CN107739506A - Light-operated nitric oxide production composite film material of release and its preparation method and application - Google Patents
Light-operated nitric oxide production composite film material of release and its preparation method and application Download PDFInfo
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Abstract
The invention discloses a kind of light-operated nitric oxide production composite film material of release and its preparation method and application.The preparation method of the material comprises the following steps：First synthesize spherical dendroid daiamid (N N PAMAM D3), then uniform particle diameter golden nanometer particle surface modification N N PAMAM D3, the nanogold of N N PAMAM modifications is prepared, then nitric oxide is loaded, obtain the light-operated nitric oxide production composite film material of release.By the nitric oxide production composite film material of light-operated release and the lyophilized compacting film forming of polycaprolactone (PCL) blending, can obtain can under near-infrared laser irradiation control release nitric oxide production composite film material.The material particle size is homogeneous, and response is sensitive, and NO loads and storage capacity are big, and release time length, biocompatibility is good, can be applied to biological medicine engineering material field, and the material can effectively suppress the growth and breeding of bacterium and fungi, available for preparing antibacterials.
Description
Technical field
The invention belongs to bio-medical engineering material field, more particularly to a kind of light-operated nitric oxide production compound film material of release
Material and its preparation method and application.
Background technology
Find that vascular endothelial cell can synthesize, secrete blood vessel endothelium derivative relaxing factor from Furchgott in 1980 etc.
(EDRF) since, the proof EDRF of two people's independences of Furchgott in 1986 and Ignarro is NO, about NO basis and face
Bed research is flourished, and NO turns into one of most noticeable biomolecule in recent years.Substantial amounts of research shows that NO is
Important biological messenger molecule, the processes such as regulation of blood vessels, neurotransmission, inflammation and immune response being participated in, its is widely distributed, throughout
A variety of organs such as brain, blood vessel, immune, lung, reproduction.
Discovered in recent years NO can destroy the cell membrane of bacterium and gene information and prevent bacterium from obtaining energy, have efficient
It is antibacterial and be not likely to produce the characteristics such as drug resistance, receive more and more attention its application in antibacterial field, more and more
Releasable NO novel antibacterial material is appeared in the visual field of people.
Such as：Smith etc. proposed to be used for making by nucleophic NO donor N-diazeniumdiolate first in 1996
Standby releasable NO polymeric material (Chemistry 1996,39:1148-1156), but the NO donors of small molecule
Diazeniumdiolates is to be disperseed by way of noncovalent interaction in the polymeric material, so as to cause donor to hold
Easily come off from polymeric matrix, non-degradable, produce carcinogen nitrosamine；(the International such as Jong Oh Kima
Journal of Biological Macromolecules 2015,79:The chitosan for 217-225) being prepared for releasable NO is thin
Film, for the research in terms of antibacterial and its wound healing, research shows that NO can actually effectively suppress the growth of bacterium and numerous
Grow, have obvious effect simultaneously for the healing of wound.(the Advanced Healthcare such as Dongsik Park
Materials 2016,5:Releasable NO poly-dopamine hollow Nano microballoon 2019-2024) is prepared for, for antibiosis
Research, research show that NO can effectively destroy the cell membrane of bacterium, cause bacterial death.Although NO shows excellent resist
Bacterium effect and drug resistance is not likely to produce, but NO, because gas property and half-life short, material load NO content are too low, NO is difficult to
The problems such as long-time storage, so that its application clinically receives great obstruction.It is local accordingly, with respect to NO fixed point
Control release turns into the indispensable characteristic in NO delivery systems, more urgently to be resolved hurrily as current biological engineering in medicine field
Important topic.So far, by golden composite film material (Au) surface with spherical dendritic interphase (N-N-PAMAM)
Carry out modification and be used as NO donors, then coated with polycaprolactone (PCL), freeze compacting film forming, finally prepare surface and cover
Golden composite film material is covered, spherical dendritic interphase is matrix, and outermost layer is the thin-film material of polycaprolactone, in near-infrared
There is not been reported for the lower nitric oxide production film composite material of control release of laser irradiation and its application.
The content of the invention
The shortcomings that primary and foremost purpose of the present invention is to overcome prior art and deficiency, there is provided a kind of light-operated release nitric oxide
Composite film material preparation method.
The nitric oxide production compound film material of light-operated release being prepared another object of the present invention is to provide methods described
Material.
A further object of the present invention is the application for providing the light-operated nitric oxide production composite film material of release.
The purpose of the present invention is achieved through the following technical solutions：A kind of system of the light-operated nitric oxide production composite film material of release
Preparation Method, comprise the following steps：
(1) 3 generation ethylenediamine is the N-N-PAMAM primitives (N-N-PAMAM-D of core3) synthesis
A, the methanol solution of ethylenediamine is instilled in the methanol solution of methyl acrylate under the conditions of ice-water bath, stirred,
It is warming up to and reaction is stirred at room temperature, obtains N-N-PAMAM-D0.5(0.5 generation ethylenediamine is core PAMAM primitives)；Will under the conditions of ice-water bath
It is dissolved in methanol, then is instilled in the methanol solution of ethylenediamine, is stirred, and is warming up to and reaction is stirred at room temperature, obtain N-N-
PAMAM-D1(1 generation ethylenediamine is the N-N-PAMAM primitives of core)；
B, the N-N-PAMAM-D that will be obtained in step a1Instead of ethylenediamine, repeat step a operations, N-N-PAMAM-D is obtained2
(2 generation ethylenediamines are the PAMAM primitives of core)；Again with N-N-PAMAM-D2(2 generation ethylenediamines are the PAMAM primitives of core) replaces second two
Amine, repeat step a operations, obtains N-N-PAMAM-D3(3 generation ethylenediamines are the dendritic interphase of core)；
(2) preparation of the nanogold material (Au@N-N-PAMAM) of N-N-PAMAM modifications
The N-N-PAMAM-D that will be obtained in step (1) b3(3 generation ethylenediamines are the dendritic interphase of core) is dissolved into
In water, gold chloride (HAuCl is added dropwise4), it is stirred under room temperature condition, adds NaBH4(sodium borohydride) continues to stir,
Dialysis, dry, obtain Au@N-N-PAMAM (the nanogold material of N-N-PAMAM modifications)；
(3) synthesis of the light-operated nitric oxide production composite film material (Au@N-N-PAMAM/NONOate) of release
The Au@N-N-PAMAM obtained in step (2) are dissolved in absolute methanol, sodium methoxide ultrasound is then added and stablizes 10
~30min, then NO gases are passed through, room temperature is reacted, and after reaction terminates, is washed, is dried, and it is nitric oxide production to obtain light-operated release
Composite film material (Au@N-N-PAMAM/NONOate).
