CN110051852A - A kind of high encapsulation performance lignin nanosphere as well as preparation method and application thereof - Google Patents
A kind of high encapsulation performance lignin nanosphere as well as preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a kind of high encapsulation performance lignin nanosphere, structure is to be grafted cyclodextrin monomer structure on lignin molecule.The invention also discloses preparation methods.Nanosphere stable structure disclosed by the invention provides a new way for the higher value application of enzymolysis xylogen product.
Description
Technical field
The invention belongs to small-molecule drugs to contain technical field；It is received more particularly, to a kind of high encapsulation performance lignin
Rice ball and preparation method thereof.
Background technique:
Cancer is a worldwide great public health problem, it has also become endanger human health major disease it
One.The treatment means of tumour have a means such as operation, chemotherapy at present, but due to tumor-localizing is difficult, diffusion of cancer cell etc. it is many because
Element influences, and operation is difficult complete tumor resection tissue, so, chemotherapy is the main means for the treatment of cancer at this stage.Anticancer drug
The proliferation of cancer cell can effectively be inhibited, there is extraordinary therapeutic effect.But conventional medicine used in clinic at present, it is such as molten
There are the stability poor, first pass effect such as liquid, suspension or lotion, toxic side effect and the disadvantages such as bioavailability is low, are not able to satisfy
The requirement of clinical treatment, it is therefore desirable to establish newtype drug transmission system to improve utilization ratio of drug and therapeutic effect, drop simultaneously
Low poisonous side effect of medicine.
The middle airborne nanoparticles of nanotechnology preparation have the characteristics that high-specific surface area, are to break through the important way of these problems
Diameter.Camptothecine is a kind of alkaloid extracted from the distinctive Nyssaceae plant camptotheca acuminata of China, to treatment Several Kinds of Malignancy tool
There is significant curative effect, is a kind of important chemotherapeutics with other anti-tumor drug uses without cross resistance.But camptothecine dissolves
Property it is poor, metabolism is fast in vivo, half-life period is extremely short, simultaneously because a kind of dose dependent drug, clinical directly to use toxic side effect
Greatly.
Ideal drug delivery system have material source is wide, synthesis cost is low, surface can chemical modification and low toxicity even
The features such as non-toxic.Organic chemical synthesis material or inorganic material, can be strong to human body due to its source or preparation process etc.
Health or Environmental security bring risk.
Therefore, it in the case where hollow nano material starts to turn to botanical material, finds safe, renewable and " green "
Load medicine body be particularly important.
Summary of the invention:
The problem that the present invention is complicated for traditional fibre element aeroge preparation process, mechanical property is poor, it is creatively first
It is secondary using natural reproducible timber as raw material, pass through a kind of wooden sponge oil absorption material of top-down strategy Development.
Technical solution of the present invention
The invention discloses a kind of high encapsulation performance lignin nanosphere, structure is to be grafted ring paste on lignin molecule
Essence monome structure.
The nanosphere is beta-cyclodextrin/enzymolysis xylogen polymer.
The nanosphere be it is hollow, there is the spherical micro-nano particle of opening on surface；
The nanometer bulb diameter is 100-300nm；The nanosphere is amphiphilic polymer.
Further, the nanometer bulb diameter is 180-250nm.
Further, the nanosphere is using lignin and cyclodextrin as raw material, using close silane chemistries, sulfonationization reaction,
Self-assembly method is prepared.
The preparation method of the high encapsulation performance lignin nanosphere, step are as follows:
(1) lignin raw material is added in organic solvent, silane coupling agent reaction is added, obtains sediment；
(2) sediment for obtaining step (1) dissolves in organic solvent again, and cyclodextrin and catalyst, reaction is added
Afterwards, it is added in hydrochloric acid solution, obtains sediment；
(3) sediment that step (2) obtains is added in organic solvent, stirs, water droplet is added in solution, or will be molten
Liquid is to be added drop-wise in water.
(4) solution that step (3) obtains is handled, removes remaining organic solvent, it is then that solution is dry, both
?.
Further, the lignin raw material is enzymolysis xylogen, alkali lignin, high-boiling alcohol lignin, lignin sulfonic acid
One or more of salt；
Further, the organic solvent is one or more of tetrahydrofuran, dioxane, dimethylformamide；
Further, the silane coupling agent is 3- aminopropyl triethoxysilane, in 3- aminopropyl trimethoxysilane
It is any one or several；
Further, the ratio of lignin and silane coupling agent is 0.05~0.5g/ml in step (1), and the reaction time is
0.5h~5h；
Further, cyclodextrin described in step (2) is the cyclodextrin containing p-toluenesulfonyl, and the catalyst is iodate
Potassium；
Further, solution contains 0.4~6mg/mL of lignin before titration described in step (3)；
Further, mixing speed described in step (3) is 300~1500rpm；Rate of addition described in step (3) is
0.5~6mL/min；
Preferably, the volume ratio of water and organic solvent is 2:1~7:1 in final solution described in step (3)；
Preferably, processing described in step (4) is dialysis；
Preferably, lignin raw material is added in organic solvent by the step (1), and silane coupling agent reaction is added
Afterwards, it is centrifuged, washing precipitating, and dry；
Preferably, the step (2) obtains sediment by centrifugation, is also washed and dry.
Preferably, dialysis described in step (4) is to be carried out using bag filter；The time of the dialysis is 12~48 h；Step
Suddenly water described in (3) is deionized water.
