CN108794654A - A kind of biodegradable isotope of redox-sensitive type polymer and its preparation method and application - Google Patents
A kind of biodegradable isotope of redox-sensitive type polymer and its preparation method and application Download PDFInfo
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- CN108794654A CN108794654A CN201810467742.3A CN201810467742A CN108794654A CN 108794654 A CN108794654 A CN 108794654A CN 201810467742 A CN201810467742 A CN 201810467742A CN 108794654 A CN108794654 A CN 108794654A
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
- C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
- C08B37/0072—Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The present invention discloses a kind of biodegradable isotope of redox-sensitive type polymer and its preparation method and application.It is hyaluronic acid that the polymer, which has nucleocapsid structure, water-wet side, that is, shell, and hydrophobic side, that is, kernel is Vitamin E succinate.Hyaluronic acid and Vitamin E succinate are done connecting bridge by the present invention by disulfide bond, it is prepared into the polymer with redox response performance, nano-micelle can be spontaneously formed by hydrophobe active force in water, have many advantages, such as that biological degradability is good, toxic side effect is small, response is good.The polymer of the present invention is using hyaluronic acid existing for human body and natural vitamin E succinate forms nano-micelle in water, it can be achieved that a variety of drug loadings, have good application prospect in medicine.
Description
Technical field
The present invention relates to field of pharmaceutical preparations and chemical field, specially a kind of biodegradable redox
Sensitive polymer, in aqueous solution since hydrophobe effect spontaneously forms amphiphilic nano micella, tumor locus can be with
Response releases drug.It, can the invention discloses the preparation of the polymer micelle and as the application of anti-cancer medicament carrier
To effectively improve the water solubility of insoluble drug.
Background technology
Since many anticancer drug poorly water-solubles, the toxicity of normal tissue are big, its application is limited, with nanotechnology
Rapid development, there are many Nano medications to list, wherein nano-carrier is based on liposome and nano-micelle.Nano-micelle
Hydrophobic drug is contained in its hydrophobic cores by hydrophobe active force, hydrophily shell then improve its it is water-soluble and
Stability.In addition to this, by changing and modifying water-wet side and the hydrophobic side of nano-micelle, the immunogene of drug can be improved
Property, realize intelligent release, improve targeting etc..Polyethylene glycol is a kind of excellent hydrophilic polymer, as stealth material
Using extensive, studies have found that, while polyethylene glycol brings macrocyclic advantage in vivo, also bring cumulative toxicity.
Therefore using material contain in human body, good biocompatibility in itself as water-wet side, for the pH conditions of tumor tissues, enzyme
Hydrophilic material is connect by the connecting key of the sensitivity such as system with hydrophobic material, the infiltration and delay enhanced by tumor locus
Effect (Enhanced permeation and retention, EPR) is broken in tumor locus response, releases drug, with
Reach the effect of improving the water-soluble of hydrophobic drug while improving drug, there is actual meaning.
Gambogicacid (Gambogic Acid, GA, C38H44O8) be a kind of principal active component with antitumor action it
One, as the extract in Chinese medicine gamboge, application has thousands of years.GA has been demonstrated to all have in many tumor types anti-
Function of tumor becomes the hot spot of the antitumor research of natural products in recent years, due to its toxic side effect is larger, poorly water-soluble, selection
Property it is low, limit its current antitumor clinical research.
Glutathione (glutathione, GSH) is the tripeptides of naturally occurring in human body, paddy Guang in tumor tissues and cell
Sweet peptide content is high, but the normal cell of cancer patient, compared with healthy population, glutathione content is relatively low, due in tumour cell
GSH contents height often generates drug resistance to chemotherapy, some researchers attempt to such as Buthionine sulfoximine (BSO) consumption
The drug of GSH, to reduce the content of GSH in cancer cell.But it uses the effect of BSO limited and there is no specific aim, drug also can be same
When reduce normal cell in GSH content so that because the side effect that chemicotherapy is brought further deteriorates.Tumor locus is highly concentrated
The glutathione of degree can be with Reduction of Disulfide, and normal structure and blood vessel glutathione concentrations are low, and disulfide bond can be stabilized,
And the glutathione of high concentration itself can also be aoxidized after Reduction of Disulfide, to be consumed.