The temperature of room temperature described in step (1) a, (2) and (3) is 5~35 DEG C.
The temperature of ice-water bath described in step (1) a is 0 DEG C.
The time of stirring reaction described in step (1) a is all 12~48h.
Ethylenediamine described in step (1) a is the ethylenediamine (anhydrous ethylenediamine) after drying process.
Described anhydrous ethylenediamine is prepared preferably by following steps：Anhydrous potassium hydroxide is added to ethylenediamine
Middle stirring 6~24 hours, is then evaporated under reduced pressure, obtains anhydrous ethylenediamine；The addition of described anhydrous potassium hydroxide presses every liter
Ethylenediamine matches 2~4 grams of anhydrous potassium hydroxide and calculated.
Methyl acrylate described in step (1) a is the methyl acrylate (anhydrous methyl acrylate) after drying process.
Described anhydrous methyl acrylate is prepared preferably by following steps：Anhydrous sodium sulfate is added to propylene
Stirred 6~24 hours in sour methyl esters, then air-distillation, obtain anhydrous methyl acrylate；The addition of described anhydrous sodium sulfate
Amount matches 2~4 grams of anhydrous sodium sulfates by every liter of methyl acrylate and calculated.
The methanol solution of ethylenediamine described in step (1) a is methanol and ethylenediamine by volume 10:1~5 proportioning obtains
Solution.
The methanol solution of methyl acrylate described in step (1) a is methanol and methyl acrylate by volume 10:1~5
Match obtained solution.
The mol ratio 1 of ethylenediamine and methyl acrylate described in step (1) a:4~8 (ethylenediamine enters with methyl acrylate
Row reaction when both mol ratio).
N-N-PAMAM-D described in step (1) a0.5Mol ratio with ethylenediamine is 1:4~24；Preferably 1:4~12
(N-N-PAMAM-D0.5Mol ratio both when being reacted with ethylenediamine).
N-N-PAMAM-D described in step (1) a0.5Dosage is to match 0.5~5g N-N-PAMAM- by every ml methanol
D0.5Calculate.
N-N-PAMAM-D described in step (1) b1Mol ratio with methyl acrylate is preferably 1:8~16.
Described in step (1) b with N-N-PAMAM-D1Instead of ethylenediamine, the intermediate product of repeat step a operation acquisitions
N-N-PAMAM-D1.5Mol ratio with ethylenediamine is preferably 1:8~24.
N-N-PAMAM-D described in step (1) b2Mol ratio with methyl acrylate is preferably 1:16~32.
Described in step (1) b with N-N-PAMAM-D2Instead of ethylenediamine, the intermediate product of repeat step a operation acquisitions
N-N-PAMAM-D2.5Mol ratio with ethylenediamine is preferably 1:16~48.
Dissolving described in step (2) is preferably ultrasonic dissolution.
The time of stirring described in step (2) is preferably 0.5~24h.
The time for continuing stirring described in step (2) is preferably 2~4h.
Dialysis described in step (2) is to be dialysed in bag filter；Preferably molecular cut off be 3000~
Dialysed in 5000 bag filter；More preferably dialysed 1~3 day in the bag filter that molecular cut off is 3000~5000.
The condition of drying described in step (2) is：Dried 12~48 hours under the conditions of 50~80 DEG C；Preferably：First
Freeze-drying, then dried 12~48 hours in 50~80 DEG C of vacuum drying chamber.
N-N-PAMAM-D described in step (2)3, gold chloride and sodium borohydride mol ratio be 1:20~50：100~
250。
N-N-PAMAM-D described in step (2)3Dosage match 0.2~1mg N-N-PAMAM-D by every milliliter of water3Meter
Calculate.
Water described in step (2) is preferably ultra-pure water.
Absolute methanol described in step (3) is preferably made by the steps to obtain：Calcium hydride is added in methanol,
Stirring 6~24 hours, then air-distillation, obtains absolute methanol；The dosage of described calcium hydride matches 2~4 by every liter of methanol
Gram calcium hydride calculates.
The mol ratio of Au@N-N-PAMAM and sodium methoxide described in step (3) are 1:400~450.
The addition of sodium methoxide described in step (3) by its in final concentration of 5~20% (w/w) of the reaction system based on
Calculate.
The dosage of Au N-N-PAMAM described in step (3) matches 0.05~0.2g Au by every milliliter of absolute methanol
N-N-PAMAM is calculated.
Reaction described in step (3) is to be reacted in autoclave；Realized preferably by following steps：First lead to
Enter after high pure nitrogen maintenance reaction kettle (10~20psi) 5~15min excludes the air in reactor and reacted again, reaction knot
Shu Hou, then it is passed through 10~20psi high pure nitrogen maintenance 10~20min discharges NO.
The time of reaction described in step (3) is preferably 3~7 days.
Washing described in step (3) is to be washed with absolute methanol and ice absolute ether；Preferably first with without water beetle
Alcohol washs 1~3 time, then is washed 1~2 time with ice absolute ether.
A kind of light-operated nitric oxide production composite film material of release, is prepared by the method described in any of the above-described.
A kind of nitric oxide production composite film material of light-operated release of polycaprolactone cladding, is coated by PCL (polycaprolactone)
The above-mentioned light-operated nitric oxide production composite film material of release obtains.
The preparation method of the nitric oxide production composite film material of light-operated release of described polycaprolactone cladding, including following step
Suddenly：
(I) PCL (polycaprolactone) is added in DMF (DMF) and chloroform mixed solution, stirred
Mix uniformly, obtain PCL solution；
(II) above-mentioned Au@N-N-PAMAM/NONOate (the light-operated nitric oxide production composite film material of release) are distributed to step
Suddenly in the PCL solution obtained in (I), solvent flashing is then stirred for, obtains the light-operated release nitric oxide of polycaprolactone cladding
Composite film material (Au@N-N-PAMAM/NONOate@PCL).
