimethylaminos third
Base) carbodiimide hydrochloride and N-hydroxy-succinamide, ultrasound is completely dissolved which, and mixed liquor is standby；
(3) under magnetic stirring, gained mixed liquor in step (2) is added dropwise in step (1) resulting solution, room temperature
Lower reaction 40-50h, after the completion of reaction, dialysis, and lyophilization is carried out to reaction mixture, that is, obtain heparin-tocopheryl succinate
Acid ester polymer；
(4) Folic Acid is dissolved in into DMF, is dissolved under magnetic agitation, add 1- ethyls-(3- dimethylaminos
Propyl group) carbodiimide hydrochloride and N-hydroxy-succinamide, ultrasound is completely dissolved which, standby；
(5) obtained heparin-vitamin e succinate polymer is dissolved in into Methanamide, then by step (4) prepare it is molten
Liquid is added dropwise over wherein under magnetic stirring, plus triethylamine adjusts pH in right amount to 9, and lucifuge reacts 40- to the system at room temperature
50h, after the completion of reaction, dialysis, and lyophilization is carried out to reaction mixture, that is, obtain the heparin-tocopheryl succinate of modified with folic acid
Acid ester polymer.
Heparin, adipic dihydrazide, 1- ethyls-(3- dimethylaminos third in above-mentioned synthetic method, described in step (1)
Base) carbodiimide hydrochloride, the mass ratio that feeds intake of hydroxy benzo triazole is for 1:5-20:1.92-2.88:1.36-2.04.Heparin
It is that every 0.2-1 gram of heparin is dissolved in 100 milliliters of distilled water with the usage ratio scope of distilled water.The ratio of lyophilized products and Methanamide
Scope is that every 20-100 milligrams lyophilized products are dissolved in 3 milliliters of Methanamides.Described heparin be Enoxaparin Sodium, relative molecular mass
For 2000～8000Da, average molecular mass is 4350Da.Bag filter molecular cut off is 3500Da.
Vitamin e succinate, 1- ethyls described in step (2)-(3- dimethylaminopropyls) carbodiimide hydrochloride
Mol ratio with N-hydroxy-succinamide is 1：2：2, in step (2), the usage ratio of DMF is per milligram
Vitamin e succinate 0.3-0.6 milliliters.
In step (3), mixed liquor obtained by step (2) and the volume ratio of formamide solution obtained by step (1) are 1:1.Made
It is 3500Da with bag filter molecular cut off, successively to methanol：Water=4:1 (V/V), methanol：Water=1:1 (V/V), water is each saturating
Analysis one day, is dialysed three days altogether.
Step (4) Folic Acid, 1- ethyls-(3- dimethylaminopropyls) carbodiimide hydrochloride and N- hydroxysuccinimidyls acyl are sub-
The mol ratio of amine is 1：2：2；In step (4), the usage ratio of N,N-dimethylformamide is every milligram of Folic Acid 0.2-0.5 milli
Rise.
In step (5), heparin-vitamin e succinate polymer and the mass ratio that feeds intake of Folic Acid are 1-5:1.Methanamide
Consumption be every milligram of heparin-vitamin e succinate polymer with 0.01 milliliter.Used bag filter molecular cut off is
3500Da, the sodium carbonate-bicarbonate buffer to pH 9.6 successively, water each dialyse one day, dialyse two days altogether.
The self-assembled nanometer grain of the heparin of above-mentioned modified with folic acid-vitamin e succinate polymer.The preparation side of nanoparticle
Method：Add PBS (pH=7.4), stirring to make which be uniformly dispersed in polymer lyophilized powder, 2min, ultrasonic arteries and veins are processed with Probe Ultrasonic Searching
Wash 2s open, stop 2s, gained colloid solution is crossed into 0.45 μm of microporous filter membrane then, obtain the heparin-vitamin e succinate clarified
Polymer self assembles nanoparticle solution.
The present invention carries out hydrophobicity transformation to which by lipophilic vitamin e succinate is grafted on heparin molecule,
Heparin-vitamin e succinate polymer is synthesized.It is to tie with core-shell structure copolymer that the polymer can be self-assembled in aqueous
The nanoparticle of structure, and the anticarcinogen of slightly solubility is contained in hydrophobic inner core, to increase the dissolubility of medicine and change its internal distribution.
In addition, the present invention introduces Folic Acid on heparin skeleton, make the self-assembled nanometer grain can be with active targeting in tumor tissues, raising is controlled
The effectiveness for the treatment of and safety.