Hyaluronic acid (Hyaluronan, HA) is a kind of anionic property, biodegradable natural polysaccharide, is connective group
The main cell epimatrix knitted.HA has the characteristics that：1) HA has biocompatibility, and is originally existing object in human body
Matter；2) HA molecular weight is high, and is graft polymers, can form grafting micella, compares block polymer micelle, can improve load
Dose and encapsulation rate；3) in a variety of cancer cells, hyaluronic acid enzyme level can all increase, and the HA that can degrade easily is low molecular weight
Segment, to realize that the enzyme response after cancer cell endocytosis discharges；4) hydrophilic macromolecule HA is used as polyethylene glycol (PEG) light recently
The safer substitute of grid, to extend the blood circulation time of nano-particle；(5) physiological stability and biofacies that HA can be carried
Capacitive.
Vitamin E succinate (Vitamin E succinate, VES, C33H54O5), it is a kind of vitamin E family member,
It is widely used in health food.It not only has the production retention that stability is good, is not easy the moisture absorption, is not easy microbiological contamination, also has
There is the function of inhibiting kinds of tumor cells growth.Since its hydrophobicity is by force, on the growth of normal cell without influence, can be used as excellent
Hydrophobic material.
Therefore, using the special physiological environment of tumor locus, response discharges drug, is used in combination one kind that can replace poly- second two
Alcohol, biodegradable material prepare nano-micelle and are particularly important.
Invention content
An object of the present invention is to provide a kind of high molecular polymer prodrug of intelligent response release drug, will be transparent
Matter acid, by being covalently bonded on disulfide bond, is prepared into poly- with redox response performance with Vitamin E succinate
Close object, can spontaneously form nano-micelle by hydrophobe active force in water, have biological degradability is good, toxic side effect is small,
The advantages that response is good.
It is real the second object of the present invention is to using hyaluronic acid-S-S- Vitamin E succinate polymer as pharmaceutical carrier
Existing a variety of drug loadings, improve the water solubility of drug, simultaneously because reductive glutathione contains in tumor tissues and tumour cell
Amount is high, not only can can also reduce the toxic side effect to normal cell with target tumor tissue with hydrolytic cleavage disulfide bond.
The technical solution adopted by the present invention is：A kind of biodegradable isotope of redox-sensitive type polymer, the life
The isotope of redox-sensitive type polymer of Biodegradable is with nucleocapsid, and shell is hyaluronic acid, and inner casing is tocopheryl succinate
Acid esters has the hyaluronic acid-S-S- Vitamin E succinate polymer of glutathione reduction response performance.
Preferably, above-mentioned a kind of biodegradable isotope of redox-sensitive type polymer, hyaluronic acid average molecular weight
For 3.5kDa.
A kind of preparation method of biodegradable isotope of redox-sensitive type polymer, includes the following steps：By vitamin E
Succinate is reacted with 2-aminoethyl disulfide dihydrochloride, obtains Vitamin E succinate derivative；Again by Vitamin E succinate derivative
It is reacted with hyaluronic acid, obtains hyaluronic acid-S-S- Vitamin E succinate polymer.Specially：
1) Vitamin E succinate is taken to be dissolved in dichloromethane, stirring to complete molten, addition 1- (3- dimethylaminos under ice bath
Propyl) -3- ethyl-carbodiimide hydrochlorides (EDC) and I-hydroxybenzotriazole (HOBT), room temperature, which is protected from light, to be stirred overnight, in gained
2-aminoethyl disulfide dihydrochloride is added in reaction solution, another that methanol hydrotropy is added, it is 7-8 to adjust pH with triethylamine, and for 24 hours, gained produces for stirring
Object NaHCO3Aqueous solution washs, and anhydrous magnesium sulfate drying, filtering is added in organic layer, and vacuum rotary steam removes dichloromethane, vacuum
It is dry, obtain Vitamin E succinate derivative.