The molecular weight of PCL (polycaprolactone) described in step (I) is preferably 5000~50000.
The volume ratio of N,N-dimethylformamide (DMF) and chloroform described in step (I) is 1:1~4.
The time of stirring described in step (I) is 1~2h.
The concentration of PCL solution described in step (I) is mass percent 5~30%.
The PCL and Au@N-N-PAMAM/NONOate (the light-operated nitric oxide production composite membranes of release described in step (I)
Material) mass ratio be 1:0.05~5.
Disperse to realize preferably by following steps described in step (II)：First 100~300W ultrasonic vibrations 30~
After 60min, it is subsequently placed in ice bath, 1~3KW ultrasonic cell disruptor ultrasounds, 5~30min.
The time of stirring described in step (II) is preferably 5~24h.
The light-operated release of the described nitric oxide production composite film material of light-operated release or polycaprolactone cladding is nitric oxide production
Application of the composite film material in bio-medical engineering material.
The light-operated release of the described nitric oxide production composite film material of light-operated release or polycaprolactone cladding is nitric oxide production
Application of the composite film material in antibacterials are prepared.
Described antibacterials include suppressing bacterium and the growth of fungi and the medicine of breeding.
Described bacterium is preferably staphylococcus aureus.
The light-operated release of the described nitric oxide production composite film material of light-operated release or polycaprolactone cladding is nitric oxide production
Composite film material can be also used for preparing the medicine for promoting wound healing and anti-inflammatory.
The present invention is had the following advantages relative to prior art and effect：
(1) the preparation side of the present invention nitric oxide production composite film material material of control release under near-infrared laser irradiation
Method；This method reaction preparation synthesizes spherical dendritic interphase (N-N-PAMAM)；Then the Jenner of uniform particle diameter is prepared
Rice corpuscles, and by certain chemical method in its surface modification N-N-PAMAM, the nanogold of N-N-PAMAM modifications is prepared,
Nitric oxide is loaded in autoclave, obtains the Au composite film materials of spherical dendritic interphase modification as an oxidation
Nitrogen donor
(Au@N-N-PAMAM/NONOate)；Then it is Au N-N-PAMAM/NONOate is scattered in organic solvent with gathering
The lyophilized compacting film forming of caprolactone (PCL) blending, finally give can under near-infrared laser irradiation control release it is nitric oxide production thin
Film composite antibacterial material.
(2) present invention greatly improves NO load capacity using the spherical polyamide-amide of high algebraically as NO donors, for
The influence of bacterial biof iotalm has obvious inhibition, and can be good at absorption and certain killing to electronegative bacterium
Effect.
(3) present invention is echoed dendroid polyester-polyamide-amine with nanogold using one pot of hair, and reaction efficiency is high, structure is easy
It is single in accuracy controlling, molecular weight distribution.
(4) present invention quick under near-infrared laser irradiation can raise temperature, have to bacterium certain using Au as core
Fragmentation effect, and surface PCL coatings are quickly dissolved, make the cationic polymer for having loaded NO exposed outside, serve control
System release NO effect.
(5) for the present invention using Au as core, outer layer is that cationic polymer polyamide-amide can be adsorbed effectively largely carefully
Bacterium, greatly improve bactericidal effect.
(6) NO donors can be wrapped in inside by the present invention well using PCL as face coat hydrophobic material, protection with
Store substantial amounts of NO；And fusing point is relatively low, near-infrared irradiation under can quick response, so as to carry out its material intelligent response effect；
PCL soft textures, it can be made into various shapes material, film-type, spheroidal, cube etc..
(7) material of the present invention is in addition to the cytotoxicity for advantageously reducing product, and it is as antibacterials controlled release carrier, anti-
There is potential application value in the field of transmitting to bacterium medicine altogether.
(8) the NO donor products obtained in the present invention possess the growth and breeding for effectively suppressing bacterium and fungi, to common
Pathogenic bacteria, dermatophyte, wound infection bacterium etc. there is significant inhibition, and with promoting the work(such as wound healing and anti-inflammatory
Can, provide support in the application for preparing biological medicine engineering material for it.
(9) present invention, which provides one kind, can store a large amount of NO, and the novel antibacterial material of control release according to demand；This is received
Rice material particle size is homogeneous, and response is sensitive, and NO loads and storage capacity are big, and release time length, biocompatibility is good, and fungistatic effect is bright
It is aobvious, important application prospect is shown in antibiosis.
Brief description of the drawings
Fig. 1 is the structural representation of composite film material of the present invention.
Fig. 2 is Au@N-N-PAMAM, Au and N-N-PAMAM potential diagram.
Fig. 3 is Au@N-N-PAMAM, Au and N-N-PAMAM the heating curve figure under near-infrared irradiation.
Fig. 4 is that Au@N-N-PAMAM/NONOate@PCL discharge NO curve maps at different conditions.
Fig. 5 is to compare Au@N-N-PAMAM@PCL and Au@N-N-PAMAM under laser irradiation to Escherichia coli by turbidity
Fungistatic effect figure；Wherein, 1 Au@N-N-PAMAM/NONOate+808nm are represented, 2 represent Au@N-N-PAMAM/NONOate@PCL
+ 808nm, 3 represent blank control.
Embodiment
With reference to embodiment, the present invention is described in further detail, but the implementation of the present invention is not limited to this.
1st, the preparation method of absolute methanol used in following examples is according to following operating procedure：Calcium hydride is added to
In methanol, stir 6~24 hours, then air-distillation, obtain absolute methanol, the addition of the calcium hydride is with every 500mL first
1~2 gram of meter is added in alcohol.
2nd, methyl acrylate used in following examples is anhydrous methyl acrylate, the preparation side of anhydrous methyl acrylate
Method is according to following operating procedure：Anhydrous sodium sulfate is added in methyl acrylate and stirred 6~24 hours, then air-distillation,
Anhydrous methyl acrylate is obtained, the addition of the anhydrous sodium sulfate in every 500mL methyl acrylates to add in terms of 1~2 gram.
3rd, it is anhydrous ethylenediamine that following examples, which use ethylenediamine, and the preparation method of anhydrous ethylenediamine is according to following operation
Step：Anhydrous potassium hydroxide is added in ethylenediamine and stirred 6~24 hours, is then evaporated under reduced pressure, obtains anhydrous ethylenediamine, institute
The addition of anhydrous potassium hydroxide is stated to be added in every 500mL ethylenediamines in terms of 1~2 gram.