Preferably, the hydrochloric acid solution is 2M hydrochloric acid.
Preferably, the washing of the step (1) is that anhydrous ether rinses precipitating；
Preferably, the drying of the step (1) is to dry, 50-75 DEG C；
Preferably, the washing of the step (2) is precipitated as anhydrous ether and rinses precipitating；
Preferably, the drying of the step (2) is freeze-drying.
The high encapsulation performance lignin nanosphere is used to prepare the application in pharmaceutical carrier.
Nanosphere stable structure disclosed by the invention provides a new way for the higher value application of enzymolysis xylogen product
Diameter.Some lignin-base micro-nano balls contain the application of drug molecule it has been reported that but by introducing on lignin molecule chain
With cavity structure, periphery is hydrophilic, inner cavity is hydrophobic cyclodextrin monomer grinds to expand the network function of lignin-base hollow ball
Study carefully and still belongs to blank.Lignin hollow micro-nano ball grafted cyclodextrin is increased containing can be specific with drug interaction
Controlled site.
The present invention.Beta-cyclodextrin/enzymolysis xylogen as a kind of novel amphiphilic polymer, the invention discloses its
Self assembly balling-up behavior in water/THF solution and containing and sustained release behavior to anticancer drug camptothecine.Due to cyclodextrin monomer
Introducing, improve the spacial framework of enzymolysis xylogen strand, to the surface nature of lignin-base hollow micro-nano ball,
The High efficient encapsulation and time-release effect of drug are significant.
Detailed description of the invention:
Fig. 1: CD-EHL preparation and representation；(A) β-CD is grafted the schematic diagram of EHL；(B) molecular weight of EHL and CD-EHL
Component；(C) hydrogen nuclear magnetic resonance spectrogram of 6-Ts- β-CD, EHL and CD-EHL；(D) the infrared analysis spectrum of EHL and CD-EHL
Figure；
The TEM image of Fig. 2: 1 hollow micro-nano ball: (A) LHNPs (B) CD-LHNPs:(A) LHNPs (B) CD-LHNPs
CD-LHNPs；
The DLS size distribution of Fig. 3: LHNPs and CD-LHNPs；
Fig. 4: the N2 adsorption desorption curve of (A) EHL, LHNPs and CD-LHNPs；(B) specific surface area and pore volume；Fig. 5:
LHNPs and CD-LHNPs stability in PBS (pH 7.4) at 37 DEG C.(A) average diameter (B) PDI (C) zeta current potential；
Fig. 6: LHNPs and CD-LHNPs form a film on gold plaque after contact angle；
XPS map (the XPS range curve of (A) LHNPs and CD-LHNPs of Fig. 7: LHNPs and CD-LHNPs；(B)
LHNPs XPS swarming curve；(C) CD-LHNPs XPS swarming curve)；
Fig. 8: medicine hollow micro-nano ball is carried to the release profiles of HCPT；Illustration is that (A) and (B) is respectively HCPT@LHNPs
With the drug release schematic diagram of HCPT@CD-LHNPs.
Specific embodiment
The invention will now be further described with reference to specific embodiments, the advantages and features of the present invention will be with description and
It is apparent.But examples are merely exemplary, and it is not intended to limit the scope of the present invention in any way.Those skilled in the art answer
It should be appreciated that without departing from the spirit and scope of the invention can details to technical solution of the present invention and form repair
Change or replace, but these modifications and replacement are fallen within the protection scope of the present invention.
A kind of embodiment 1: preparation method of high encapsulation performance lignin nanosphere
1, raw material: enzymolysis xylogen (EHL) is purchased from Hong Kong Lai He Bioisystech Co., Ltd, and (after THF purification, GPC is measured
The weight average molecular weight of EHL is 532g/mol, PDI 1.34).Tetrahydrofuran (THF is analyzed pure) is purchased from Beijing chemical reagent factory.
Mono- 6-O- (p-toluenesulfonyl)-beta-cyclodextrin be purchased from Shanghai Mike's woods biochemical technology Co., Ltd (6-TsO- β-CD, MW:
1289.17g/mol > 98%).Concentrated hydrochloric acid (HCl), N- methyl pyrrolidone are purchased from Beijing chemical reagent factory.3- aminopropyl three
Ethoxysilane (APTES), hydroxycamptothecin (HCPT) are purchased from Shanghai Mike's woods biochemical technology Co., Ltd.DMSO is purchased from the U.S.
Sigma company.Bag filter is purchased from Spectrumlabs company, the U.S..
2, preparation method:
(1) it modifies enzymolysis xylogen: enzymolysis xylogen being modified using APTES, obtain that there is amino on molecule
Lignin (A-EHL)；
(2) it synthesizes beta-cyclodextrin modified enzymolysis xylogen polymer: A-EHL obtained by step (1) and beta-cyclodextrin adds
Enter N- first class pyrrolidones, handled, obtains beta-cyclodextrin modified enzymolysis xylogen polymer (CD-EHL)；
(3) it prepares lignin-base hollow micro-nano ball: CD-EH is dissolved in THF, stir, deionized water is added, goes
Except remaining THF and free lignin molecule, the hollow nano drug-carrying microsphere of beta-cyclodextrin/lignin (CD-LHNPs) is obtained；
(4) it is freeze-dried: by step (3) treated timber, being put into vacuum freeze drier and freeze after water washing
It is 24~36 hours dry, both.