2) appropriate hyaluronic acid (M3.5kDa) is dissolved in PBS buffer solutions, stirs 12h, 1- (3- bis- is added under ice bath
Methylaminopropyl) -3- ethyl-carbodiimide hydrochlorides (EDC) and n-hydroxysuccinimide (NHS), it is protected from light stirring 4h, obtains nothing
Color clear viscous shape liquid；Vitamin E succinate derivative is dissolved in n,N-Dimethylformamide (DMF), under ice bath by
It is added dropwise in colorless transparent viscous liquid, for 24 hours, gained reaction solution dialysis, freeze-drying obtains hyaluronic acid-S-S- dimension lifes for stirring
Plain E succinates polymer.
Preferably, the dialysis, bag filter molecular weight are 3.5kDa, and dialysis medium is distilled water.
Above-mentioned biodegradable isotope of redox-sensitive type polymer is as pharmaceutical carrier in the antitumor drug system of preparation
Application in agent.Drug and above-mentioned hyaluronic acid-S-S- Vitamin E succinate mixed with polymers are prepared into medicament-carried nano glue
Beam.Include the following steps：Drug and hyaluronic acid-S-S- Vitamin E succinate polymer are codissolved in dichloromethane, revolved
Dichloromethane is evaporated off, adds appropriate distilled water, first 60-70 DEG C of heating water bath 2-8h；Then at ice bath, ultrasonic power 45-
It is ultrasonically treated under 315W, filters, obtain medicament-carried nano micelle.
Preferably, the mass ratio of drug and hyaluronic acid-S-S- Vitamin E succinate polymer is 1:(1-10).
Preferably, the drug is selected from camptothecine, gambogicacid, adriamycin, gambogicacid, curcumin, Afatinib, Ji Fei
For Buddhist nun, Imatinib, daunorubicin, Nimodipine, ciclosporin A and Vindesine.
Compared with the existing technology, the invention has the advantages that：
The polymer of the present invention can be self-assembly of micella in aqueous solution, improve the water solubility of antitumor drug, pass through
Disulfide bond links, and release response performance is good, enhances the targeting of antitumor drug, while substantially prolonging antitumor drug and existing
The residence time of tumour, the critical micelle concentration test specification polymeric medicine attachment are easy to form micella, cell experiment table
Bright its has good inhibiting effect to liver cancer.The polymeric medicine attachment has the function of targeting intelligence release drug, grain size
In 100nm or so, contribute to nano-particle penetrating in tumor locus, and after response fracture, drug release.The present invention passes through
Using hyaluronic acid polymer targeted drug conveying technology, the glutathione of tumor locus high concentration is as target spot, development and design
HA-SS-VES polymeric medicine transport systems increase the effect of gambogicacid targeted therapy, reduce toxic side effect, to improve life
Object availability.
It is hyaluronic acid that polymer micelle provided by the invention, which has nucleocapsid structure, water-wet side, that is, shell, and hydrophobic side is i.e. interior
Core is Vitamin E succinate.Hyaluronic acid and Vitamin E succinate are done connecting bridge by the present invention by disulfide bond, are prepared
At the polymer with redox response performance, nano-micelle can be spontaneously formed by hydrophobe active force in water, is had
Have the advantages that biological degradability is good, toxic side effect is small, response is good.Polymer micelle, can be swollen by glutathione reduction
Tumor position and tumour cell targeting drug release and realization drug accumulation, toxic side effect, the raising for reducing normal tissue are antitumor
Effect.The polymer of the present invention forms nanometer in water using hyaluronic acid and natural vitamin E succinate existing for human body
Micella has good application prospect, it can be achieved that a variety of drug loadings in medicine.
Description of the drawings
Fig. 1 a are the grain size distribution of medicament-carried nano micelle prepared by embodiment 2.