4th, the Au@N-N-PAMAM dried used in following examples preparation method is according to following operating procedure：Will
Au@N-N-PAMAM are placed in vacuum drying chamber, are dried 12~48 hours under the conditions of 40~80 DEG C.
Embodiment 1
The synthesis of (1) 3 generation spherical dendritic interphase：
Ethylenediamine is dissolved in methanol at 0 DEG C of ice-water bath, then instilled in the methanol solution of methyl acrylate, is stirred,
25 DEG C of stirring reaction 12h are warming up to, it is core PAMAM primitives (N-N-P AMAM-D to obtain 0.5 generation ethylenediamine0.5)；Will under ice-water bath
N-N-PAMAM-D0.5It is dissolved in methanol, instills in the methanol solution of ethylenediamine, stir, is warming up to 25 DEG C of stirring reactions
12h, obtain the N-N-PAM AM primitives (N-N-PAMAM-D that 1 generation ethylenediamine is core1)；Wherein, described ethylenediamine and acrylic acid
The mol ratio 1 of methyl esters：4；Described N-N-PAMAM-D0.5Mol ratio with ethylenediamine is 1:4；The dosage of the methanol is with every
10ml methanol dissolves 1ml methyl acrylate meter；The dosage of the methanol is in terms of every 10ml methanol dissolving 1ml ethylenediamine；Institute
The N-N-PAMAM-D stated0.5Dosage press 0.5g N-N-PAM AM-D matched per ml methanol0.5Meter.
(2) 3 generation ethylenediamines are the dendroid polyamide N-N-PAMAM of core synthesis
By N-N-PAMAM-D at 0 DEG C of ice-water bath1It is dissolved in methanol, then instills in the methanol solution of methyl acrylate, stirs
Uniformly, 25 DEG C of stirring reaction 12h are warming up to, it is core PAMAM primitives (N-N-PAMAM-D to obtain 1.5 generation ethylenediamines1.5)；Ice-water bath
It is lower by N-N-PAMAM-D1.5It is dissolved in methanol, instills in the methanol solution of ethylenediamine, stir, it is anti-is warming up to 25 DEG C of stirrings
12h is answered, obtains the N-N-PAMAM primitives (N-N-PAMAM-D that 2 generation ethylenediamines are core2)；By N-N-PAMAM-D at 0 DEG C of ice-water bath2
It is dissolved in methanol, then instills in the methanol solution of methyl acrylate, stir, is warming up to 25 DEG C of stirring reaction 12h, obtains
2.5 generation ethylenediamines are core PAMAM primitives (N-N-PAMAM-D2.5)；By N-N-PAMAM-D at 0 DEG C of ice-water bath2.5It is dissolved in methanol,
Instill in the methanol solution of ethylenediamine, stir, be warming up to 25 DEG C of stirring reaction 12h, obtain the N-N- that 3 generation ethylenediamines are core
PAMAM primitives (N-N-PAM AM-D3)；Wherein, the N-N-PAMAM-D1With the mol ratio 1 of methyl acrylate：8；The N-N-
PAMAM-D2With the mol ratio 1 of methyl acrylate:16；Described N-N-PAMAM-D1.5Mol ratio with ethylenediamine is 1:8；Institute
The N-N-PAMAM-D stated2.5Mol ratio with ethylenediamine is 1:16；The dosage of the methanol dissolves the third of 1ml with every 10ml methanol
E pioic acid methyl ester meter；The dosage of the methanol is in terms of every 10ml methanol dissolving 1ml ethylenediamine；Described N-N-PAMAM-D1(N-
N-PAMAM-D1.5, N-N-PA MAM-D2, N-N-PAMAM-D2.5) dosage press 0.5g N-N-PAMAM- matched per ml methanol
D1(N-N-PAMAM-D1.5, N-N-PAMAM-D2, N-N-PAMAM-D2.5) meter.
Embodiment 2
The synthesis of (1) 3 generation spherical dendritic interphase：
Ethylenediamine is dissolved in methanol at 0 DEG C of ice-water bath and being instilled again in the methanol solution of methyl acrylate, is stirred, is risen
For temperature to 35 DEG C of stirring reaction 48h, it is core PAMAM primitives (N-N-PAMAM-D to obtain 0.5 generation ethylenediamine0.5)；By N- under ice-water bath
N-PAMAM-D0.5It is dissolved in methanol, instills in the methanol solution of ethylenediamine, stir, is warming up to 35 DEG C of stirring reaction 48h,
Obtain the N-N-PAMAM primitives (N-N-PAMAM-D that 1 generation ethylenediamine is core1)；Wherein, described ethylenediamine and methyl acrylate
Mol ratio 1：8；Described N-N-PAMAM-D0.5Mol ratio with ethylenediamine is 1:12；The dosage of the methanol is with every 10ml
Methanol dissolves 5ml methyl acrylate meter；The dosage of the methanol dissolves 5ml ethylenediamine with every 10ml methanol；Described N-
N-PAMAM-D0.5Dosage press 5g N-N-PAMAM-D matched per ml methanol0.5Meter.