Embodiment 2: being tested for the property the high encapsulation performance lignin nanosphere that embodiment 1 obtains and structural characterization:
1, test method:
(1) gel chromatography analysis (GPC)
Appropriate amount of sample is taken to be dissolved in chromatographic grade tetrahydrofuran, after membrane filtration, using polystyrene standard sample as benchmark molecule
Quality measures molecular weight analyte with gel permeation chromatograph (Malvern company).
(2) transmission electron microscope observation analysis (TEM)
Lignin-base micro-nano ball colloidal solution (about 1.2mg/mL) is taken with liquid-transfering gun, is added drop-wise to the logical net containing carbon film
On, room temperature is observed under transmission electron microscope (JEM-2100 transmission electron microscope, Japan Electronics Corporation) after thoroughly drying
It takes pictures, the result is shown in Figure 1
(3) Dynamic laser scattering analysis (DLS)
Configured 1mL colloidal solution to be put into sample cell with liquid-transfering gun, setting temperature is 25 DEG C, angle of scattering 90o,
The average value for measuring 16~20 data is final result.Test equipment is Zetasizer Nano laser particle analyzer, Britain
Malvern company, as a result sees Fig. 2.
(4) hydrogen nuclear magnetic resonance spectrum analysis (1H NMR)
After sample to be tested drying, with the core of III 500MHz of Bruker-avance (German Brooker company) test sample
Magnetic hydrogen spectrum.Sample about 20mg, solvent are deuterated dimethyl sulfoxide (DMSO), and setting instrument parameter is 90o pulse, when 25s relaxation
Between, it scans 128 times.
(5) Fourier infrared spectrum analysis (FTIR)
By sample to be tested it is dry after, take after appropriate amount of sample pressing potassium bromide troche in Nicolet IS10 infrared spectrometer (beauty
Guo Ni high-tensile strength company) on test.Test scope is 4000-500cm-1.
(6) uv-visible absorption spectroscopy analysis (UV-vis)
Configured colloidal solution is measured with UV-3600 ultraviolet-visible spectrophotometer (Japanese Shimadzu Corporation).It surveys
Try range: 200~800nm, scanning speed 2nm/s.Deionized water is chosen according to different test objects or tetrahydrofuran is made
For background solution.
(7) specific surface area analysis
After sample to be tested drying, 100mg sample is taken, using nitrogen as adsorbing medium, with specific surface area analysis instrument (Nova
1200e, Kang Ta) measure sample specific surface area and pore volume.
(8) contact angle is analyzed
The sample solution for being 5mg/mL or so by concentration, drop spontaneously dry film forming on silicon wafer.Repeat said sample process 5
It is secondary.At room temperature, sample is done into water contact angle measurement.Test equipment: JC2000D contact angle analyzer (upper marine morning number section
Skill equipment Co., Ltd).
(9) X-ray photoelectron spectroscopic analysis (XPS)
Sample after taking appropriate drying measures sample table with X-ray energy spectrum analyzer (Axis Ultra, Kratos, Britain)
The element of face 1~5nm depth forms.Aluminium target monochromatic X-ray source is used in test process.
(10) constituent content analysis
Sample after taking appropriate drying measures entirety C, H, O content in sample with Flash EA1112 elemental analyser.It surveys
Test result takes the average value of test result twice.
2 test results
(1) beta-cyclodextrin/enzymolysis xylogen performance characterization
Grafting is carried out to lignin and is changed as shown in Figure 1A for the spacial framework for improving enzymolysis xylogen strand
Property.Molecular weight distribution using gel permeation chromatography (GPC) test product is as shown in Figure 1B, it can be seen from the figure that EHL passes through
After β-CD graft modification, weight average molecular weight increases, and molecular weight increases to 701g/mol from 532g/mol.The polydispersion of EHL
FACTOR P DI is 1.34, and the PDI of CD-EHL is 1.57, this is primarily due to the ratio of high molecular weight moieties in modified product
Example is than caused by former EHL high.
In order to prove that β-CD is grafted on EHL, tests and structural characterization is carried out to the CD-EHL of synthesis, main research means are
Infrared absorption spectrum and nuclear magnetic resonance spectroscopy.Fig. 1 C is the 1H-NMR spectrogram of 6-Ts-O- β-CD, EHL, CD-EHL.In CD-EHL
On the nuclear magnetic spectrogram of product, not only there is Hydrogen Proton (6.76-7.72ppm), the methoxy proton signal of lignin phenyl ring
The signal peak of (3.84ppm) and aliphatic lateral chain proton (2.6-0.7ppm) relevant to phenyl ring, and there is β-CD proton
The signal peak of (3.42-3.19ppm, 4.86-4.42).Importantly, nearby occurring the signal of secondary amine proton at 8.22ppm
Peak shows that substitution reaction has occurred between β-CD and lignin containing amino.In addition, belonging in the region 7.75-7.43ppm
Proton signal peak on sulfonyl disappears, and further confirming that does not have that β-CD's is residual on the EHL product of measured β-CD modification
It stays.