It is an advantage of the current invention that：Under mild conditions, with EDC and NHS as activator, you can complete the conjunction of compound
Into simple process；Raw material used in the present invention has good biocompatibility and biodegradability, the nanoparticle of preparation
A kind of excellent anti-cancer medicament carrier is can serve as, to increase the dissolubility of medicine and improve its internal distribution.
Description of the drawings
The proton nmr spectra of Fig. 1 heparin-vitamin e succinate polymer；
The proton nmr spectra of the heparin of Fig. 2 modified with folic acid-vitamin e succinate polymer；
The electromicroscopic photograph of Fig. 3 heparin-vitamin e succinate nanoparticle；
The grain-size graph of Fig. 4 heparin-vitamin e succinate nanoparticle；
The I of Fig. 5 pyrenes1/I3Value is with heparin-vitamin e succinate polymer concentration variation relation figure.
Specific embodiment
With reference to case study on implementation, the invention will be further described.
The synthesis of 1. heparin of embodiment-vitamin e succinate polymer
(1) weighing 0.5g heparin and being dissolved in 100mL distilled water, stirring makes which adipic dihydrazide be added after fully dissolving
6.53g, 1- ethyl-(3- dimethylaminopropyls) carbodiimide hydrochloride 0.96g, hydroxy benzo triazole 0.68g.Use 0.1M
System pH is adjusted to 6.8 by sodium hydroxide solution, obtains crude product, water is dialysed 3 days under room temperature after stirring reaction 24h, and lyophilizing is standby.
(2) lyophilized products 50mg in step (1) are taken, 3mL Methanamides are dissolved under magnetic stirring, it is standby.
(3) 10mg vitamin e succinate is weighed, 3ml DMFs are dissolved in.Add equivalent to dimension life
The 1- ethyls of plain 2 times of moles of E succinates-(3- dimethylaminopropyls) carbodiimide hydrochloride and equivalent to Vitamin E
The N-hydroxy-succinamide of 2 times of moles of succinate, ultrasound is completely dissolved which, standby.
(4) under magnetic stirring, resulting solution in step (3) is added dropwise to into resulting solution in step (2), under room temperature
Reaction 48h.After the completion of reaction, dialyse 3 days, and lyophilization is carried out to reaction mixture, that is, obtain heparin-VE succinic acid
Ester polymer.
The proton nmr spectra of gained heparin-vitamin e succinate polymer is shown in Fig. 1.Chemical shift 5.0～
The absworption peak of 5.7ppm, 3.0～4.6ppm, 2～2.2ppm is respectively belonging to heparin anomeric proton, the proton on sugared ring, acetyl
Proton on aminomethyl.Chemical shift is that the absworption peak at 0.8ppm belongs to CH on vitamin e succinate alkyl chain3On
Hydrogen.The proton nmr spectra of polymer illustrates that vitamin e succinate has successfully been grafted on heparin skeleton.According to nuclear-magnetism
Resonance hydrogen spectrum quantitative result, the substitution value of vitamin e succinate is 8.9%.
The synthesis of the heparin of 2. modified with folic acid of embodiment-vitamin e succinate polymer
(1) weighing 0.5g heparin and being dissolved in 100mL distilled water, stirring makes which adipic dihydrazide be added after fully dissolving
6.53g, 1- ethyl-(3- dimethylaminopropyls) carbodiimide hydrochloride 0.96g, hydroxy benzo triazole 0.68g.Use 0.1M
System pH is adjusted to 6.8 by sodium hydroxide solution, obtains crude product, water is dialysed 3 days under room temperature after stirring reaction 24h, and lyophilizing is standby.
Lyophilized products 50mg are taken, 3mL Methanamides are dissolved under magnetic stirring, it is standby.
(2) 10mg vitamin e succinate is weighed, 3mL DMFs are dissolved in.Add equivalent to dimension life
The 1- ethyls of plain 2 times of moles of E succinates-(3- dimethylaminopropyls) carbodiimide hydrochloride and equivalent to Vitamin E
The N-hydroxy-succinamide of 2 times of moles of succinate, ultrasound is completely dissolved which, standby.
(3) under magnetic stirring, resulting solution in step (2) is added dropwise to into resulting solution in step (1), under room temperature
Reaction 48h.After the completion of reaction, dialyse 3 days, and lyophilization is carried out to reaction mixture, that is, obtain heparin-VE succinic acid
Ester polymer.