(2) 3 generation ethylenediamines are the dendroid polyamide N-N-PAMAM of core synthesis
By N-N-PAMAM-D at 0 DEG C of ice-water bath1It is dissolved in methanol and instills again in the methanol solution of methyl acrylate, stirs
Uniformly, 35 DEG C of stirring reaction 48h are warming up to, it is core PAMAM primitives (N-N-PAMAM-D to obtain 1.5 generation ethylenediamines1.5)；Ice-water bath
It is lower by N-N-PAMAM-D1.5It is dissolved in methanol, instills in the methanol solution of ethylenediamine, stir, it is anti-is warming up to 35 DEG C of stirrings
48h is answered, obtains the N-N-PAMAM primitives (N-N-PAMAM-D that 2 generation ethylenediamines are core2)；By N-N-PAMAM-D at 0 DEG C of ice-water bath2
It is dissolved in methanol and instills again in the methanol solution of methyl acrylate, stir, is warming up to 35 DEG C of stirring reaction 48h, obtains 2.5
It is core PAMAM primitives (N-N-PAMAM-D for ethylenediamine2.5)；By N-N-PAMAM-D at 0 DEG C of ice-water bath2.5It is dissolved in methanol, drips
In the methanol solution for entering ethylenediamine, stir, be warming up to 35 DEG C of stirring reaction 48h, obtain the N-N- that 3 generation ethylenediamines are core
PAMAM primitives (N-N-PAMAM-D3)；Wherein, the N-N-PAMAM (D1) with the mol ratio 1 of methyl acrylate：16；The N-
N-PAM AM-D2With the mol ratio 1 of methyl acrylate:32, described N-N-PAMAM-D1.5Mol ratio with ethylenediamine is 1:
24；Described N-N-PAMAM-D2.5Mol ratio with ethylenediamine is 1:48；The dosage of the methanol is dissolved with every 10ml methanol
5ml methyl acrylate meter；The dosage of the methanol is in terms of every 10ml methanol dissolving 5ml ethylenediamine；Described N-N-
PAMAM-D1(N-N-PAMAM-D1.5, N-N-PAMAM-D2, N-N-PAMAM-D2.5) dosage press 5g N- matched per ml methanol
N-PAMAM-D1(N-N-PA MAM-D1.5, N-N-PAMAM-D2, N-N-PAMAM-D2.5) meter.
Embodiment 3
The synthesis of (1) 3 generation spherical dendritic interphase：
Ethylenediamine is dissolved in methanol at 0 DEG C of ice-water bath and being instilled again in the methanol solution of methyl acrylate, is stirred, is risen
For temperature to 30 DEG C of stirring reaction 24h, it is core PAMAM primitives (N-N-PA MAM-D to obtain 0.5 generation ethylenediamine0.5)；By N- under ice-water bath
N-PAMAM-D0.5It is dissolved in methanol, instills in the methanol solution of ethylenediamine, stir, is warming up to 35 DEG C of stirring reaction 24h,
Obtain the N-N-PAMA M primitives (N-N-PAMAM-D that 1 generation ethylenediamine is core1)；Wherein, described ethylenediamine and methyl acrylate
Mol ratio 1：6；Described N-N-PAMAM-D0.5Mol ratio with ethylenediamine is 1:8；The dosage of the methanol is with every 10ml first
Alcohol dissolves 3ml methyl acrylate meter；The dosage of the methanol is in terms of every 10ml methanol dissolving 3ml ethylenediamine；Described N-
N-PAMAM-D0.5Dosage press 2.5g N-N-PAMAM-D matched per ml methanol0.5Meter.
(2) 3 generation ethylenediamines are the dendroid polyamide N-N-PAMAM of core synthesis
By N-N-PAMAM-D at 0 DEG C of ice-water bath1It is dissolved in methanol and instills again in the methanol solution of methyl acrylate, stirs
Uniformly, 30 DEG C of stirring reaction 24h are warming up to, it is core PAMAM primitives (N-N-PAMAM-D to obtain 1.5 generation ethylenediamines1.5)；Ice-water bath
It is lower by N-N-PAMAM-D1.5It is dissolved in methanol, instills in the methanol solution of ethylenediamine, stir, it is anti-is warming up to 30 DEG C of stirrings
24h is answered, obtains the N-N-PAMAM primitives (N-N-PAMAM-D that 2 generation ethylenediamines are core2)；By N-N-PAMAM-D at 0 DEG C of ice-water bath2
It is dissolved in methanol and instills again in the methanol solution of methyl acrylate, stir, is warming up to 30 DEG C of stirring reaction 24h, obtains 2.5
It is core PAMAM primitives (N-N-PAMAM-D for ethylenediamine2.5)；By N-N-PAMAM-D at 0 DEG C of ice-water bath2.5It is dissolved in methanol, drips
In the methanol solution for entering ethylenediamine, stir, be warming up to 35 DEG C of stirring reaction 24h, obtain the N-N- that 3 generation ethylenediamines are core
PAMAM primitives (N-N-PAMAM-D3)；Wherein, the N-N-PAMAM (D1) with the mol ratio 1 of methyl acrylate：12；The N-
N-PAM AM-D2With the mol ratio 1 of methyl acrylate:25；Described N-N-PAMAM-D1.5Mol ratio with ethylenediamine is 1:
16；Described N-N-PAMAM-D2.5Mol ratio with ethylenediamine is 1:32；The dosage of the methanol is dissolved with every 10ml methanol
3ml methyl acrylate meter；The dosage of the methanol is in terms of every 10ml methanol dissolving 3ml ethylenediamine；Described N-N-
PAMAM-D1(N-N-PAMAM-D1.5, N-N-PAMAM-D2, N-N-PAMAM-D2.5) dosage press per ml methanol match 2.5g
N-N-PAMAM-D1(N-N-PAM AM-D1.5, N-N-PAMAM-D2, N-N-PAMAM-D2.5) meter.
It is prepared by the nanogold material of embodiment 4N-N-PAMAM modifications
Weigh the dendritic interphase (N-N- that 3 generation ethylenediamines obtained by the embodiment 1 of certain mass are core
PAMAM-D3) be dissolved in ultra-pure water, ultrasonic dissolution.Gold chloride is added dropwise with certain mol ratio in gold chloride and dendrimer
(HAuCl4), after 30min is stirred at room temperature, it is rapidly added NaBH4Continue to stir 2h, after reaction terminates, reaction solution is transferred to and cut
Stay in the bag filter that molecular weight is 3000, dialyse 1 day, removing partly precipitated, (partly precipitated is Au composite film materials, and reservation is treated
With), freeze-drying obtains final product Au@N-N-PAMAM；Wherein, the N-N-PAMAM-D3, gold chloride and sodium borohydride
(NaBH4) mol ratio be 1:20:100；The addition of the ultra-pure water is with every 5ml dissolving 1mg N-N-PAMAM-D3Meter.
It is prepared by the nanogold material of embodiment 5N-N-PAMAM modifications
Weigh the dendritic interphase (N-N- that 3 generation ethylenediamines obtained by the embodiment 2 of certain mass are core
PAMAM-D3) be dissolved in ultra-pure water, ultrasonic dissolution.Gold chloride is added dropwise with certain mol ratio in gold chloride and dendrimer
(HAuCl4), after 24h is stirred at room temperature, it is rapidly added NaBH4Continue to stir 4h, after reaction terminates, reaction solution is transferred to retention
Molecular weight is in 5000 bag filter, is dialysed 3 days, removes partly precipitated (partly precipitated is Au composite film materials, is retained stand-by),
Freeze-drying obtains final product Au@N-N-PAMAM；Wherein, the N-N-PAMAM-D3, gold chloride and sodium borohydride mole
Than for 1:50：250；The addition of the ultra-pure water is with every 5ml dissolving 5mg N-N-PAMAM-D3Meter.