The infrared analysis spectrogram of EHL and CD-EHL is shown in Fig. 1 D.EHL is wooden in the absorption peak of 1700cm-1 (C=O) nearby
C=O stretching vibration on element.Absorption peak at 1598cm-1,1514cm-1 (C-C), 1425cm-1 (C-H on phenyl ring skeleton)
It is caused by the stretching vibration absorption peak of phenyl ring skeleton structure.Infrared spectrum compared to EHL, CD-EHL go out at 1645cm-1
, there is C-N stretching vibration peak near 1540 in the stretching vibration peak for having showed N-H.In addition, due to the modification of β-CD, CD-EHL
Occurs the O-H stretching vibration absworption peak on β-CD near 1414cm-1, the stretching vibration peak of C-O is moved by 1035cm-1
To at 1028cm-1.Above analysis shows sulfonylation has occurred between β-CD and EHL, β-CD is grafted on EHL.
(2) preparation of beta-cyclodextrin/enzymolysis xylogen hollow micro-nano ball and performance characterization
Hydrophilic on the outside of cyclodextrin cavity, inside is hydrophobic, thus after being grafted cyclodextrin monomer structure on lignin molecule at
For a kind of unique amphiphilic polymer.The present invention utilizes CD-EHL self assembly in selective solvent, is prepared for a kind of sky
Between the bigger lignin-base hollow micro-nano ball of network.
The TEM that Fig. 2 is LHNPs and CD-LHNPs schemes.Although it is amphipathic with other that lignin self assembly prepares micro-nano ball
Polymer self assembles are similar at the method for micella, but lignin is self-assembly of nanoparticle the characteristics of own.LHNPs and
CD-LHNPs shows as hollow, and there are the spherical micro-nano particle of opening, diameter 200nm or so in surface.CD-LHNPs is shown in figure
More coarse than LHNPs outside shell, this may be when the β-CD that layer structure is hydrophilic nmature be in micro-nano ball self assembly because dredging
It is related that water effect is mainly distributed on outer surface of spheroid.
DLS detection can provide certain information for the difference of the self assembly behavior of two kinds of lignin.As shown in Fig. 3,
The average diameter of LHNPs is 200nm or so, and the average diameter of CD-LHNPs is 220nm or so, the test result of this and TEM
It is consistent.The narrow distribution of particle in solution illustrates that the size of micro-nano ball is more stable, this is because two kinds of lignin possess
Lesser PDI value.Furthermore it is possible to see under identical preparation process condition, the average diameter of CD-LHNPs is greater than LHNPs, this
Being primarily due to strong-hydrophobicity makes lignin molecule be easier to gather together and prepare lignin ball, and cyclodextrin reduces EHL points
The hydrophobicity of son.
Fig. 4 A is the N2 adsorption desorption curve of EHL, LHNPs and CD-LHNPs, and illustration is to analyze to obtain based on DFT method
Obtain particle graph of pore diameter distribution.It can be seen that the nitrogen adsorption curve type of product is IV property of Brunauer, the aperture of micro-nano ball
Distribution shows that lignin micro-nano ball is micropore and mesoporous material between 1nm to 6nm.Fig. 4 B is shown as EHL and wooden
The specific surface area and pore volume of plain base hollow micro-nano ball.Statistics indicate that after lignin self assembly balling-up, specific surface area and hole
Gap volume is significantly increased.In addition, the specific surface and pore volume of CD-LHNPs are respectively 64.51m2g-1 and 0.20cm3g-1,
The specific surface and pore volume of LHNPs is respectively 49.37m2g-1 and 0.155cm3g-1, and the EHL of β-CD grafting prepares micro-nano
The specific surface area and pore volume of ball are higher by 23% He than the specific surface area and pore volume of the pure EHL micro-nano ball prepared respectively
22%.Prove that β-CD can be significantly expanded the spatial network of lignin-base hollow-particle.
The stability of lignin-base hollow micro-nano ball at physiological ph for further evaluation, by tracking hollow micro-nano
Rice ball is incubated for average grain diameter, PDI value and the zeta potential value of micro-nano ball in 6 days at any time at PBS (pH 7.4), 37 DEG C
Variation.Found out by Fig. 5 A, the size that the average grain diameter of two kinds of nano lignin balls is totally held essentially constant within incubation period.
In addition, being reflected by Fig. 5 B, the PDI value of CD-LHNPs also keeps relative stability.Although the PDI value of LHNPs has small range wave
It is dynamic but not significant.For zeta potential change figure (Fig. 5 C), over time, it can be observed that the slight wave of numerical value
It is dynamic.This may be the effect of the ion as present in PBS solution, these ions can be adsorbed on the surface of micro-nano ball.It surveys
Test result shows in 6 days, lignin-base nano hollow ball colloidal stability with higher in PBS solution, not the group of will form
Aggressiveness.
In order to study the surface hydrophilicity and hydrophobicity of lignin-base hollow micro-nano ball, experiment is tested using static contact angle
Two kinds of micro-nano balls form a film on gold plaque after contact angle, sample solution concentration 5mg/mL.As can be seen from Figure 6 CD-LHNPs
Contact angle (3.43o) is significantly less than the contact angle (41.9o) of LHNPs.Since experiment uses TFH as good solvent, water is bad
Solvent is to prepare lignin-base hollow micro-nano ball, therefore the hydrophilic segment of lignin can exist because of hydrophobic effect in self assembling process
The shell outer layer of micro-nano ball is assembled.So increasing the ratio of hydrophilic radical on its strand after grafted by beta cyclodextrin EHL
Example, the surface contact angle of CD-LHNPs is smaller after self assembly.
