CN109875956A - A kind of ginsenoside-warfarin self-assembled nanometer gel and its application - Google Patents
A kind of ginsenoside-warfarin self-assembled nanometer gel and its application Download PDFInfo
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- CN109875956A CN109875956A CN201910267918.5A CN201910267918A CN109875956A CN 109875956 A CN109875956 A CN 109875956A CN 201910267918 A CN201910267918 A CN 201910267918A CN 109875956 A CN109875956 A CN 109875956A
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- warfarin
- ginsenoside
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Abstract
The invention discloses a kind of ginsenoside-warfarin self-assembled nanometer gel and its applications, it is specifically to mix warfarin and ginsenoside gel nano particles in water, it is made to be self-assembly of ginsenoside-warfarin nanogel transportation system after sonicated 15min；The average grain diameter of the nanogel is 15 ~ 60 nm.Innovative for the first time combine ginsenoside with warfarin of the present invention is prepared into nanogel, its gained nanogel can not only prepare cardiovascular drugs, and it also has very strong inhibiting effect to the proliferation of cancer cell, migration and adherency, therefore can be used for preparing medicine for anti transfer of tumor.
Description
Technical field
The invention belongs to pharmaceutical preparation technical fields, and in particular to a kind of ginsenoside-warfarin self-assembled nanometer gel
And its application.
Background technique
Tumour (Cancer) is to threaten a kind of disease of the very disruptive of whole mankind's health, and in China, tumour has become residence
The primary cause of death of the people, and metastases are the major causes of death of tumor patient, clinically 90% or more tumor patient is dead
In metastases rather than primary tumor, although primary tumor by operation after can obtain certain control, face
Face the danger of tumor recurrence and transfer, tumour cell is difficult to be cured by the means of operation once shifting.Tumour turns
Shifting is directly to be expanded from tumour original site to surrounding, or settled by blood road or lymphatic metastasis oncocyte in remote organization
Development forms the process of nascent tumor.In general, metastases will undergo adherency, the various protease of secretion, migration and part
Proliferation forms transfer stove.So inhibiting tumor cell adhesion, the degradation of tumour extracellular matrix, cancer cell motility, tumour new
The formation of angiogenic is the current main method for inhibiting metastases.
Warfarin (Warfarin) is bicoumarin derivative class compound, it is current clinically cardiovascular disease application
One of widest oral anticoagulation is mainly used for preventing and treating a variety of thromboembolisms, ischemic such as cardiovascular and cerebrovascular internal medicine, orthopaedics
Property disease.It, which mainly passes through, inhibits vitamin K-dependent clotting factor II, VII, IX and X and Protein S, PROTEIN C and albumen Z
Synthesis is in liver to play anticoagulation.Warfarin is mainly metabolized by the P450 system of liver.S-warfarin's
Metabolic enzyme is mainly liver drug enzyme CYP2C9, and the product after metabolism is S-7-hydroxywarfarin, the generation of R-warfarin
Thanking to enzyme is mainly Liver drug enzyme CYP3A4 and CYP1A2, and product generated is R-6-hydroxywarfarin, R-8- after metabolism
Hydroxywarfarin and R-10-hydroxywarfarin.Warfarin is most commonly used for the mouth of venous thromboembolism treatment
Anticoagulation, including compressibility tumor patient are taken, warfarin has good curative effect.
Ginseng (Ginseng) is herbaceos perennial, is known as " King of Herbs ", is the medicinal material of Chinese tradition.
General ginsenoside (Ginsenosides) is the main active of ginseng.Existing document proves that ginsenoside has enhancing body
Immunity improves the bioactivity such as cardiovascular function, anti-inflammatory, anti-oxidant, platelet aggregation-against, neuroprotection.Research shows that people
Joining to the protective effect of blood vessel inner skin cell function is its key factor for adjusting cardiovascular system, and mechanism of action mainly wraps
It includes: the expression for inhibiting Surface of Vascular Endothelial Cells adhesion factor, the aggregation for reducing blood platelet, the activity for adjusting cell stimulation factor
With the expression etc. for inhibiting inflammatory factor.Recent study as a result, it has been found that, general ginsenoside and its monomeric compound are to promoting tumour
Apoptosis promotes tumor cell differentiation, raising tumour cell antitumor to the sensibility and raising body of chemotherapeutics
Immunity etc. plays an important role.
