CN109646450A - Purposes of the DNA tetrahedron in preparation treatment corneal injury drug - Google Patents
Purposes of the DNA tetrahedron in preparation treatment corneal injury drug Download PDFInfo
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Abstract
In order to solve the problems, such as that current corneal injury lacks specific drug, the present invention provides purposes of the DNA tetrahedron in preparation treatment corneal injury drug, and the DNA tetrahedron is by the single-stranded tetrahedron nanostructure formed by base pair complementarity of four DNA.The present invention can effectively facilitate regeneration, realize the healing of corneal damage, and have no toxic side effect, and preparation process is simple.
Description
Technical field
The present invention relates to opthalmological fields, in particular to use of the DNA tetrahedron in preparation treatment corneal injury drug
On the way.
Background technique
Corneal injury is clinical common and handles intractable one of eye traumas, based on chemical burn, and in chemical burn
Most commonly alkali burn.Aseptic ulcer of the cornea, perforation, eyeball adhesion and secondary glaucoma for occurring after corneal injury etc.
The even more common cause disabled of eye.
Clinically the therapeutic modality of corneal injury includes thoroughly cleaning conjunctival sac, subconjunctival injection vitamin C, atropic in time
Eye etc. is suffered from product mydriasis, part and whole body antibacterial anti-inflammatory, nutrition cornea, amnion transplantation, autohemotherapy, covering, but these drugs are only
The state of an illness can slightly be alleviated, therapeutic effect is poor.
There is research using corticosteroid treatment corneal injury, it makees with anti-inflammatory and immunosupress as the result is shown
With with certain therapeutic effect.But corticosteroid hormone can inhibit regeneration, and have other potential secondary works
With generally therapeutic effect is still inadequate.
Summary of the invention
The object of the present invention is to provide a kind of new treatment corneal injury drugs.
Present invention firstly provides purposes of the DNA tetrahedron in preparation treatment corneal injury drug, the DNA tetrahedrons
It is by the single-stranded tetrahedron nanostructure formed by base pair complementarity of four DNA；Preferably, the damage is alkali burn.
Further, the DNA tetrahedron is single-stranded through 90~98 DEG C of denaturation 10~15min, 2~8 by four DNA
DEG C annealing 20~30min be prepared.
Further, the DNA tetrahedron is single-stranded through 95 DEG C of denaturation 10min, 4 DEG C of annealing 20min by four DNA
It is prepared.
Further, a length of 10-100bp of the tetrahedral rib of the DNA.
Further, the tetrahedral four single-stranded sequences of the DNA are formed as shown in NO.1~4 SEQ ID.
Further, the drug is eye drops.
Further, the use concentration of the drug is 100~500nM.
Further, the use concentration of the drug is 250nM.
The present invention also provides a kind of drug for treating corneal injury, the drug is with DNA tetrahedron above-mentioned for work
Property ingredient is prepared plus pharmaceutically acceptable auxiliary material；Preferably, the damage is alkali burn.
Further, the drug is eye drops.
Inventor is by providing a kind of different from conventional medicament pharmacology to corneal injury and the tetrahedral research of DNA
Drug.Conventional medicament is mainly by anti-inflammatory, so that cornea voluntarily restores, effect is poor；And the present invention then has promotion corneal epithelium
The effect of cell Proliferation and migration, the effect for treating corneal injury are preferable.
The invention has the following beneficial effects:
1) DNA tetrahedron of the invention is safe and non-toxic；
2) DNA tetrahedron of the invention can promote the proliferation and migration of corneal epithelial cell；
3) four sides DNA physical efficiency of the invention promotes regeneration, and then promotes corneal epithelium healing；
4) DNA tetrahedron synthetic method of the invention is simple.
Obviously, above content according to the present invention is not being departed from according to the ordinary technical knowledge and customary means of this field
Under the premise of the above-mentioned basic fundamental thought of the present invention, the modification, replacement or change of other diversified forms can also be made.
Above content of the invention is described in further detail again below by way of specific embodiment.But it should not be by this
The range for being interpreted as the above-mentioned theme of the present invention is only limitted to example below.All technologies realized based on above content of the present invention are equal
Belong to the scope of the present invention.
Detailed description of the invention
The schematic diagram of Fig. 1: DNA tetrahedron synthesis.
Fig. 2: DNA tetrahedron transmission electron microscope detection figure.
Fig. 3: DNA tetrahedron dynamic light scattering detects grain size distribution.
Fig. 4: three migration tests；A, cell scratch test；B, transwell test violet staining result；C, cell
Scratch test for 24 hours quantitative statistics as a result, D, transwell test statistics as a result, E, RTCA test result.
