CN102100672A - Vascular endothelial growth factor chitosan microsphere and application thereof - Google Patents
Vascular endothelial growth factor chitosan microsphere and application thereof Download PDFInfo
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Abstract
The invention provides a vascular endothelial growth factor chitosan microsphere. The matrix of the microsphere is chitosan with deacetylation degree of more than or equal to 90.0 percent and viscosity of 100mPa.s, the coated active protein is a vascular endothelial growth factor, and the microsphere has the grain size of 200 to 300 nanometers. The chitosan microsphere serves as a carrier, the vascular endothelial growth factor is coated, and experiments prove that: the chitosan microsphere can well encapsulate and envelop the vascular endothelial growth factor and can well control the release of the vascular endothelial growth factor in a longer time. Moreover, the carrier is not needed to be taken out after administration and can be completely degraded and metabolized in vivo, decomposition products and metabolic products of the carrier are harmless to a human body, and the chitosan microsphere can be applied in preparing medicaments for promoting vascular endothelial cell proliferation and promoting growth of new blood vessels.
Description
Technical field
The invention belongs to biomedicine field, be specifically related to a kind of VEGF chitosan microball, this chitosan microball can wrap VEGF and carry and control its release, can be in the application in short vascular endothelial cell proliferation of preparation and the short new vessels growth medicine.
Background technology
(vascular endothelial growth factor VEGF) is a kind of histiocyte that extensively is stored in, the glycoprotein with various biological function to VEGF.VEGF has the function of very strong short vascular endothelial cell proliferation, short new vessels growth.By strengthening the expression of VEGF, VEGF and gene therapy thereof are improving myocardial ischemia, atherosclerosis, the damage of control artery and vein vascular and treatment of vascular restenosis, are promoting aspects such as cardiovascular transplanting, orthopaedics ischemic diseases and fractures that important effect is all arranged.If suppress the expression of VEGF, its biological effect of antagonism has then been carried out new way for tumor treatment.But merely that VEGF is implanted in the body, VEGF is easy to be spread, dilute, degrade in body, and bioavailability is low, and effect is poor.This just need add VEGF in the suitable carriers, makes it avoid proteasome degradation or diffusion, at the local long period sustained release of needs, realizes keeping local higher concentration within a certain period of time, is beneficial to its biological activity of effective performance.
Chitosan is that chitosan is to extract a kind of bioactive substance that obtains from discarded carapaces such as shrimp, Eriocheir sinensis; a kind of important derivant that after carrying out deacetylation under the strong alkaline condition, forms by chitin; chemical name is polydextrose amine (1-4)-2-amino-B-D glucose; chitosan is not only originated abundant; preparation is simple; and have good biocompatibility, and can degrade fully in vivo and metabolism, its catabolite and metabolite are harmless to health.
Utilize Preparation of Chitosan slow release, controlled release preparation to obtain effect preferably at present, especially utilize the chitosan microball entrapped drug to cause people's keen interest.As seal anticarcinogen (52Fu, cisplatin etc.), antibiotic medicine (dexamethasone etc.), diuretic (theophylline) and biochemical drug (calf thymus DNA) etc. with chitosan microball; The basic fibroblast growth factor chitosan microball has good slow release usefulness.The chitosan microball entrapped drug has following characteristics: 1. the effect of obvious control drug release and prolongation drug effect is arranged; 2. increase the targeting of medicine; 3. reduce the toxic and side effects of institute's entrapped drug; 4. improve stability of drug; 5. improve the permeability of hydrophobic drug cell membrane.
The preparation method of chitosan microball has emulsion-crosslinking method, solvent evaporated method, multi-emulsion method, spray drying method, precipitation/coacervation and chitosan solution pack.Emulsion-crosslinking method is one of the most sophisticated method of preparation chitosan microball, and the microsphere sphere that makes is good, and particle diameter is even, and good swellable is arranged.But owing to used chemical cross-linking agents such as glutaraldehyde or formaldehyde, protein-based cytokine there is certain destruction, makes its application that certain limitation be arranged.Because polypeptide protein class medicine all contains amino, can have an effect and inactivation with the aldehyde radical of cross-linking agent.And adopt precipitation/cohesion rule of Berthold not need cross-linking agent such as organic solvent and glutaraldehyde, and the reaction condition gentleness, operation is simple, and pH is closely neutral, and is less to protein-based cytokine influence.