It is prepared by the nanogold material of embodiment 6N-N-PAMAM modifications
Weigh the dendritic interphase (N-N- that 3 generation ethylenediamines obtained by the embodiment 3 of certain mass are core
PAMAM-D3) be dissolved in ultra-pure water, ultrasonic dissolution.Gold chloride is added dropwise with certain mol ratio in gold chloride and dendrimer
(HAuCl4), after 12h is stirred at room temperature, it is rapidly added NaBH4Continue to stir 3h, after reaction terminates, reaction solution is transferred to retention
Molecular weight is in 4000 bag filter, is dialysed 2 days, removes partly precipitated (partly precipitated is Au composite film materials, is retained stand-by),
Freeze-drying obtains final product Au@N-N-PAMAM；Wherein, the N-N-PAMAM-D3, gold chloride and sodium borohydride mole
Than for 1:30：150；The addition of the ultra-pure water is with every 5ml dissolving 3mg N-N-PAMAM-D3Meter.
The synthesis (Au@N-N-PAMAM/NONOate) of the releasable nitric oxide nanoparticle of embodiment 7
After being dissolved in absolute methanol after the Au@N-N-PAMAM of the gained of step embodiment 4 are dried, it is stable to add sodium methoxide ultrasound
Autoclave is positioned over after 10min to seal and detect air-tightness.High pure nitrogen maintenance reaction kettle (10psi) 5min excludes reaction
Air in kettle, then pass to NO gases (40psi) and react 3 days at room temperature.After reaction terminates, NO is by 10psi high pure nitrogen
Discharge and open reactor after continuing to 10min~20min, take out reaction product.2 times are washed with absolute methanol, Ran Houyong
Ice absolute ether washs 1 time, vacuum drying, obtains final product (Au@N-N-PAMAM/NONOate).Wherein, the Au@N-N-
The mol ratio of PAMAM and sodium methoxide is 1:400；The concentration of the sodium methoxide is mass percent 5%；Described absolute methanol with
The dissolving 0.5g Au@N-N-PAMAM meters per 10ml；The Au@N-N-PAMAM of drying preparation method walks according to following operation
Suddenly：Au@N-N-PAMAM are placed in vacuum drying chamber, dried 12 hours under the conditions of 50 DEG C.
The synthesis (Au@N-N-PAMAM/NONOate) of the releasable nitric oxide nanoparticle of embodiment 8
After being dissolved in absolute methanol after the Au@N-N-PAMAM of the gained of step embodiment 5 are dried, it is stable to add sodium methoxide ultrasound
Autoclave is positioned over after 30min to seal and detect air-tightness.High pure nitrogen maintenance reaction kettle (20psi) 15min excludes anti-
The air in kettle is answered, NO gases (80psi) is then passed to and reacts 7 days at room temperature.After reaction terminates, NO is by 10psi~20psi's
High pure nitrogen is discharged and opens reactor after continuing to 20min, takes out reaction product.3 times are washed with absolute methanol, Ran Houyong
Ice absolute ether washs 2 times, vacuum drying, obtains final product (Au@N-N-PAMAM/NONOate).Wherein, the Au@N-N-
The mol ratio of PAMAM and sodium methoxide is 1:450；The concentration of the sodium methoxide is mass percent 20%；Described absolute methanol
In terms of every 10ml dissolving 2g Au@N-N-PAMAM；The Au@N-N--PAMAM of drying preparation method walks according to following operation
Suddenly：Au@N-N-PAMAM are placed in vacuum drying chamber, dried 48 hours under the conditions of 80 DEG C.
The synthesis (Au@N-N-PAMAM/NONOate) of the releasable nitric oxide nanoparticle of embodiment 9
After being dissolved in absolute methanol after the Au@N-N-PAMAM of the gained of step embodiment 6 are dried, it is stable to add sodium methoxide ultrasound
Autoclave is positioned over after 20min to seal and detect air-tightness.High pure nitrogen maintenance reaction kettle (20psi) 10min excludes anti-
The air in kettle is answered, NO gases (60psi) is then passed to and reacts 5 days at room temperature.After reaction terminates, NO is by 20psi High Purity Nitrogen
Gas is discharged and opens reactor after continuing to 20min, takes out reaction product.Washed 2 times with absolute methanol, it is then anhydrous with ice
Ether washs 2 times, vacuum drying, obtains final product (Au@N-N-PAMAM/NONOate).Wherein, the Au@N-N-PAMAM and
The mol ratio of sodium methoxide is 1:420；The concentration of the sodium methoxide is mass percent 15%；Described absolute methanol is with every 10ml
Dissolve 1g Au@N-N-PAMAM meters；The Au@N-N-PAMAM of drying preparation method is according to following operating procedure：By Au@
N-N-PAMAM dries 36h under the conditions of being placed in 60~80 DEG C of vacuum drying chamber.
The nitric oxide production composite film material synthesis of controllable release of the polycaprolactone of embodiment 10 cladding
A certain amount of PCL (polycaprolactone molecular weight is 5000) particle is weighed, is dissolved in volume ratio for 1:1 N, N- dimethyl
In formamide (DMF) and chloroform mixed solution, the PCL solution that concentration is mass percent 5% is configured to, room temperature is fully stirred
1h is mixed, to solution stable homogeneous, the Au N-N-PAMAM/NONOate magnetic coupling membrane materials for weighing the gained of embodiment 7 add
It is added in the PCL solution configured.After ultrasonic 150W ultrasonic vibrations 30min, solution is placed in ice bath and uses supersonic cell powder
Broken machine ultrasound (ultrasonic 1KW/5min, makes magnetic nanoparticle dispersed in PCL solution, then the quick stirring 5h of machinery is waved
Solvent is sent out, obtains the nitric oxide production composite film material of controllable release (the Au@N-N-PAMAM/ of final product polycaprolactone cladding
NONOate@PCL)；Wherein, the PCL and Au@N-N-PAMAM/NONOate mass ratioes are 1:5.