Effective component general ginsenoside in ginseng has very strong inhibiting effect to the proliferation of cancer cell, can induce swollen
Apoptosis of tumor inhibits tumor cell proliferation, transfer and angiogenesis.Warfarin can improve the existence of cancer patient, have latent
Anti-tumor activity, and the two is incorporated in application not yet someone in terms of anti-tumor metastasis and reports.The present invention uses nanometer skill
Art, innovative for the first time is prepared into nanogel for the warfarin for treating cardiovascular drugs and ginsenoside, have compared with
Small nano-scale can pass through EPR effect, that is, solid tumor high-permeability and retention effect (enhanced permeability and
Retention effect) drug is effectively transmitted in tumor tissues, play the effect of anti-tumor metastasis.
Summary of the invention
It, can be from the purpose of the present invention is to provide a kind of ginsenoside-warfarin self-assembled nanometer gel and its application
The new way of an anti-tumor metastasis aspect use in conjunction is explored in the drug of two kinds of traditional treatment cardiovascular diseases.
To achieve the above object, the present invention adopts the following technical scheme:
A kind of ginsenoside-warfarin self-assembled nanometer gel, is by warfarin and ginsenoside gel nano particles in water
Middle mixing makes it be self-assembly of ginsenoside-warfarin nanogel transportation system after sonicated 15min.
The concentration of ginsenoside gel nano particles is 1 ~ 25 in the ginsenoside-warfarin self-assembled nanometer gel
Mg/mL, warfarin concentration be 1 ~ 25 mg/mL.
The ginsenoside-warfarin self-assembled nanometer gel average grain diameter is 15 ~ 60 nm, stabilization with higher
Property.
The preparation of the ginsenoside gel nano particles includes the following steps:
1) with one of Araliaceae China ginseng, Korean ginseng, American Ginseng, Vietnam's ginseng or the total soap of ginseng of a variety of extractions
Glycosides is raw material, and acidolysis reaction is carried out in acidic aqueous solution and obtains ginsenoside acid hydrolysis solution；
2) by the purified removal impurity of ginsenoside acid hydrolysis solution obtained by step 1) to obtain the final product.
Acidic aqueous solution described in step 1) is the aqueous solution of organic and or inorganic acids, pH value < 7, most preferably 1-3；
The temperature of the acidolysis reaction is 50 ~ 105 DEG C, and the time is 1 ~ 72h；
The concrete operations purified in step 2 are as follows: ginsenoside acid hydrolysis solution is stood 2 hours in -25 DEG C~35 DEG C or more, then
It is centrifuged or is filtered removal precipitating, clear liquid organic base and/or inorganic base are adjusted into pH to 7.5~14, obtain sediment；25
DEG C~85 DEG C at, sediment is dissolved in organic solvent, solution is then cooled to -20 DEG C~10 DEG C, is centrifuged or is filtered
After removal precipitating, clear liquid is concentrated under reduced pressure, then is dissolved in organic solvent again, and solution is cooled to -20 DEG C~10 DEG C, warp
After centrifugation or filtering removal precipitating, clear liquid is concentrated under reduced pressure and is dried.
The organic solvent is one of dimethyl sulfoxide, methanol, ethyl alcohol, n-butanol, propyl alcohol, tetrahydrofuran, pyridine
Or it is a variety of；The drying is constant pressure and dry, dry or spray drying is concentrated under reduced pressure.
Gained ginsenoside-warfarin self-assembled nanometer gel cannot be only used for preparing cardiovascular drugs, it may also be used for system
Standby medicine for anti transfer of tumor.
Present invention has the advantage that:
(1) ginsenoside prepared by the present invention-warfarin self-assembled nanometer gel is remarkably improved ginsenoside and warfarin suppression
The effect of Nasopharyngeal neoplasms processed；
(2) ginsenoside prepared by the present invention-warfarin self-assembled nanometer gel have lesser partial size, higher stability and
Drugloading rate；
(3) ginsenoside of the present invention-warfarin self-assembled nanometer gel has linear structure.
Detailed description of the invention
Fig. 1 is ginsenoside-warfarin self-assembled nanometer gel partial size (A) and potential energy diagram (B).
Fig. 2 tries hard to for the atom that ginsenoside-warfarin independently fills nanogel.
Fig. 3 be various concentration under warfarin solution (War), ginsenoside blank nanogel solution (Gs), warfarin and
Ginsenoside physical mixed solution (War+Gs) and ginsenoside-warfarin organize the thin of nanogel solution (War-Gs NPs) certainly
Cellular toxicity experimental result comparison diagram.
Fig. 4 be different time under warfarin solution (War), ginsenoside blank nanogel solution (Gs), warfarin and
Ginsenoside physical mixed solution (War+Gs) and ginsenoside-warfarin organize the reality of nanogel solution (War-Gs NPs) certainly
Test cell migration situation comparison diagram.