It is constituted to study the structure of hollow micro-nano ball, the element composition of hollow micro-nano ball surface is measured by XPS
(see Fig. 7), test result and C1 swarming result are listed in table 1.The hydrophobic grouping of lignin is mainly aromatic rings, therefore C content is got over
Big hydrophobicity is stronger.As can be seen from the table, after grafted by beta cyclodextrin, the C content of CD-LHNPs is reduced, this is modified
Caused by lignin molecule hydrophilic segment relative scale increased.It is by amino during testing that N constituent content, which increases,
Caused by introducing.Since hydrophilic radical is mainly hydroxyl, carboxyl on lignin, so outside the shell of the bigger nanosphere of O/C
Layer hydrophily is stronger.The surface layer O/C of CD-LHNPs is 0.23 value 0.19 for being greater than LHNPs, so CD-LHNPs, which possesses, compares LHNPs
The outer surface of relative hydropathic.Fig. 7 B and 7C are results after the XPS swarming about LHNPs and CD-LHNPs.The C1s enfeoffment of LHNPs
It as a result is 284.8eV (C-C, C-H), characteristic peak occur in 286.14eV (C-O), 289.03eV (C=O).CD-LHNPs exists
There is new characteristic peak at 285.52eV (C-N).Compared with LHNPs, CD-LHNPs (C-C, C-H, 284.8eV) functional group content
It is reduced to 43.93% from 68.82%, alcoholic extract hydroxyl group content (C-OH, 286.14eV) increases to 31.23% from 29.55%.So with
LHNPs is compared, and CD-LHNPs possesses the surface of relative hydropathic, this is consistent with the contact angle test result of nanosphere.
Constituent content analysis the results are shown in Table 1,
The surface-element of table 1 LHNPs and CD-LHNPs is distributed
Embodiment 3:CD-LHNPs to HCPT contain and the research of sustained release performance
The drugloading rate (DL) of two kinds of lignin-base hollow micro-nano balls is with encapsulation rate (EE) with the variation of dosage percentage
As shown in table 2.It can be seen that, lignin-base hollow micro-nano ball has preferable carry to hydrophobic drug camptothecine from table 2
Medicine ability.With the increase of dosage percentage, drugloading rate is gradually increased, micro-nano when dosage percentage is 40% or so
Balloon borne dose and encapsulation rate are relatively best.In addition, can be seen that the Drug loading capacity of CD-LHNPs is better than LHNPs by data in table,
This is because the specific surface area and pore volume of CD-LHNPs are all larger than LHNPs.
2 LHNPs and CD-LHNPs drugloading rate of table and encapsulation rate are with dosage with the variation of m0/m
Note: m0 is dosage (mg)；M is the quality (mg) of nanoparticle
Currently, lignin-base nano material prepares the main limitation of drug delivery platform from them and is contained medicine
It interacts between object weaker.If do not interacted specifically between lignin-base hollow micro-nano ball and drug,
Drug loading will reduce and treatment level is not achieved.Even if being required in addition, the load capacity of drug reaches treatment, if it is released
Excessive velocities are put, cannot achieve the controlled release of drug, it is also difficult to reach therapeutic purposes.Therefore it is digested using beta-cyclodextrin modified wooden
After element, it can not only increase the network structure of lignin molecule, but also can generate more can be with the spy of drug interaction
Anchor point.
In order to simulate the release behavior of drug under tumor microenvironment or intracellular (pH 5.5) and physiological pH (pH 7.4), I
Select the buffer solution of two kinds of pH value as dissolution medium, to the medicine of HCPT@LHNPs and HCPT@CD-LHNPs at 37 DEG C
Object release is evaluated.Cumulative release curve shows that two kinds of nanoparticles all have apparent slow release effect.In drug release
Early period (0-10h), since HCPT disperses unevenly in LHNPs system, part HCPT is adsorbed on nanoparticle surface, so
There is the phenomenon that quick release in HCPT@LHNPs release profiles.And HCPT@CD-LHNPs since surface has more beta-cyclodextrins
As the specific site with drug interaction, so discharging the stage herein, the release of HCPT is relatively slowly very much.In pH7.4
Under the conditions of, after discharging 60h, the Cumulative release amount of HCPT is respectively 47.2% He in HCPT@LHNPs and HCPT@CD-LHNPs
32.7%.And acid condition, there is 61.4% and 41.7% HCPT to be released respectively.The result shows that in Jie of pH=7.4
In matter, two kinds of medicine-carried nano particles all show slower HCPT rate of release, and lysosomal acid environment in the cell
The releasing effect of lower drug enhances, this advantageously reduces the toxic side effect for carrying the sub- normal tissue of powder.
In conclusion although two kinds of nano particles have good control action, HCPT@CD- to the release of HCPT
For LHNPs since there are β-CD in structure, the synergistic effect in terms of drug release is better than LHNPs.
Embodiment 4:
A kind of high encapsulation performance lignin nanosphere, structure are to be grafted cyclodextrin monomer structure on lignin molecule.
Embodiment 5:
A kind of high encapsulation performance lignin nanosphere, structure are to be grafted cyclodextrin monomer structure on lignin molecule；
The nanosphere is beta-cyclodextrin/enzymolysis xylogen polymer.
Embodiment 6:
A kind of high encapsulation performance lignin nanosphere, structure are to be grafted cyclodextrin monomer structure on lignin molecule；
The nanosphere is beta-cyclodextrin/enzymolysis xylogen polymer；The nanosphere be it is hollow, there is the spherical shape of opening on surface
Micro-nano particle.