Summary of the invention
The purpose of this invention is to provide a kind of VEGF chitosan microball, the substrate of microsphere is chitosan (deacetylation 〉=90.0%, viscosity＜100 mPas, available from sigma company), the activated protein of parcel is VEGF (human VEGF 121, available from Pepro-tech company), entrapment efficiency is 74.99%, the dose that bag carries is that every 20mg microsphere contains 0.15-1.45ugVEGF.
The present invention adopts precipitation/coacervation of Berthold to prepare chitosan microball, the reaction condition gentleness, and operation is simple, and pH is closely neutral, and is less to the VEGF influence.
The concentration of chitosan and cross-linking agent sodium polyphosphate is 2.5g/L among the present invention, and volume ratio is 4:1.
A kind of VEGF chitosan microball provided by the invention can be in the application in short vascular endothelial cell proliferation of preparation and the short new vessels growth medicine.Experiment confirm, chitosan microball can carry out good bag to VEGF and carry and seal, and can carry out good control to the release of VEGF in a long time.
Characteristics of the present invention are to utilize chitosan microball as carrier, the parcel VEGF, through experiment confirm, chitosan microball can carry out good bag to VEGF and carry and seal, and can carry out good control to the release of VEGF in a long time.And carrier need not to take out once more after administration, can degrade fully in vivo and metabolism, its catabolite and metabolite are harmless to health, at field of medicaments good prospects for application are arranged, as accelerating osteogenetic process, promote the healing of fracture, quicken the generation of wound surface blood vessel etc.
Description of drawings
Fig. 1 is VEGF chitosan microball atomic force microscope figure (scale 1000 nanometers).
Fig. 2 is VEGF chitosan microball sem photograph (scale 500 nanometers).
Fig. 3 is a VEGF chitosan microball release in vitro curve.
The specific embodiment
The present invention is further described in conjunction with the accompanying drawings and embodiments.
Adopt the Berthold legal system of improvement to be equipped with chitosan microball, method is as follows: get in the glacial acetic acid that the 200mg chitosan is dissolved in 80ml 2%, add 1ml tween 80 magnetic agitation 2 hours, sonic oscillation to solution is clarified.The concentration that slowly drips 20ml under the room temperature magnetic agitation is the cross-linking agent sodium polyphosphate of 2.5mg/ml, magnetic agitation 2 hours.10000rpm/min, centrifugal 15 minutes, gained precipitation pure water centrifuge washing was repeatedly washed 3 times, collects and send lyophilizing to preserve, and obtains barren chitosan microball.The concentration of chitosan and cross-linking agent sodium polyphosphate is 2.5g/L, and volume ratio is 4:1.
The preparation of VEGF chitosan microball: accurately weigh chitosan lyophilizing microsphere 20mg in the EP pipe, add 0.9ml 2% glacial acetic acid and 0.1ml VEGF, sonic oscillation.Place 4 ℃ of shaking tables (135r/min) mixing, 10000rpm/min after 6 hours, centrifugal 15 minutes, precipitation pure water centrifuge washing was repeatedly washed 3 times, and precipitation is sent freezing lyophilizing, and last gained is the VEGF chitosan microball of preparation.Collect centrifugal liquid and washing supernatant.Gained tiny balloon outward appearance is spheroidal, good evenness, and regular particles does not have adhesion, and particle diameter is more even, and how between the 200-300 nanometer, spherome surface is more smooth, and the microsphere surface morphological observation is seen atomic force microscope (referring to Fig. 1) and scanning electron microscope (referring to Fig. 2).The dose that bag carries is that every 20mg microsphere contains 0.15-1.45ugVEGF.
Get embodiment 1 gained centrifugal liquid (1ml), wash supernatant (1ml) at every turn, with 50 times of PBS dilutions, get 1ml in centrifuge tube as sample to be tested, according to the operation of ELISA test kit description, measure its absorbance (A450) value.According to VEGF concentration in the normal equation calculation sample of standard curve, thus VEGF total amount in the centrifugal liquid of extrapolating, washing supernatant and the amalgamation liquid.
Table 1 sample VEGF concentration determination
The VEGF concentration determination of table 2 titer
Drawing concentration of standard solution linear equation: y=0.0014x+0.1477(x according to table 2 is concentration, y is an absorbance), calculate respective concentration (seeing Table 1), parallel three groups of experiments, the total amount that merges centrifugal liquid and cleaning mixture is respectively 0.096792ug, 0.09758ug, 0.10601ug, meansigma methods is 0.1001ug.