Fig. 5 is warfarin solution (War), ginsenoside blank nanogel solution (Gs), warfarin and ginsenoside object
Manage the experimental cell migration of mixed solution (War+Gs) and ginsenoside-warfarin from group nanogel solution (War-Gs NPs)
Rate calculated result comparison diagram.
Specific embodiment
In order to make content of the present invention easily facilitate understanding, With reference to embodiment to of the present invention
Technical solution is described further, but the present invention is not limited only to this.
Embodiment 1
It weighs 5.0 g general ginsenosides and the aqueous acetic acid that pH is 1.8 is added, 4 h are reacted at 90 DEG C, reactant is put in room temperature
After setting 2 h, with 0.45 μm of membrane filtration, impurity is removed；Filtrate is staticly settled, is subtracted with 10% sodium carbonate liquor pH to 7.5
Press collected by suction sediment；After sediment is heated to 60 DEG C of dissolutions in dehydrated alcohol, in 4 DEG C of 2 h of placement, with membrane filtration,
After collecting filtrate decompression concentration, then concentrate is put into dehydrated alcohol and is dissolved, 2 h are hereafter placed at 4 DEG C, filtered with 2 μm
Filtrate decompression is concentrated and dried up to ginsenoside nanogel after film filtering；Warfarin and ginsenoside gel powder are taken, is added two
Secondary water makes 1 ~ 10 mg/mL of concentration of final concentration of 1 ~ 10 mg/mL of ginsenoside, warfarin in solution, ultrasonic vibration 15
Min independently accommodates a meter gel solution to get ginsenoside-warfarin.
2 ginsenosides of embodiment-warfarin nanogel characterization
With the partial size (size, nm) and potential (zeta potential, mv) of dynamic light scattering (DLS) measurement nanogel, knot
Fruit is as shown in Figure 1.
As seen from Figure 1, nanogel prepared by the present invention has small partial size and negative potential.
3 ginsenosides of embodiment-warfarin nanogel structure characterization
The three-dimensional structure of nanogel is measured with atomic force microscope (AFM), as a result as shown in Figure 2.
From Figure 2 it can be seen that ginseng soap prepared by the present invention-linear structure of warfarin.
The assessment of 4 ginsenosides of embodiment-warfarin nanogel biocatalytic particle pharmacodynamics
Cytotoxicity experiment: the typeⅡ pneumocyte of logarithmic growth phase is digested with the pancreatin containing EDTA, uses cell counter
Cell number is calculated, cell is configured to 0.7-1.0 × 10 with culture medium4The cell suspending liquid of/mL.It will be thin with the volley of rifle fire of 100 μ L
Born of the same parents' suspension is added in 96 orifice plates, and the amount in every hole is 100 μ L, and number of cells is about 0.5-0.8 × 104.96 orifice plates are put
Enter intercellular incubator overnight incubation.In advance with 1640 culture mediums preparation various concentration warfarin solution (War) (10,
20,50,100,200 μ g/mL), ginsenoside blank nanogel solution (Gs) (10,20,50,100,200 μ g/mL),
Warfarin and ginsenoside physical mixed solution (War+Gs) (10,20,50,100,200 μ g/mL) and ginsenoside-Hua Fa
Woods organizes nanogel solution (War-Gs NPs) (10,20,50,100,200 μ g/mL) certainly.With the volley of rifle fire of 100 μ L by orifice plate
In the suction of old culture medium discard, the culture medium containing drug prepared is added in hole according to the amount of every 100 μ L of hole, is put into
24 h of iuntercellular incubator culture.Mother liquor MTT and serum-free prepare according to the ratio of 1:9 in advance without 1640 phenol red culture mediums
It is good, the volley of rifle fire suction of 100 μ L of the culture medium in 96 orifice plates is discarded, it is then with the volley of rifle fire of 100 μ L that the MTT prepared is molten again
In liquid adding hole, 96 orifice plates are brought into intercellular incubator and are then incubated for 4 h.MTT solution is discarded, with the volley of rifle fire of 100 μ L
The DMSO of 100 μ L is added to every hole, 96 orifice plates are placed on shaking table and rock 5-10 min, keep the purple crystal in orifice plate complete
Dissolution.Each hole light absorption value (OD value) is measured at 490 nm, calculates the survival rate of cell, as a result such as Fig. 3.