Fig. 1 b are the zeta potential diagrams of medicament-carried nano micelle prepared by embodiment 2.
Fig. 2 is the TEM figures of medicament-carried nano micelle prepared by embodiment 2.
Fig. 3 is that the variation of medicament-carried nano micelle drug release under the glutathione of various concentration prepared by embodiment 2 is bent
Line chart.
Specific implementation mode
The technical solution further illustrated the present invention below by specific implementation mode.Those skilled in the art should be bright
, the embodiment, which is only to aid in, understands the present invention, should not be regarded as a specific limitation of the invention.
It is prepared by 1 hyaluronic acid-S-S- Vitamin E succinate polymer (HA-SS-VES) of embodiment
(1) preparation method
1, Vitamin E succinate (1.06g, 2mmol) is taken to be dissolved in 50mL dichloromethane, in 250mL round-bottomed flasks
EDC (13mmol) and HOBT (13mmol) is added, room temperature, which is protected from light, to be stirred overnight to complete molten in stirring under ice bath.React molten in gained
2-aminoethyl disulfide dihydrochloride (1.35g, 6mmol) is added in liquid, it is another that 10mL methanol hydrotropies are added, triethylamine is added and adjusts pH to 7-8, stirs
It mixes for 24 hours, the NaHCO of products therefrom 1mol/L3Aqueous solution washs, and anhydrous magnesium sulfate drying is added in organic layer, and filtering, 40 DEG C subtract
Pressure revolving removes dichloromethane, and vacuum drying obtains 0.944g Vitamin E succinate derivatives, yield 71.1%.MS(ESI)
M/z (%):665.4[M+H]+；IR(KBr,cm-1)：3435,2922,2862,2369,1647,1749,1145,920.1HNMR
(400MHz,CHCl3):δ7.57(s,H),3.3-3.5(m,2H),2.9-3.2(m,2H),2.5(dt,1H),2.4-2.5(m,
3H),2.1-2.3(m,9H),1.5-1.7(m,4H),1.0-1.4(m,17H),0.5-0.9(m,12H)。
2,5g hyaluronic acids (M3.5kDa, 0.5mmol) are dissolved in 20mL PBS buffer solutions, hydration 12h, under ice bath
EDC (13mmol) and NHS (13mmol) is added, is protected from light and is stirred overnight, obtain colorless transparent viscous liquid.By 1mmol vitamin Es
Succinate derivative is dissolved in 20mL DMF, is added dropwise in colorless transparent viscous liquid under ice bath, and stirring for 24 hours, will
Solution is added dropwise in a large amount of ice water after reaction, collect precipitation, after water dissolution, dialysis two days (bag filter molecular weight be 3.5kDa,
Dialysis medium is distilled water) small-molecule drug and impurity are removed, freeze-drying obtains white sparkling and crystal-clear shape solid, as hyaluronic acid-S-S-
Vitamin E succinate polymer (HA-SS-VES).IR(KBr,cm-1):3442,2974,2926,2845,2574,1716,
1640,1263,1172,1101,1039,947,813；Compared to independent hyaluronic acid, there is the change of compound in the one-dimensional H spectrums of product
Displacement study has1H NMR (DMSO) δ 7.46-7.60 (m, 2H), 1.5-1.7 (m, 4H), 1.0-1.4 (m, 17H), 0.5-0.9 (m,
12H), the synthesis success of provable polymer.
Embodiment 2HA-SS-VES medicament-carried nano micelles
(1) preparation of medicament-carried nano micelle
20mg gambogicacids and 50mg polymer HA-SS-VES are taken, is placed in 250mL eggplant-shape bottles, 10mL dichloromethane is added
It is dissolved.40 DEG C of vacuum rotary steams remove dichloromethane, obtain yellow pharmaceutical film, rear that 50mL distilled water is added, in 65 DEG C of water-baths
Middle aquation 4h, oscillation shake up.Probe Ultrasonic Searching processing (ultrasonic cell disruption instrument) 3 times, each 2min, ultrasonic power in ice bath
For 225W, 0.45 μm of miillpore filter is crossed to get the pesticide-carrying nano micellar solution of the polymer supported gambogicacids of HA-SS-VES.