(4) weigh 4mg Folic Acid and be dissolved in 2mL DMFs, dissolve under magnetic agitation, add 2 times of moles
1- ethyls-(3- dimethylaminopropyls) carbodiimide hydrochloride and the N- hydroxyls equivalent to 2 times of moles of vitamin e succinate
Base butanimide, ultrasound are completely dissolved which, standby.
(5) obtained heparin-vitamin e succinate polymer 20mg in step (3) is weighed, under magnetic agitation, makes which molten
In 2mL Methanamides, the solution obtained in step (4) is added dropwise over wherein under magnetic stirring, separately adds triethylamine appropriate, adjust
PH to 9.Lucifuge reacts 48h to the system at room temperature.After the completion of reaction, dialyse 2 days, and lyophilization carried out to reaction mixture,
Heparin-vitamin e succinate the polymer of modified with folic acid is obtained.
The proton nmr spectra of the heparin-vitamin e succinate polymer of gained modified with folic acid is shown in Fig. 2.Signal exists
6.7,7.6ppm absworption peak correspondence folate molecule H13/15, the proton of H12/16 positions；Absworption peak correspondence of the signal in 8.7ppm
The proton of 7, folate molecule pterin ring.Result above shows Folic Acid is grafted to heparin-vitamin e succinate polymerization successfully
On thing.
Jing ultraviolet spectrophotometrys quantitative determine folate content, the heparin-vitamin e succinate polymerization of the modified with folic acid
The Folic Acid substitution value of thing is 4.1%.
The preparation of 3. heparin of embodiment-vitamin e succinate polymer self assembles nanoparticle
(1) made polymer lyophilized powder in 10mg embodiments 1, plus 5mL PBS (pH=7.4) are weighed, 2h is stirred, is made
Which is uniformly dispersed.
(2) process 2min with Probe Ultrasonic Searching, ultrasonic pulse opens 2s, stop 2s, then by gained colloid solution cross 0.45 μm it is micro-
Hole filter membrane, obtains the heparin-vitamin e succinate polymer self assembles nanoparticle solution clarified.
Fig. 3 is that heparin-vitamin e succinate polymer self assembles nanoparticle is saturating in H-7000 types Jing after phosphotungstic acid dyeing
Observation result under radio mirror.In more regular spherical, particle diameter is about 50nm to nanoparticle as seen from the figure.
The particle diameter and Zeta potential of nanoparticle, particle size results such as Fig. 4 institutes are determined with Malvern Zetasizer Nano-ZS
Show, the mean diameter of nanoparticle is 44.23nm, and Zeta potential is -16.3mV.
Fluorescent probe is made with pyrene, nanoparticle self assembly behavior in aqueous is studied with fluorophotometer.Such as Fig. 5 institutes
Show, the critical aggregation concentration of polymer is about 0.028mg/mL, illustrate that the polymer has good amphipathic, can be in water
In be self-assembled into nanoparticle and contain hydrophobic drug, and can keep stable under conditions of dilution.
Prepared heparin-vitamin e succinate polymer self assembles nanoparticle can be anti-as good hydrophobicity
Cancer drug carrier, to increase the dissolubility of medicine, changes its internal distribution, improves safety and the effectiveness of chemotherapy.Such as this
Bright synthesized heparin-vitamin e succinate self-assembled nanometer grain can successful load paclitaxel, HPLC measurement result tables
Bright, drug loading can reach more than 5%.
Claims (10)
1. the heparin of a kind of modified with folic acid-vitamin e succinate polymer, its repeat unit structure formula are as follows：
Wherein：R1It is the vitamin e succinate being connected with said structure by hydroxy-acid group；
R2It is the Folic Acid being connected with said structure by hydroxy-acid group.