Fig. 5: three proliferation tests；A, CCK-8 test result；B, RTCA test result；The examination of C, BrdU immunofluorescence dyeing
Test result.
Fig. 6: rabbit cornea damages curative effect figure；A, the substantially sight of lagophthalmos after corneal injury；B, the scoring of clinical examination
Statistical result, the cornea light transmittance scoring of 7 days 8 rabbits；The cornea of C, the scoring statistical result of clinical examination, 14 days 4 rabbits are saturating
Luminosity scoring；D, the scoring statistical result of clinical examination, the corneal epithelium healing rate of 7 days 8 rabbits；E, the scoring system of clinical examination
Count the corneal epithelium healing rate as a result, 14 days 4 rabbits.
Specific embodiment
The tetrahedral preparation of embodiment DNA and identification
1. method
The preparation method of 1.1 DNA tetrahedrons (TDN)
TDN is to pass through a quick, simple, specific PCR by four DNA single-stranded (S1, S2, S3, S4) of unique design
Program (95 DEG C of maintenance 10min, fast cooling to 4 DEG C of maintenance 20min, 4 DEG C of long-term preservations) self assembly.Four single-stranded to press
TM buffer (the 10mM containing 96 μ l is added to according to equimolar ratio (every single-stranded storing liquid that 1 μ l concentration is added and is 100 μM)
Tris-HCl, 50mM MgCl2, pH 8.0) 200 μ l EP pipes in, reaction solution is heated to 95 DEG C of maintenance 10min, then fastly
Speed cools to 4 DEG C and has synthesized TDN.
1.2 4 single-stranded particular sequences of DNA are as follows:
1.3 polyacrylamide gel electrophoresises, dynamic light scattering (DLS), atomic force microscope (AFM), transmission electron microscope (TEM)
TDN is characterized with charge measurement:
1. DLS: the TDN being synthesized is diluted to 250nM with secondary distilled water and then carries out on ZETAPals analyzer
Observation.
2. AFM: it is by under tapping scan pattern that atomic force microscope, which carries out characterization to the surface topography of TDN nano particle,
What Shimadzu SPM-9700 atomic force microscope was completed.TDN is diluted to 20nM with TM buffer solution, then being somebody's turn to do 10 μ l
Solution drop, wait do about 15min, is then observed on fresh mica sheet.
3. TEM: transmission electron microscope observes the microstructure of TDN, the distribution that display TDN nano material is partial size 10nm
Uniform little particle.
4. Zeta potential: using Zetasizer Nano ZS90 (Malvem Instruments Ltd, U.K.)
Measure single-stranded, TDN current potential.
2. result
There is tetrahedral structure under the visual field in transmission electron microscope, shows that DNA tetrahedron assembles successfully (Fig. 2).Dynamic light scattering knot
Fruit shows that tetrahedral partial size is about 10nm (Fig. 3).From the above results, it can be seen that, the synthesis of TDN is successful.
1 Cell migration assay of experimental example
Wound healing is dynamic, stringent orderly biological process, and re-epithelialization plays very important work wherein
With.The re-epithelialization of the surface of a wound depends on migration of the epithelial cell from edge of wound to surface of a wound center.In order to probe into whether TDN helps
In the migration of Human glioma, inventor implements following experiment.
1. method
Scratch test, the influence of transwell test and RTCA method detection TDN to the migration of Human glioma.
Scratch test: by cell with 1.5 × 105The density in a/hole is inoculated into 12 orifice plates and is cultivated, when cell is paved with
After 80-90%, the scratch that twice intersect vertically is marked with sterile rifle point, after washing cell fragment, TDN concentration, which is added, is
The cell culture medium person of 125nM, 250nM, 375nM are test group, and it is control group that the cell culture medium person without TDN, which is added,.?
0h, 12h acquire the image that scratch is closed for 24 hours, carry out qualitative and semi-quantitative analysis.
Transwell test: 8 μm of transwell choice of membrane pore size.5 are inoculated in the upper chamber of the 24 hole cells transwell
×104The cell in a/hole, culture volume are that growth medium is substituted for the tire ox blood containing 1% after culture for 24 hours by 250 μ l
The DMEM culture medium of cleer and peaceful 125nM and 250nM TDN, this group are experimental group；Control group is changed to the fetal calf serum and not containing 1%
DMEM culture medium containing TDN.After 24 hours, PBS rinses cell 3 times of migration, after fixing 20min with methanol, violet staining
And figure is adopted, analyze migrating cell number in experimental group and control group.