Embodiment 7:
A kind of high encapsulation performance lignin nanosphere, structure are to be grafted cyclodextrin monomer structure on lignin molecule；
The nanosphere is beta-cyclodextrin/enzymolysis xylogen polymer；The nanosphere be it is hollow, there is the spherical shape of opening on surface
Micro-nano particle；The nanosphere is amphiphilic polymer.
Embodiment 8:
A kind of high encapsulation performance lignin nanosphere, structure are to be grafted cyclodextrin monomer structure on lignin molecule；
The nanosphere is beta-cyclodextrin/enzymolysis xylogen polymer；The nanosphere be it is hollow, there is the spherical shape of opening on surface
Micro-nano particle；The nanometer bulb diameter is 100-300nm.
Embodiment 9:
A kind of high encapsulation performance lignin nanosphere, structure are to be grafted cyclodextrin monomer structure on lignin molecule；
The nanosphere is beta-cyclodextrin/enzymolysis xylogen polymer；The nanosphere be it is hollow, there is the spherical shape of opening on surface
Micro-nano particle；The nanometer bulb diameter is 180-250nm nm.
Embodiment 10:
A kind of high encapsulation performance lignin nanosphere, structure are to be grafted cyclodextrin monomer structure on lignin molecule；
The nanosphere is beta-cyclodextrin/enzymolysis xylogen polymer；The nanosphere be it is hollow, there is the spherical shape of opening on surface
Micro-nano particle；The nanometer bulb diameter is 180-250nm nm；The nanosphere is adopted using lignin and cyclodextrin as raw material
It is prepared with conjunction silane chemistries, sulfonation reaction, self-assembly method.
Embodiment 11:
A kind of high encapsulation performance lignin nanosphere, structure are to be grafted cyclodextrin monomer structure on lignin molecule；
The nanosphere using lignin and cyclodextrin as raw material, using close silane chemistries, sulfonation reaction, self-assembly method preparation and
At.
Embodiment 12:
A kind of preparation method of high encapsulation performance lignin nanosphere, it is characterised in that step are as follows:
(1) lignin raw material is added in organic solvent, silane coupling agent reaction is added, obtains sediment；
(2) sediment for obtaining step (1) dissolves in organic solvent again, and cyclodextrin and catalyst, reaction is added
Afterwards, it is added in hydrochloric acid solution, obtains sediment；
(3) sediment that step (2) obtains is added in organic solvent, stirs, water droplet is added in solution, or will be molten
Liquid is to be added drop-wise in water.
(4) solution that step (3) obtains is handled, removes remaining organic solvent, it is then that solution is dry, both
?.
Embodiment 13:
A kind of preparation method of high encapsulation performance lignin nanosphere, it is characterised in that step are as follows:
(1) lignin raw material is added in organic solvent, silane coupling agent reaction is added, obtains sediment；
(2) sediment for obtaining step (1) dissolves in organic solvent again, and cyclodextrin and catalyst, reaction is added
Afterwards, it is added in hydrochloric acid solution, obtains sediment；
(3) sediment that step (2) obtains is added in organic solvent, stirs, water droplet is added in solution, or will be molten
Liquid is to be added drop-wise in water.
(4) solution that step (3) obtains is handled, removes remaining organic solvent, it is then that solution is dry, both
?；
The lignin raw material is lignosulfonates；The organic solvent is dioxane；The silane is even
Connection agent is 3- aminopropyl triethoxysilane.
Embodiment 16:
A kind of preparation method of high encapsulation performance lignin nanosphere, it is characterised in that step are as follows:
(1) lignin raw material is added in organic solvent, silane coupling agent reaction is added, obtains sediment；
(2) sediment for obtaining step (1) dissolves in organic solvent again, and cyclodextrin and catalyst, reaction is added
Afterwards, it is added in hydrochloric acid solution, obtains sediment；
(3) sediment that step (2) obtains is added in organic solvent, stirs, water droplet is added in solution, or will be molten
Liquid is to be added drop-wise in water.
(4) solution that step (3) obtains is handled, removes remaining organic solvent, it is then that solution is dry, both
?；
The lignin raw material is high-boiling alcohol lignin；The organic solvent is dimethylformamide；The silicon
Alkane coupling agent is 3- aminopropyl triethoxysilane kind；The ratio of lignin and silane coupling agent is 0.06g/ml in step (1),
Reaction time is 3h；Cyclodextrin described in step (2) is the cyclodextrin containing p-toluenesulfonyl, and the catalyst is iodate
Potassium.
Embodiment 17:
A kind of preparation method of high encapsulation performance lignin nanosphere, it is characterised in that step are as follows:
(1) lignin raw material is added in organic solvent, silane coupling agent reaction is added, obtains sediment；
(2) sediment for obtaining step (1) dissolves in organic solvent again, and cyclodextrin and catalyst, reaction is added
Afterwards, it is added in hydrochloric acid solution, obtains sediment；
(3) sediment that step (2) obtains is added in organic solvent, stirs, water droplet is added in solution, or will be molten
Liquid is to be added drop-wise in water.