(2) investigation of medicament-carried nano micelle water bath time
By (one) preparation method, change water bath time, in 65 DEG C of water-baths, aquation 2,4,6,8h respectively, with grain size,
PDI is main investigation parameter with encapsulation rate, and the results are shown in Table 1.When hydration time increases to 8h by 2h, the grain size of nanoparticle,
Encapsulation rate does not have apparent difference, considers to save the time, selects hydration time for 2h.The nanoparticle grain size of aquation 2h is
154.5nm, encapsulation rate 90.49%.
Table 1
(3) investigation of medicament-carried nano micelle ultrasonic power
By (one) preparation method, changing ultrasonic power size, ultrasonic power is respectively 45W, 135W, 225W, 315W,
Wherein power is 5% (45W), has a large amount of precipitation to generate after the solution ultrasound of 15% (135W), illustrates the nanoparticle to be formed
Less, most of drug unentrapped settles.As can be seen from Table 2, nanoparticle solution is made in 25% power, grain size and PDI are equal
It is bigger than nanoparticle made from 35% power.For encapsulation rate, encapsulation rate highest when ultrasonic power is 35% is 90.65%, therefore selects
It is 35% i.e. 315W to select ultrasonic power.
Table 2
(4) medicament-carried nano micelle medicine matter than investigation
By (one) preparation method, change the mass ratio (m/m) of gambogicacid and polymer HA-SS-VES, respectively 1:
10；1:5；1:2；1:1.25；1:1.Parameter is investigated to be main with grain size, PDI and encapsulation rate, as a result such as table 3, by table 3 as it can be seen that rattan
The mass ratio of yellow acid and polymer HA-SS-VES are by 1:10 increase to 1:1.25, encapsulation rate is higher.Continue growing gambogicacid
Amount to ratio is 1:1, encapsulation rate declines, and shows the amount for reaching polymer HA-SS-VES maximums package gambogicacid.Final choice medicine
The mass ratio of object and polymer HA-SS-VES are 1:1.25.
Table 3
(5) medicament-carried nano micelle is prepared by optimal prescription
40mg gambogicacids and 50mg polymer HA-SS-VES are taken, is placed in 250mL eggplant-shape bottles, 10mL dichloromethane is added
It is dissolved.40 DEG C of vacuum rotary steams remove dichloromethane, obtain yellow pharmaceutical film, rear that 50mL distilled water is added, in 65 DEG C of water-baths
Middle aquation 2h, oscillation shake up.Probe Ultrasonic Searching processing (ultrasonic cell disruption instrument) 3 times, each 2min, ultrasonic power in ice bath
For 315W, 0.45 μm of miillpore filter is crossed to get the pesticide-carrying nano micellar solution of the polymer supported gambogicacids of HA-SS-VES, such as Fig. 1 a
And shown in Fig. 1 b, grain size 95.71nm, PDI 0.247, current potential is -31.7mV, shows that carrier micelle grain size is smaller, Ke Yijin
Enter tumor locus, penetrability is good, and current potential absolute value is more than 20, shows that carrier micelle stability is good.
(6) medicament-carried nano micelle tem observation
Carrier micelle is prepared by above-mentioned (five), the form of carrier micelle is observed using TEM (transmission electron microscope).It will system
Pesticide-carrying nano micellar solution dilute 5 times, draw 10 μ L and be added drop-wise on the copper mesh of 200 mesh, naturally dry, then with 0.2%
Phosphotungstic acid is dyed, and after drying, the form of observation nanoparticle is carried out using transmission electron microscope, as shown in Fig. 2, medicament-carried nano micelle
At uniform spherical, grain size is less than 100nm, and form is good.