The nitric oxide production composite film material synthesis of controllable release of the polycaprolactone of embodiment 11 cladding
A certain amount of PCL (polycaprolactone molecular weight is 50000) particle is weighed, is dissolved in volume ratio for 1：4 N, N- diformazan
In base formamide (DMF) and chloroform mixed solution, the PCL solution that concentration is mass percent 30%, room temperature are configured to
2h is sufficiently stirred, to solution stable homogeneous, weighs the Au N-N-PAMAM/NONOate composite magnetic coatings of the gained of embodiment 8
Material is added in the PCL solution configured.After 300W ultrasonic vibrations 60min, solution is placed in ice bath and uses supersonic cell
Pulverizer ultrasound 3KW/5min, make magnetic nanoparticle dispersed in PCL solution, then the quick stirring 24h volatilizations of machinery
Solvent, obtain the nitric oxide production composite film material of controllable release (the Au@N-N-PAMAM/ of final product polycaprolactone cladding
NONOate@PCL)；Wherein, the PCL and Au@N-N-PAMAM/NONOate mass ratioes are 1:0.05.
The nitric oxide production composite film material synthesis of controllable release of the polycaprolactone of embodiment 12 cladding
A certain amount of PCL (polycaprolactone molecular weight is 30000) particle is weighed, is dissolved in volume ratio for 1:2 N, N- diformazan
In base formamide (DMF) and chloroform mixed solution, the PCL solution that concentration is mass percent 20% is configured to, room temperature is filled
Divide stirring 1.5h, to solution stable homogeneous, weigh the Au N-N-PAMAM/NONOate composite magnetic coatings of the gained of embodiment 9
Material is added in the PCL solution configured.After 200W ultrasonic vibrations 40min, solution is placed in ice bath and uses supersonic cell
Pulverizer ultrasound 2KW/5min, make magnetic nanoparticle dispersed in PCL solution, then the quick stirring 12h volatilizations of machinery
Solvent, obtain the nitric oxide production composite film material of controllable release (the Au@N-N-PAMAM/ of final product polycaprolactone cladding
NONOate@PCL)；Wherein, the PCL and Au@N-N-PAMAM/NONOate mass ratioes are 1:2.
Embodiment 13
Gained Au@N-N-PAMAM of embodiment 4, the gained sediment Au of embodiment 4, the gained N-N- of embodiment 1 are weighed respectively
Each 0.1mg of PAMAM are configured to 0.1mg/ml solution, and ultrasonic dissolution is uniform, survey current potential as shown in Fig. 2 Au surfaces are negatively charged, N-
N-PAMAM positively chargeds, Au@N-N-PAMAM positively chargeds represent that N-N-PAMAM has succeeded and echoed with nanogold.
Embodiment 14
Gained Au@N-N-PAMAM of embodiment 4, the gained sediment Au of embodiment 4, the gained N-N- of embodiment 1 are weighed respectively
PAMAM is configured to 1mg/ml concentration, is placed under 808nm near-infrareds and irradiates certain time, experimental result as shown in fig. 3, it was found that
Au@N-N-PAMAM and Au have obvious photo-thermal effect, and can further illustrate that Au and N-N-PAMAM is successfully echoed.
Embodiment 15
The Au@N-N-PAMAM/NONOate@PCL 1mg for weighing the gained of embodiment 12 are configured to 1mg/ml concentration, one group of warp
Near-infrared irradiates (wavelength 808nm), and one group is blank control, and experimental result is as shown in figure 4, find not shine through near infrared light
The Au@N-N-PAMAM/NONOate@PCL penetrated have prolonged drug release effect, and the experimental group NO through infrared radiation has obvious
Phenomenon of burst release, it is final to determine that PCL successfully coats NO donors, and the controlled-release effect of the material is obvious.
Embodiment 16
The Au@N-N- of the gained Au@N-N-PAMAM/NONOate@PCL of embodiment 12 and the gained of embodiment 9 are weighed respectively
Each 0.25mg of PAMAM/NONOate are dissolved in 5ml physiological saline and add 50 μ l (absorbance OD thereto590=1) golden yellow Portugal
In grape coccus (ATCC29213) test tube, wherein test tube 1 is that Au@N-N-PAMAM/NONOate@PCL irradiate 5min through near-infrared
Afterwards, continue cultivate 12h, test tube 2 be Au@N-N-PAMAM/NONOate equally through near-infrared irradiate 5min after, continue cultivate 12h,
Test tube 3 continues to cultivate 12h, compared through Maxwell nephelometry, experimental result is such as blank control while after near-infrared irradiates 5min
Shown in Fig. 5, the test tube 3 that compares finds that test tube 1,2 is clarified, and bacterial growth is significantly suppressed, and illustrates Au@N-N-PAMAM/
NONOate@PCLAu@N-N-PAMAM/NONOate have obvious fungistatic effect, and the material is expected to resist as a kind of new
Bacterium reagent.
Above-described embodiment is the preferable embodiment of the present invention, but embodiments of the present invention are not by above-described embodiment
Limitation, other any Spirit Essences without departing from the present invention with made under principle change, modification, replacement, combine, simplification,
Equivalent substitute mode is should be, is included within protection scope of the present invention.
Claims (10)
1. a kind of preparation method of the light-operated nitric oxide production composite film material of release, it is characterised in that comprise the following steps：
(1) 3 generation ethylenediamine is the synthesis of the N-N-PAMAM primitives of core
A, the methanol solution of ethylenediamine is instilled in the methanol solution of methyl acrylate under the conditions of ice-water bath, stirred, heated up
To reaction is stirred at room temperature, N-N-PAMAM-D is obtained0.5；It is dissolved under the conditions of ice-water bath in methanol, then instills the first of ethylenediamine
In alcoholic solution, stir, be warming up to and reaction is stirred at room temperature, obtain N-N-PAMAM-D1；
B, the N-N-PAMAM-D that will be obtained in step a1Instead of ethylenediamine, repeat step a operations, N-N-PAMAM-D is obtained2；Again
With N-N-PAMAM-D2Instead of ethylenediamine, repeat step a operations, N-N-PAMAM-D is obtained3；
(2) preparation of the nanogold material of N-N-PAMAM modifications
The N-N-PAMAM-D that will be obtained in step (1) b3It is dissolved into water, gold chloride is added dropwise, is stirred under room temperature condition
Mix, add NaBH4Continue to stir, dialyse, dry, obtain Au@N-N-PAMAM；
(3) synthesis of the light-operated nitric oxide production composite film material of release
The Au@N-N-PAMAM obtained in step (2) are dissolved in absolute methanol, then add sodium methoxide ultrasound stablize 10~
30min, then NO gases are passed through, room temperature is reacted, and after reaction terminates, is washed, is dried, and it is nitric oxide production multiple to obtain light-operated release
Close membrane material.