(4) solution that step (3) obtains is handled, removes remaining organic solvent, it is then that solution is dry, both
?；
The lignin raw material is lignosulfonates；The organic solvent is dioxane；The silane is even
Connection agent is 3- aminopropyl triethoxysilane；The ratio of lignin and silane coupling agent is 0.05~0.5g/ml in step (1),
Reaction time is 2h；Cyclodextrin described in step (2) is the cyclodextrin containing p-toluenesulfonyl, and the catalyst is iodate
Potassium；Solution contains lignin 0.5mg/mL before titration described in step (3)；Mixing speed described in step (3) is 600rpm；Step
Suddenly rate of addition described in (3) is 5mL/min；The volume ratio of water and organic solvent is in final solution described in step (3)
2:1；Processing described in step (4) is dialysis；Lignin raw material is added in organic solvent by the step (1), and silicon is added
After the reaction of alkane coupling agent, centrifugation, washing precipitating, and it is dry；The step (2) obtains sediment by centrifugation, is also washed
It washs and dries；
The hydrochloric acid solution is 2M hydrochloric acid；
The drying of the step (2) is freeze-drying.
Embodiment 18:
A kind of preparation method of high encapsulation performance lignin nanosphere, it is characterised in that step are as follows:
(1) lignin raw material is added in organic solvent, silane coupling agent reaction is added, obtains sediment；
(2) sediment for obtaining step (1) dissolves in organic solvent again, and cyclodextrin and catalyst, reaction is added
Afterwards, it is added in hydrochloric acid solution, obtains sediment；
(3) sediment that step (2) obtains is added in organic solvent, stirs, water droplet is added in solution, or will be molten
Liquid is to be added drop-wise in water.
(4) solution that step (3) obtains is handled, removes remaining organic solvent, it is then that solution is dry, both
?；
The lignin raw material is high-boiling alcohol lignin；The organic solvent is dimethylformamide；The silicon
Alkane coupling agent is 3- aminopropyl triethoxysilane kind；In step (1) ratio of lignin and silane coupling agent be 0.05~
0.5g/ml, reaction time 3h；Cyclodextrin described in step (2) is the cyclodextrin containing p-toluenesulfonyl, the catalyst
For potassium iodide；Solution contains 3 mg/mL of lignin before titration described in step (3)；Mixing speed described in step (3) is
500rpm；Rate of addition described in step (3) is 2mL/min；Water and organic solvent in final solution described in step (3)
Volume ratio be 7:1；Processing described in step (4) is dialysis；Lignin raw material is added to organic molten by the step (1)
In agent, after silane coupling agent reaction is added, centrifugation, washing precipitating, and it is dry；The step (2) is precipitated by centrifugation
Object is also washed and dry；
The washing of the step (1) is that anhydrous ether rinses precipitating；The drying of the step (2) is freeze-drying.
Embodiment 19:
A kind of preparation method of high encapsulation performance lignin nanosphere, it is characterised in that step are as follows:
(1) lignin raw material is added in organic solvent, silane coupling agent reaction is added, obtains sediment；
(2) sediment for obtaining step (1) dissolves in organic solvent again, and cyclodextrin and catalyst, reaction is added
Afterwards, it is added in hydrochloric acid solution, obtains sediment；
(3) sediment that step (2) obtains is added in organic solvent, stirs, water droplet is added in solution, or will be molten
Liquid is to be added drop-wise in water.
(4) solution that step (3) obtains is handled, removes remaining organic solvent, it is then that solution is dry, both
?；
The lignin raw material is alkali lignin；The organic solvent is dimethylformamide；The silane is even
Connection agent is 3- aminopropyl trimethoxysilane；The ratio of lignin and silane coupling agent is 0.08g/ml, reaction in step (1)
Time is 1h；Cyclodextrin described in step (2) is the cyclodextrin containing p-toluenesulfonyl, and the catalyst is potassium iodide；Step
Suddenly solution contains lignin 0.8mg/mL before titration described in (3)；Mixing speed described in step (3) is 500rpm；Step (3)
Described in rate of addition be 3mL/min；The volume ratio of water and organic solvent is 2:1 in final solution described in step (3)；Step
Suddenly processing described in (4) is dialysis；Lignin raw material is added in organic solvent by the step (1), is added silane coupled
After agent reaction, centrifugation, washing precipitating, and it is dry；The step (2) obtains sediment by centrifugation, is also washed and is done
It is dry；
The hydrochloric acid solution is 2M hydrochloric acid；
The washing of the step (1) is that anhydrous ether rinses precipitating；The drying of the step (1) is to dry, 60
℃；The washing of the step (2) is precipitated as anhydrous ether and rinses precipitating；The drying of the step (2) is freeze-drying.
Embodiment 20:
A kind of preparation method of high encapsulation performance lignin nanosphere, it is characterised in that step are as follows:
(1) lignin raw material is added in organic solvent, silane coupling agent reaction is added, obtains sediment；
(2) sediment for obtaining step (1) dissolves in organic solvent again, and cyclodextrin and catalyst, reaction is added
Afterwards, it is added in hydrochloric acid solution, obtains sediment；
(3) sediment that step (2) obtains is added in organic solvent, stirs, water droplet is added in solution, or will be molten
Liquid is to be added drop-wise in water.