(7) the glutathione sensitivity release of medicament-carried nano micelle is investigated
Carrier micelle is prepared by above-mentioned (five), takes 1mL carrier micelles, is transferred in bag filter (MWCO, 3.5kDa), with
10mL PBS (pH7.4), 0.1% (w/v) SDS and GSH (0mM, 2mM, 10mM, 40mM) are dissolution medium, and release time is
48h, temperature are 37 DEG C, while as a contrast with the dialyzate group without GSH, taken in different time intervals 1mL dialyzates into
Row efficient liquid phase chromatographic analysis, while the corresponding fresh buffers of 1mL are supplemented to restore volume.It is detected with high performance liquid chromatography
Drug concentration is discharged, as a result such as Fig. 3.As seen from Figure 3, under the glutathione of 0mM and 2 μM of concentration, copolymer is almost not broken,
Burst size is few, illustrates that it can keep certain stability under low concentration glutathione content, and in the paddy of 10mM and 40mM
Under the sweet peptide concentration of Guang, release is rapid.Under the glutathione concentrations of 40mM, 10h is the burst size that can reach 65% or so, explanation
It is with excellent response performance.
Claims (10)
1. a kind of biodegradable isotope of redox-sensitive type polymer, which is characterized in that the biodegradable oxidation
It is with nucleocapsid to restore sensitive polymer, and shell is hyaluronic acid, and inner casing is Vitamin E succinate, has paddy Guang
Hyaluronic acid-S-S- Vitamin E succinate the polymer of sweet peptide reduction response performance.
2. a kind of biodegradable isotope of redox-sensitive type polymer according to claim 1, which is characterized in that transparent
Matter acid average molecular weight is 3.5kDa.
3. a kind of preparation method of biodegradable isotope of redox-sensitive type polymer as claimed in claim 1 or 2, feature
It is, includes the following steps：Vitamin E succinate is reacted with 2-aminoethyl disulfide dihydrochloride, obtains Vitamin E succinate derivative
Object；Vitamin E succinate derivative is reacted with hyaluronic acid again, obtains the polymerization of hyaluronic acid-S-S- Vitamin E succinate
Object.
4. a kind of preparation method of biodegradable isotope of redox-sensitive type polymer according to claim 3, special
Sign is, includes the following steps：
1) Vitamin E succinate is taken to be dissolved in dichloromethane, stirring to complete molten, addition 1- (3- dimethylaminos third under ice bath
Base) -3- ethyl-carbodiimide hydrochlorides and I-hydroxybenzotriazole, room temperature, which is protected from light, to be stirred overnight；Add in gained reaction solution
Enter 2-aminoethyl disulfide dihydrochloride, another that methanol hydrotropy is added, it is 7-8 to adjust pH with triethylamine, is stirred for 24 hours, products therefrom NaHCO3Water
Solution washs, and anhydrous magnesium sulfate drying, filtering is added in organic layer, and vacuum rotary steam removes dichloromethane, and vacuum drying obtains vitamin
E succinate derivatives；
2) appropriate hyaluronic acid is dissolved in PBS buffer solutions, stirs 12h, 1- (3- dimethylamino-propyls) -3- is added under ice bath
Ethyl-carbodiimide hydrochloride and n-hydroxysuccinimide are protected from light stirring 4h, obtain colorless transparent viscous liquid；By vitamin
E succinate derivatives are dissolved in n,N-Dimethylformamide, are added dropwise in colorless transparent viscous liquid, are stirred under ice bath
It mixes for 24 hours, gained reaction solution dialysis, freeze-drying obtains hyaluronic acid-S-S- Vitamin E succinate polymer.
5. preparation method according to claim 4, which is characterized in that the dialysis, bag filter molecular weight are 3.5kDa, thoroughly
Analysis medium is distilled water.
6. biodegradable isotope of redox-sensitive type polymer as claimed in claim 1 or 2 is anti-in preparation as pharmaceutical carrier
Application in tumor drug formulation.
7. application according to claim 6, which is characterized in that by drug and hyaluronic acid-as claimed in claim 1 or 2
S-S- Vitamin E succinate mixed with polymers prepares medicament-carried nano micelle.