2. the preparation method of the light-operated nitric oxide production composite film material of release according to claim 1, it is characterised in that：
The mol ratio 1 of ethylenediamine and methyl acrylate described in step (1) a:4~8；
N-N-PAMAM-D described in step (1) a0.5Mol ratio with ethylenediamine is 1:4~24；
N-N-PAMAM-D described in step (2)3, gold chloride and NaBH4Mol ratio be 1:20~50:100~250；
The mol ratio of Au@N-N-PAMAM and sodium methoxide described in step (3) are 1:400~450.
3. the preparation method of the light-operated nitric oxide production composite film material of release according to claim 1, it is characterised in that：
The methanol solution of ethylenediamine described in step (1) a is methanol and ethylenediamine by volume 10:1~5 proportioning obtains molten
Liquid；
The methanol solution of methyl acrylate described in step (1) a is methanol and methyl acrylate by volume 10:1~5 proportioning
Obtained solution.
4. the preparation method of the light-operated nitric oxide production composite film material of release according to claim 1, it is characterised in that：
N-N-PAMAM-D described in step (1) a0.5Dosage is to match 0.5~5g N-N-PAMAM-D by every ml methanol0.5
Calculate；
N-N-PAMAM-D described in step (2)3Dosage match 0.2~1mg N-N-PAMAM-D by every milliliter of water3Calculate；
The dosage of Au N-N-PAMAM described in step (3) matches 0.05~0.2g Au N-N- by every milliliter of absolute methanol
PAMAM is calculated.
5. the preparation method of the light-operated nitric oxide production composite film material of release according to claim 1, it is characterised in that：
The time of stirring reaction described in step (1) a is 12~48h；
The time of stirring described in step (2) is 0.5~24h；
The time for continuing stirring described in step (2) is 2~4h；
Dialysis described in step (2) is to be dialysed in the bag filter that molecular cut off is 3000~5000；
The condition of drying described in step (2) is：Dried 12~48 hours under the conditions of 50~80 DEG C；
The time of reaction described in step (3) is 3~7 days；
Washing described in step (3) is to be washed with absolute methanol and ice absolute ether.
A kind of 6. light-operated nitric oxide production composite film material of release, it is characterised in that：By described in any one of Claims 1 to 5
Method be prepared.
A kind of 7. nitric oxide production composite film material of light-operated release of polycaprolactone cladding, it is characterised in that：Coated and weighed by PCL
Profit requires that the nitric oxide production composite film material of light-operated release described in 6 obtains；Its preparation method comprises the following steps：
(I) PCL is added in DMF and chloroform mixed solution, stirred, obtain PCL solution；
(II) the nitric oxide production composite film material of light-operated release described in claim 6 is distributed to the PCL obtained in step (I)
In solution, solvent flashing is then stirred for, obtains the nitric oxide production composite film material of light-operated release of polycaprolactone cladding.
8. the nitric oxide production composite film material of light-operated release of polycaprolactone cladding according to claim 7, its feature exist
In：
The molecular weight of PCL described in step (I) is 5000~50000；
The volume ratio of N,N-dimethylformamide and chloroform described in step (I) is 1:1~4；
The concentration of PCL solution described in step (I) is mass percent 5~30%；
The mass ratio of PCL and the light-operated nitric oxide production composite film material of release described in step (I) are 1:0.05~5.
9. described in the nitric oxide production composite film material of light-operated release according to claim 6 or any one of claim 7~8
Polycaprolactone cladding application of the nitric oxide production composite film material of light-operated release in bio-medical engineering material.
10. any one of the nitric oxide production composite film material of light-operated release according to claim 6 or claim 7~8 institute
Application of the nitric oxide production composite film material of light-operated release for the polycaprolactone cladding stated in antibacterials are prepared.
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| CN108969769A (en) * | 2018-07-11 | 2018-12-11 | 暨南大学 | Penicillin and nitric oxide production polymer and its preparation method and application are loaded simultaneously |
| CN109970881A (en) * | 2019-03-01 | 2019-07-05 | 暨南大学 | 3D printing realizing controlled-release nitric oxide nano-bracket material and preparation method and application |
| CN110615894A (en) * | 2019-06-15 | 2019-12-27 | 威海晨源分子新材料有限公司 | Hyperbranched polyesteramine and application thereof in water-based paint |
| CN110787298A (en) * | 2019-10-24 | 2020-02-14 | 暨南大学 | Preparation and application of star-shaped hollow nano material capable of simultaneously loading NO and antibiotics for synergistic antibacterial |
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| CN108969769B (en) * | 2018-07-11 | 2021-07-27 | 暨南大学 | Polymer simultaneously carrying penicillin and nitric oxide as well as preparation method and application thereof |
| CN109970881A (en) * | 2019-03-01 | 2019-07-05 | 暨南大学 | 3D printing realizing controlled-release nitric oxide nano-bracket material and preparation method and application |
| CN109970881B (en) * | 2019-03-01 | 2021-06-11 | 暨南大学 | 3D printing controlled-release nitric oxide nano stent material, and preparation method and application thereof |
| CN110615894A (en) * | 2019-06-15 | 2019-12-27 | 威海晨源分子新材料有限公司 | Hyperbranched polyesteramine and application thereof in water-based paint |
| CN110787298A (en) * | 2019-10-24 | 2020-02-14 | 暨南大学 | Preparation and application of star-shaped hollow nano material capable of simultaneously loading NO and antibiotics for synergistic antibacterial |
| CN110787298B (en) * | 2019-10-24 | 2021-09-17 | 暨南大学 | Preparation and application of star-shaped hollow nano material capable of simultaneously loading NO and antibiotics for synergistic antibacterial |
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