(4) solution that step (3) obtains is handled, removes remaining organic solvent, it is then that solution is dry, both
?；
The lignin raw material is enzymolysis xylogen；The organic solvent be tetrahydrofuran, dioxane,；It is described
Silane coupling agent be 3- aminopropyl triethoxysilane；The ratio of lignin and silane coupling agent is 0.1g/ in step (1)
Ml, reaction time 4h；Cyclodextrin described in step (2) is the cyclodextrin containing p-toluenesulfonyl, and the catalyst is iodine
Change potassium；Solution contains lignin 5mg/mL before titration described in step (3)；Mixing speed described in step (3) is 100rpm；
Rate of addition described in step (3) is 2mL/min；The volume ratio of water and organic solvent in final solution described in step (3)
For 7:1；Processing described in step (4) is dialysis；Lignin raw material is added in organic solvent by the step (1), is added
After silane coupling agent reaction, centrifugation, washing precipitating, and it is dry；The step (2) obtains sediment by centrifugation, also carries out
It washs and dries；
Dialysis described in step (4) is to be carried out using bag filter；The time of the dialysis is 40h；Described in step (3)
Water is deionized water；
The hydrochloric acid solution is 2M hydrochloric acid；
The washing of the step (1) is that anhydrous ether rinses precipitating；The drying of the step (1) is to dry, 70
℃；The washing of the step (2) is precipitated as anhydrous ether and rinses precipitating；The drying of the step (2) is freeze-drying；
The high encapsulation performance lignin nanosphere is used to prepare pharmaceutical carrier.
Claims (10)
1. a kind of high encapsulation performance lignin nanosphere, it is characterised in that: its structure is to be grafted cyclodextrin on lignin molecule
Monomer structure.
2. high encapsulation performance lignin nanosphere as described in claim 1, it is characterised in that: the nanosphere is β-ring paste
Essence/enzymolysis xylogen polymer.
3. high encapsulation performance lignin nanosphere as described in claim 1, it is characterised in that: the nanosphere be it is hollow,
There is the spherical micro-nano particle of opening on surface；The nanometer bulb diameter is 100-300nm；The nanosphere is amphipathic polymerization
Object.
4. high encapsulation performance lignin nanosphere as described in claim 1, it is characterised in that: the nanometer bulb diameter is
180-250nm。
5. high encapsulation performance lignin nanosphere as described in claim 1, it is characterised in that: the nanosphere is with lignin
It is raw material with cyclodextrin, is prepared using conjunction silane chemistries, sulfonation reaction, self-assembly method.
6. the preparation method of high encapsulation performance lignin nanosphere as claimed in claim 1 to 5, it is characterised in that step
Are as follows:
(1) lignin raw material is added in organic solvent, silane coupling agent reaction is added, obtains sediment；
(2) sediment for obtaining step (1) dissolves in organic solvent again, cyclodextrin and catalyst is added, after reaction,
It is added in hydrochloric acid solution, obtains sediment；
(3) sediment that step (2) obtains is added in organic solvent, stir, water droplet is added in solution, or by solution with
It is added drop-wise in water.
(4) solution that step (3) obtains is handled, removes remaining organic solvent, it is then that solution is dry, both.
7. the preparation method of high encapsulation performance lignin nanosphere as claimed in claim 6, it is characterised in that: described is wooden
Plain raw material is one or more of enzymolysis xylogen, alkali lignin, high-boiling alcohol lignin, lignosulfonates；Described has
Solvent is one or more of tetrahydrofuran, dioxane, dimethylformamide；The silane coupling agent is 3- ammonia third
Any one or more of ethyl triethoxy silicane alkane, 3- aminopropyl trimethoxysilane；In step (1) lignin with it is silane coupled
The ratio of agent is 0.05~0.5g/ml, and the reaction time is 0.5h~5h；Cyclodextrin described in step (2) is containing to toluene sulphur
The cyclodextrin of acyl group, the catalyst are potassium iodide；Solution contains 0.4~6mg/mL of lignin before titration described in step (3)；
Mixing speed described in step (3) is 300~1500rpm；Rate of addition described in step (3) is 0.5~6mL/min；Step
Suddenly the volume ratio of water and organic solvent is 2:1~7:1 in final solution described in (3)；Processing described in step (4) is dialysis；
Lignin raw material is added in organic solvent by the step (1), after silane coupling agent reaction is added, centrifugation, and washing precipitating,
And it is dry；The step (2) obtains sediment by centrifugation, is also washed and dry.
8. the preparation method of high encapsulation performance lignin nanosphere as claimed in claim 6, it is characterised in that: step (4) institute
The dialysis stated is to be carried out using bag filter；The time of the dialysis is 12~48h；Water described in step (3) is deionized water；
Hydrochloric acid solution described in step (2) is 2M hydrochloric acid.
9. the preparation method of high encapsulation performance lignin nanosphere as claimed in claim 7, it is characterised in that: the step
(1) washing is that anhydrous ether rinses precipitating；The drying of the step (1) is to dry, 50-75 DEG C；The step (2)
Washing is precipitated as anhydrous ether and rinses precipitating；The drying of the step (2) is freeze-drying.
10. the high encapsulation performance lignin nanosphere as described in claim 1-10 is any is used to prepare answering in pharmaceutical carrier
With.
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| CN115367862A (en) * | 2022-07-08 | 2022-11-22 | 华南理工大学 | Preparation and application of signal molecule modified sponge ceramic-based biofilm carrier |
| CN115710355A (en) * | 2022-11-25 | 2023-02-24 | 盐城工学院 | Biological targeting type porous lignin-based nanoparticles and preparation method and application thereof |
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Application publication date: 20190726 |