8. application according to claim 7, which is characterized in that include the following steps：Drug and hyaluronic acid-S-S- are tieed up
Raw element E succinate polymer is codissolved in dichloromethane, and revolving removes dichloromethane, adds appropriate distilled water, first 60-70
DEG C heating water bath 2-8h；It then at ice bath, is ultrasonically treated under ultrasonic power 45-315W, filters, obtain medicament-carried nano micelle.
9. application according to claim 8, which is characterized in that drug is poly- with hyaluronic acid-S-S- Vitamin E succinate
The mass ratio for closing object is 1:(1-10).
10. according to the application described in claim 6,7,8 or 9, which is characterized in that the drug be selected from camptothecine, gambogicacid,
Adriamycin, gambogicacid, curcumin, Afatinib, Gefitinib, Imatinib, daunorubicin, Nimodipine, ciclosporin A and length
Spring amide.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104436203A (en) * | 2014-11-14 | 2015-03-25 | 郑州大学 | Preparation method and application of hyaluronic acid modified by vitamin E succinate |
| CN104530256A (en) * | 2014-12-18 | 2015-04-22 | 北京中医药大学 | Hyaluronic acid-vitamin E succinate polymer as well as preparation and application thereof |
| CN104945538A (en) * | 2015-06-25 | 2015-09-30 | 浙江大学 | Hyaluronic acid vitamin E derivative and preparation and application |
-
2018
- 2018-05-14 CN CN201810467742.3A patent/CN108794654A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104436203A (en) * | 2014-11-14 | 2015-03-25 | 郑州大学 | Preparation method and application of hyaluronic acid modified by vitamin E succinate |
| CN104530256A (en) * | 2014-12-18 | 2015-04-22 | 北京中医药大学 | Hyaluronic acid-vitamin E succinate polymer as well as preparation and application thereof |
| CN104945538A (en) * | 2015-06-25 | 2015-09-30 | 浙江大学 | Hyaluronic acid vitamin E derivative and preparation and application |
Non-Patent Citations (1)
| Title |
|---|
| 张汉波: "肿瘤还原微环境响应的透明质酸胶束抗肿瘤研究", 《中国优秀硕士学位论文全文数据库 医药卫生科技辑》 * |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110354276A (en) * | 2019-07-17 | 2019-10-22 | 山东大学 | A kind of prodrug and its preparation method and application |
| CN110604820A (en) * | 2019-10-17 | 2019-12-24 | 辽宁大学 | Dual-sensitive polymer-drug conjugate and preparation method and application thereof |
| CN110755379A (en) * | 2019-11-29 | 2020-02-07 | 上海中医药大学 | Targeted drug delivery system capable of resisting drug-resistant tumors and preparation method thereof |
| CN111228034A (en) * | 2020-01-16 | 2020-06-05 | 贵州省人民医院 | Drug-loading controlled-release lacrimal duct embolus and preparation method thereof |
| CN112121010A (en) * | 2020-09-02 | 2020-12-25 | 广州市第一人民医院（广州消化疾病中心、广州医科大学附属市一人民医院、华南理工大学附属第二医院） | Reduction response type vitamin E polyethylene glycol succinate micelle containing folic acid molecules and preparation method and application thereof |
| CN112641759A (en) * | 2020-12-31 | 2021-04-13 | 中国农业科学院油料作物研究所 | Redox-enhanced drug sensitive release mesoporous silica nanoparticle and preparation method thereof |
| CN115702937A (en) * | 2021-08-04 | 2023-02-17 | 四川大学 | Modified polyphenol carrier material, targeted nano delivery system, preparation method and application |
| CN114545658A (en) * | 2022-02-25 | 2022-05-27 | 金陵科技学院 | Preparation method of drug sustained-release type interpenetrating network hydrogel contact lens |
| CN114545658B (en) * | 2022-02-25 | 2023-07-14 | 金陵科技学院 | Preparation method of drug-sustained-release interpenetrating network hydrogel contact lens |
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