Carrying drug ratio and envelop rate calculate according to following formula:
Use the ELISA test kit to detect VEGF concentration, method is easy, the accuracy height.Remain the VEGF amount in the cleer and peaceful centrifuge washing liquid by measuring, thereby infer VEGF amount mensuration carrying drug ratio and the envelop rate that wraps up microsphere.After measured, the entrapment efficiency of this microsphere is 74.99%, and carrying drug ratio is about 15ug/g.
This studies show that chitosan microball can carry out good bag to VEGF and carry and seal.
The external release Journal of Sex Research of embodiment 3 VEGF chitosan microballs
Weighing VEGF-chitosan microball 20 mg add 1ml PBS in centrifuge tube, 37 ℃ of mixings, and respectively at 1,5,10 h and 1,2,3,5,7 d get and continue mixing after supernatant 150ul replenishes 150ul PBS with centrifugal 10 min of 15000 r/min.The institute's supernatant samples of getting-20 ℃ preservation.Each time sample as specimen to be measured, according to the operation of test kit description, is measured the A450 value, calculate corresponding VEGF concentration, extrapolate VEGF content in the sample.
Table 3 different time VEGF concentration determination
The VEGF concentration determination of table 4 titer
Drawing concentration of standard solution linear equation: y=0.0014x+0.1131(x according to table 4 is concentration, and y is an absorbance), calculate respective concentration (seeing Table 3), parallel three groups of experiments.
By drawing the external elution profiles of medicine, can observe, medicine initial stage rate of release is very fast, and in the especially preceding 12-24 h, medicine accumulative total discharges and reaches 29%, and drug release is steady gradually thereafter, discharges to the 7th day and reaches 51%.The release in vitro curve is referring to Fig. 3.
Studies show that chitosan microball can well control the release of VEGF.
Claims (3)
1. VEGF chitosan microball, it is characterized in that, the substrate of microsphere is deacetylation 〉=90.0%, the chitosan of viscosity＜100 mPas, the activated protein of parcel is a VEGF, microspherulite diameter is the 200-300 nanometer, and the activated protein amount that bag carries is that every 20mg microsphere contains 0.15-1.45ug, and envelop rate is 74.99%.
2. a kind of VEGF chitosan microball according to claim 1 is characterized in that the concentration of chitosan and cross-linking agent sodium polyphosphate is 2.5g/L, and volume ratio is 4:1.
3. the application of a kind of VEGF chitosan microball according to claim 1 in short vascular endothelial cell proliferation of preparation and short new vessels growth medicine.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102600506A (en) * | 2012-03-07 | 2012-07-25 | 中国人民解放军第四军医大学 | NGF (nerve growth factor) chitosan microsphere and high-bionic stent slow releasing system and preparation method thereof |
| CN106580718A (en) * | 2016-12-29 | 2017-04-26 | 广州远想生物科技有限公司 | Cell growth factor composition and preparation method thereof, beautifying preparation and application |
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| EP0860166B1 (en) * | 1996-07-29 | 2004-12-29 | ADVANCELL - Advanced In Vitro Cell Tecnologies | Nanoparticles based on hydrophilic polymers as pharmaceutical forms |
| CN1833726A (en) * | 2005-03-18 | 2006-09-20 | 中国科学院过程工程研究所 | Chitosan pellet having bioactivity medicine and prepn. method |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0860166B1 (en) * | 1996-07-29 | 2004-12-29 | ADVANCELL - Advanced In Vitro Cell Tecnologies | Nanoparticles based on hydrophilic polymers as pharmaceutical forms |
| CN1833726A (en) * | 2005-03-18 | 2006-09-20 | 中国科学院过程工程研究所 | Chitosan pellet having bioactivity medicine and prepn. method |
Non-Patent Citations (2)
| Title |
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| 卜寿山等: "碱性成纤维细胞生长因子壳聚糖微球的研制", 《南京中医药大学学报》, vol. 21, no. 02, 31 March 2005 (2005-03-31), pages 101 - 102 * |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102600506A (en) * | 2012-03-07 | 2012-07-25 | 中国人民解放军第四军医大学 | NGF (nerve growth factor) chitosan microsphere and high-bionic stent slow releasing system and preparation method thereof |
| CN102600506B (en) * | 2012-03-07 | 2013-12-04 | 中国人民解放军第四军医大学 | NGF (nerve growth factor) chitosan microsphere and high-bionic stent slow releasing system and preparation method thereof |
| CN106580718A (en) * | 2016-12-29 | 2017-04-26 | 广州远想生物科技有限公司 | Cell growth factor composition and preparation method thereof, beautifying preparation and application |
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