As seen from Figure 3, ginsenoside-warfarin is greater than independent people from toxicity of the group nanogel to typeⅡ pneumocyte
Join saponin(e, independent warfarin medication and warfarin and ginsenoside physical mixed medication group, and with the increase of dosage, to people
The toxicity of lung cancer A549 cell is bigger.As it can be seen that ginsenoside-warfarin from group nanogel be conducive to improve ginsenoside and
Inhibiting effect of the warfarin to cancer cell.
Migration of 5 ginsenosides of the embodiment-warfarin nanogel to cancer cell
External test ginsenoside-warfarin self-assembled nanometer gel solution, which migrates typeⅡ pneumocyte, influences experiment: taking
The typeⅡ pneumocyte of logarithmic growth phase is digested with the pancreatin containing EDTA, is configured to 0.8-1.0 × 106The cell of/mL suspends
Liquid.24 orifice plates are taken, the cell suspending liquid for drawing 0.5 mL is added in orifice plate, is put into iuntercellular incubator overnight incubation.Second
When its cell monolayer is paved with orifice plate, covered in hole at 1/4,2/4 and the 3/4 of cell laterally or vertically with the small pipette tips of 10 μ L
Line-styled scratch is drawn, 2-3 times is cleaned with PBS and cleans the damaging cells drawn and fallen.Warfarin solution is prepared with culture medium
(War) (50 μ g/mL), ginsenoside solution (Gs) (50 μ g/mL), warfarin and ginsenoside physical mixed solution (War
+ Gs) (50 μ g/mL, 50 μ g/mL) and ginsenoside-warfarin self-assembled nanometer gel solution (War-Gs NPs) (50 μ
G/mL), the fresh culture that 0.5 mL contains drug is then added in corresponding orifice plate, and choose in the case where just setting microscope
The different visuals field are taken pictures, and record position of the cell in 0 h where scratch, and calculate the width of scratch.24 orifice plates are set
24 h are then incubated in intercellular incubator, photo is shot in the position recorded before again, calculates the distance of cell migration
And mobility, it is as a result as shown in Figure 4 and Figure 5 respectively.
As seen from Figure 5, the ginsenoside of 50 μ g/mL-warfarin self-assembled nanometer gel (War-Gs NPs) processing
The cell migration rate of sample is down to less than 20 %, it is seen that ginsenoside-warfarin self-assembled nanometer gel has significantly in vitro
Inhibition Nasopharyngeal neoplasms effect.
The foregoing is merely presently preferred embodiments of the present invention, all equivalent changes done according to scope of the present invention patent with
Modification, is all covered by the present invention.
Claims (4)
1. a kind of ginsenoside-warfarin self-assembled nanometer gel, it is characterised in that: by warfarin and ginsenoside gel nanometer
Particle mixes in water, it is made to be self-assembly of ginsenoside-warfarin nanogel delivery system after sonicated 15min
System.
2. ginsenoside according to claim 1-warfarin self-assembled nanometer gel, it is characterised in that: the ginseng soap
The concentration of ginsenoside gel nano particles is the concentration of 1 ~ 25 mg/mL, warfarin in glycosides-warfarin self-assembled nanometer gel
For 1 ~ 25 mg/mL.
3. ginsenoside according to claim 1-warfarin self-assembled nanometer gel, it is characterised in that: the ginseng soap
Glycosides-warfarin self-assembled nanometer gel average grain diameter is 15 ~ 60 nm.
4. a kind of ginsenoside as claimed in claim 1-warfarin self-assembled nanometer gel is preparing medicine for anti transfer of tumor
The application of aspect.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103271891A (en) * | 2013-04-28 | 2013-09-04 | 福建南方制药股份有限公司 | Ginsenoside nano-micelle, and preparation method, application and pharmaceutical composition thereof |
| CN107929737A (en) * | 2018-01-15 | 2018-04-20 | 福州大学 | A kind of pharmaceutical composition of anti-tumor metastasis and its application |
| CN108273042A (en) * | 2018-04-25 | 2018-07-13 | 福州大学 | A kind of ginsenoside-insulin nano gel and the preparation method and application thereof |
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2019
- 2019-04-03 CN CN201910267918.5A patent/CN109875956A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103271891A (en) * | 2013-04-28 | 2013-09-04 | 福建南方制药股份有限公司 | Ginsenoside nano-micelle, and preparation method, application and pharmaceutical composition thereof |
| CN107929737A (en) * | 2018-01-15 | 2018-04-20 | 福州大学 | A kind of pharmaceutical composition of anti-tumor metastasis and its application |
| CN108273042A (en) * | 2018-04-25 | 2018-07-13 | 福州大学 | A kind of ginsenoside-insulin nano gel and the preparation method and application thereof |
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Application publication date: 20190614 |