RTCA migration test: the culture medium that 165 μ l contain 1% fetal calf serum, upper layer are added in lower layer's orifice plate of RTCA
30 μ l of identical component culture medium is added in orifice plate, after upper and lower plates sub-portfolio installs, is put into cell incubator and stands 1 hour.1
As a child, cell suspension and TDN solution is added, makes cell-seeding-density 5 × 104A/hole, TDN concentration be 0nM, 125nM and
250nM.RTCA instrument detects for 24 hours in total every the cell migration situation of detection in 15 minutes, generates migration curve.
2. result
In cell scratch test, it is seen that 12h and for 24 hours when, test group cell migration number be greater than control group, be in TDN concentration
250nM group, cell migration are most fast (Fig. 4 A, C).
In Transwell test, the violet staining picture after 24 hours shows that TDN can promote cell migration, and
Facilitation is most strong (Fig. 4 B, D) when 250nM.
In RTCA test, the continuous migration situation for detecting cell for 24 hours, curve shows that TDN can stablize promotion corneal epithelium
The migration of cell, and TDN concentration be 250nM when can play the best use (Fig. 4 E).
2 cell proliferation experiment of experimental example
1. method
The proliferation behavioral implications of TDN corneal epithelial cell is detected, We conducted three tests.
CCK-8 test: cell is with 5 × 103The density in a/hole is inoculated in 96 orifice plates, for 24 hours using growth medium culture
Afterwards, it is changed to the serum free medium containing various concentration (0nM, 125nM, 250nM, 375nM) TDN, in 6h, 12h, for 24 hours,
36h carries out cck-8 photometric analysis of extinction test according to cck-8 product application method respectively, and carries out statistical using SPSS
Analysis.
BrdU cell proliferation test: corneal epithelial cell is with 1 × 104The density of a/ml is inoculated in the burnt capsule of copolymerization, is used
After growth medium culture 24, culture medium is changed to the culture medium containing 10 μm of BrdU and various concentration (0nM, 250nM) TDN,
After for 24 hours, culture medium is sucked, after being rinsed with PBS, carries out acidolysis, immunofluorescence dyeing.Analysis immunofluorescence picture is to study proliferation
Situation.
RTCA cell proliferation test: by cell with 4 × 103The density in a/hole is inoculated in 16 orifice plates, growth medium training
It supports overnight, second day replacement culture medium, the concentration of TDN has 0nM, 125nM and 250nM.It is bent according to proliferation after continuous detection 65h
The rule of proliferation of line analysis corneal epithelial cell.
2. result
Above three proliferation tests, which demonstrate TDN, can promote the proliferation of corneal epithelial cell, and concentration is in 250nM
The result (Fig. 5) of best effort concentration.
Experimental example 1 and experimental example 2 the result shows that, DNA tetrahedron can promote the proliferation and migration of corneal epithelial cell,
It can promote the migration of endothelial cell.
3 zoopery of experimental example
1. method
1.1 corneal injury modelings
Use 2.5~3kg New Zealand White Rabbit as experimental animal, manufacture internal model of alkali burned, concrete operations are as follows: rabbit into
The anesthesia of row flesh pine, eye, which drips 10g/L dicaine, makees the anesthesia of 3 subsurfaces, and the filter paper for being soaked with NaOH is attached at cornea with ophthalmic tweezers
It is removed behind center, with cornea close contact 20s, uses normal saline flushing anterior corneal surface and conjunctival sac 1min immediately.Form cornea
The clear discoid white damage zone in central boundary.
1.2 drug-treated
Animal pattern totally 8, left eye is control group, and right eye is test group, does following processing:
Test group: with 250nMDNA tetrahedron (TDN) eye drops of normal saline；Control group: physiological saline, every time
One drop, six times per day.
It puts to death after 4 test rabbit medication 7d, is put to death after 4 test rabbit medication 14d of residue.Observe control group and test group angle
The speed and cornea translucency of film associated with epithelial healing.
2. result
The cornea translucency (Fig. 6 A, B, C) and corneal epithelium healing rate (Fig. 6 A, D, E) of clinical assessment, it is seen that use TDN
The cornea of eye drip treatment, the speed of corneal healing are faster than control group, and final healing effect is also superior to control group.
Show that TDN can effectively facilitate the healing of corneal damage.
To sum up, DNA tetrahedron can effectively facilitate regeneration, realize the healing of corneal damage, and have no toxic side effect, system
Standby process is simple；DNA tetrahedron has very excellent industrialization prospect in the preparation of corneal injury drug.