2. a kind of synthetic method of the heparin of modified with folic acid-vitamin e succinate polymer, is characterized in that, including following step
Suddenly：
(1) heparin is dissolved in into distilled water, after fully dissolving, adds adipic dihydrazide, 1- ethyls-(3- dimethylaminopropyls)
System pH is adjusted to 6.8 ± 0.2 with sodium hydroxide solution by carbodiimide hydrochloride, hydroxy benzo triazole, stirs anti-under room temperature
Crude product is obtained after answering 24 ± 5h, water is dialysed, lyophilized products are dissolved in Methanamide, solution for standby under magnetic stirring for lyophilizing；
(2) vitamin e succinate is dissolved in into DMF, adds 1- ethyls-(3- dimethylaminopropyls)
Carbodiimide hydrochloride and N-hydroxy-succinamide, ultrasound are completely dissolved which, and mixed liquor is standby；
(3) under magnetic stirring, gained mixed liquor in step (2) is added dropwise in step (1) resulting solution, it is anti-under room temperature
40-50h is answered, after the completion of reaction, dialysis, and lyophilization is carried out to reaction mixture, that is, obtain heparin-vitamin e succinate
Polymer；
(4) Folic Acid is dissolved in into DMF, is dissolved under magnetic agitation, add 1- ethyls-(3- dimethylaminos third
Base) carbodiimide hydrochloride and N-hydroxy-succinamide, ultrasound is completely dissolved which, standby；
(5) obtained heparin-vitamin e succinate polymer is dissolved in into Methanamide, then solution prepared by step (4) exists
It is added dropwise over wherein under magnetic agitation, plus triethylamine adjusts pH in right amount to 9, lucifuge reacts 40-50h to the system at room temperature, instead
After the completion of answering, dialysis, and lyophilization is carried out to reaction mixture, that is, the heparin-vitamin e succinate for obtaining modified with folic acid gathers
Compound.
3. the synthetic method of the heparin of modified with folic acid according to claim 2-vitamin e succinate polymer, which is special
Levying is, the heparin, adipic dihydrazide, 1- ethyls described in step (1)-(3- dimethylaminopropyls) carbodiimide hydrochloride,
The mass ratio that feeds intake of hydroxy benzo triazole is 1:5-20:1.92-2.88:1.36-2.04；The usage ratio of heparin and distilled water
Scope is that every 0.2-1 gram of heparin is dissolved in 100 milliliters of distilled water；Lyophilized products are every 20-100 milligrams with the proportion of Methanamide
Lyophilized products are dissolved in 3 milliliters of Methanamides.
4. the synthetic method of the heparin of modified with folic acid according to claim 2-vitamin e succinate polymer, which is special
Levying is, described heparin is Enoxaparin Sodium, and relative molecular mass is 2000～8000Da, and average molecular mass is
4350Da。
5. the synthetic method of the heparin of modified with folic acid according to claim 2-vitamin e succinate polymer, which is special
Levying is, the vitamin e succinate, 1- ethyls described in step (2)-(3- dimethylaminopropyls) carbodiimide hydrochloride and N-
The mol ratio of N-Hydroxysuccinimide is 1：2：2, in step (2), the usage ratio of DMF is per milligram of dimension life
Plain E succinates 0.3-0.6 milliliters.
6. the synthetic method of the heparin of modified with folic acid according to claim 2-vitamin e succinate polymer, which is special
Levying is, in step (3), mixed liquor obtained by step (2) and the volume ratio of formamide solution obtained by step (1) are 1:1.
7. the synthetic method of the heparin of modified with folic acid according to claim 2-vitamin e succinate polymer, which is special
Levying is, step (4) Folic Acid, 1- ethyls-(3- dimethylaminopropyls) carbodiimide hydrochloride and N-hydroxy-succinamide
Mol ratio be 1：2：2；In step (4), the usage ratio of N,N-dimethylformamide is every milligram of Folic Acid 0.2-0.5 milliliter.
8. the synthetic method of the heparin of modified with folic acid according to claim 2-vitamin e succinate polymer, which is special
Levying is, in step (5), heparin-vitamin e succinate polymer and the mass ratio that feeds intake of Folic Acid are 1-5:1, Methanamide
Consumption is every milligram of heparin-vitamin e succinate polymer with 0.01 milliliter.
9. the self-assembled nanometer grain of the heparin of the modified with folic acid described in claim 1-vitamin e succinate polymer.
10. the preparation method of the self-assembled nanometer grain described in claim 9, is characterized in that, polymer lyophilized powder is added PBS,
Stirring makes which be uniformly dispersed, and processes 2min with Probe Ultrasonic Searching, and ultrasonic pulse is opened 2s, stops 2s, then by gained colloid solution mistake
0.45 μm of microporous filter membrane, obtains the heparin-vitamin e succinate polymer self assembles nanoparticle solution clarified.
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| CN112138001A (en) * | 2020-09-25 | 2020-12-29 | 山东大学 | Quercetin-low molecular weight heparin-paclitaxel conjugate, preparation method and application |
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