SEQUENCE LISTING
<110>Huaxi Hospital Attached to Sichuan Univ
<120>purposes of the DNA tetrahedron in preparation treatment corneal injury drug
<130> CD007-701012531
<160> 4
<170> PatentIn version 3.5
<210> 1
<211> 63
<212> DNA
<213>artificial sequence
<400> 1
atttatcacc cgccatagta gacgtatcac caggcagttg agacgaacat tcctaagtct 60
gaa 63
<210> 2
<211> 63
<212> DNA
<213>artificial sequence
<400> 2
acatgcgagg gtccaatacc gacgattaca gcttgctaca cgattcagac ttaggaatgt 60
tcg 63
<210> 3
<211> 63
<212> DNA
<213>artificial sequence
<400> 3
actactatgg cgggtgataa aacgtgtagc aagctgtaat cgacgggaag agcatgccca 60
tcc 63
<210> 4
<211> 63
<212> DNA
<213>artificial sequence
<400> 4
acggtattgg accctcgcat gactcaactg cctggtgata cgaggatggg catgctcttc 60
ccg 63
Claims (10)
- Purposes of the 1.DNA tetrahedron in preparation treatment corneal injury drug, the DNA tetrahedron are single-stranded logical by four DNA Cross the tetrahedron nanostructure of base pair complementarity formation；Preferably, the damage is alkali burn.
- 2. purposes as described in claim 1, which is characterized in that the DNA tetrahedron be by four DNA it is single-stranded through 90~ 98 DEG C of 10~15min of denaturation, 2~8 DEG C of 20~30min of annealing are prepared.
- 3. purposes as claimed in claim 2, which is characterized in that the DNA tetrahedron is single-stranded through 95 DEG C by four DNA Denaturation 10min, 4 DEG C of annealing 20min are prepared.
- 4. purposes as described in claim 1, which is characterized in that a length of 10-100bp of the tetrahedral rib of DNA.
- 5. purposes as described in claim 1, which is characterized in that form the tetrahedral four single-stranded sequences of the DNA such as SEQ Shown in NO.1~4 ID.
- 6. purposes as described in claim 1, which is characterized in that the drug is eye drops.
- 7. purposes as claimed in claim 4, which is characterized in that the use concentration of the drug is 100~500nM.
- 8. purposes as claimed in claim 5, which is characterized in that the use concentration of the drug is 250nM.
- 9. a kind of drug for treating corneal injury, which is characterized in that the drug is as described in Claims 1 to 5 is any DNA tetrahedron is prepared for active constituent, plus pharmaceutically acceptable auxiliary material；Preferably, the damage is alkali burn.
- 10. drug as claimed in claim 9, which is characterized in that the drug is eye drops.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111588730A (en) * | 2020-06-10 | 2020-08-28 | 中山大学中山眼科中心 | Application of FL2-siRNA in preparing medicine for treating corneal alkali burn and corneal alkali burn medicine |
| CN112007044A (en) * | 2019-09-10 | 2020-12-01 | 四川大学 | Medicine for preventing oxidative stress of retinal ganglion cells and wet macular degeneration |
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| CN107881149A (en) * | 2017-11-22 | 2018-04-06 | 四川大学 | Application of the DNA tetrahedrons during differentiation and proliferation of neural stem cells is promoted |
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| CN108546730A (en) * | 2018-04-19 | 2018-09-18 | 四川大学 | Application of the DNA tetrahedrons in promoting mouse neural stem cells migration |
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2019
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Patent Citations (5)
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| CN102643827A (en) * | 2012-04-10 | 2012-08-22 | 上海交通大学 | 4*Tbeta4 gene and method for expressing 4*Tbeta 4 protein in tobaccos |
| CN103145851A (en) * | 2013-02-22 | 2013-06-12 | 暨南大学 | Recombinant protein PACAP38-NtA, and coding gene and application thereof |
| CN107881149A (en) * | 2017-11-22 | 2018-04-06 | 四川大学 | Application of the DNA tetrahedrons during differentiation and proliferation of neural stem cells is promoted |
| CN107961243A (en) * | 2017-11-23 | 2018-04-27 | 四川大学 | Application of the DNA tetrahedrons in terms of Induces Autophagy |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112007044A (en) * | 2019-09-10 | 2020-12-01 | 四川大学 | Medicine for preventing oxidative stress of retinal ganglion cells and wet macular degeneration |
| CN111588730A (en) * | 2020-06-10 | 2020-08-28 | 中山大学中山眼科中心 | Application of FL2-siRNA in preparing medicine for treating corneal alkali burn and corneal alkali burn medicine |
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