CN104817660B - Preparation method of modified carboxymethyl chitosan nano gel - Google Patents
Preparation method of modified carboxymethyl chitosan nano gel Download PDFInfo
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- CN104817660B CN104817660B CN201510244424.7A CN201510244424A CN104817660B CN 104817660 B CN104817660 B CN 104817660B CN 201510244424 A CN201510244424 A CN 201510244424A CN 104817660 B CN104817660 B CN 104817660B
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Abstract
The invention discloses a preparation method of modified carboxymethyl chitosan nano gel, belonging to the technical field of carriers and sustained-release material. The preparation method comprises the following steps: firstly preparing methylacryloyl carboxymethyl chitosan; and performing free radical polymerization in the presence of N'-N-bis(acrylyl) cystamine serving as a cross-linking agent to prepare the modified carboxymethyl chitosan nano gel. Through determining the particle size and zeta potential of nano particles under the condition of different pH values, the modified carboxymethyl chitosan nano gel is proved to have a pH sensitivity. A protein adsorption test shows that the nano gel is capable of preventing protein adsorption. The prepared nano gel is used for successfully carrying anticancer drug doxorubicin hydrochloride; in-vitro release tests in which PBS solutions different in pH and glutathione concentration are used as media prove that the drug-carried nano particles have relatively good pH and reduction sensitivity.
Description
Technical field
This belongs to carrier and slow-release material technical field, is related to a kind of preparation of modified carboxy methyl chitosan nano gel
Method and its application.
Background technology
Carboxymethyl chitosan is a kind of soluble derivative of shitosan, is a kind of polyampholyte.Due to carboxymethyl
Shitosan has the performances such as good water solubility, biocompatibility, biodegradable, antibiotic property and no cytotoxicity, by
It is widely used in biomedical sector, such as wound repair, organizational project, drug delivery, gene therapy, bio-imaging.Make
For pharmaceutical carrier, carboxymethyl chitosan nanoparticles can improve the stability of medicine, extend the effective acting time of medicine, energy
Enough strengthen medicine to biomembranous permeability, eliminate biological barrier.By control the molecular weight of carboxymethyl chitosan, substitution value with
And carry out modifying etc. method to carrier and prepare environmental sensitivity carboxymethyl chitosan nanoparticles, medicine is controlled release and
Target administration, can reduce dosage under the premise of guarantee is pharmaceutically-active, reduce the side effect that medicine is produced to human body.
Cancer is one of primary killers of human health.As the Main Means of clinical treatment tumour, chemotherapy by
There is the shortcomings of lacking selectivity, poor stability, short Half-life in vivo and multidrug resistance in cancer therapy drug, not only cancer is controlled
Therapeutic effect is limited, can also normal tissue and cell generation toxic and side effect.In order to overcome these shortcomings of cancer treatment drugs, system
Get everything ready good biocompatibility, the anti-cancer medicament carrier of being capable of Based Intelligent Control insoluble drug release has become current research heat
Point.The present invention is prepared by free-radical polymerized method and covalently handed over the small molecule of carbon-carbon double bonds and disulfide bond as crosslinking agent
The carboxymethyl chitosan nanogel of connection, it is to avoid using toxic cross-linking agents such as glutaraldehydes, while gained nanogel has pH
With reduction doubling sensitivity, the stability of particle can be kept when nanogel is circulated in vivo, once contacting with tumour cell, be received
Rice gel will be acted on the glutathione in tumour cell, and disulfide bonds promote cross-linked structure to destroy, and increase medicine in tumour
Intracellular Targeting delivery.
The content of the invention
The purpose of the present invention is to utilize carboxymethyl chitosan to be primary raw material, by its modified side by radical polymerization
Method prepares modified carboxy methyl chitosan nano gel, and gained nanogel has pH and reduction doubling sensitivity.
In order to realize foregoing invention purpose, technical scheme is as follows:
(1) carboxymethyl chitosan is modified using methacrylic anhydride, is prepared for methacryl carboxymethyl chitosan
Sugar, and it is purified.
(2) methacryl carboxymethyl chitosan and double (acryloyl) cystamines of N, N- are dissolved in distilled water together, plus
Heat and nitrogen protection, add initiator so that the carbon-carbon double bond in system occurs radical polymerization, obtains nanogel.
(3) prepared nanogel is dialysed by medium of dialysing of distilled water, is obtained pure nanogel molten
Liquid.
(4) nanogel is used for the control release of cancer therapy drug ADMh, it was demonstrated that pharmaceutical carrier have pH and
Reduction-sensitive.
Beneficial effects of the present invention：
(1) by N, double (acryloyl) cystamines of N- carry out free-radical polymerized the present invention with methacryl carboxymethyl chitosan
Reaction is closed, while nanogel is formed, disulfide bond is introduced in structure so that nanogel has reduction-sensitive.
(2) due to coagulating containing substantial amounts of carboxyl and part amino, therefore prepared nanometer in carboxymethyl chitosan glycan molecule
Glue has pH sensitiveness.
(3) due to containing substantial amounts of carboxyl, therefore the nanogel table prepared by the present invention in carboxymethyl chitosan glycan molecule
Face carries negative electrical charge under the conditions of certain pH, can prevent protein adsorption, extends particle circulation in vivo.
(4) process of the prepared nanogel of the present invention is simple, does not use organic solution, therefore environmental protection.
(5) electrostatic that the nanogel prepared by the present invention can pass through between contained carboxyl and ADMh amino is made
With carrying out drug loading.
Description of the drawings
The preparation process schematic diagram of Fig. 1 nanogels
The stereoscan photograph figure of Fig. 2 nanogels
Particle diameter distribution of Fig. 3 nanogels in glutathione (GSH) aqueous solution after (10mM) incubation different time, temperature
37℃
Release profiles of Fig. 4 nanogels MCB5 in different pH PBSs
Release profiles (pHs of Fig. 5 medicament-carried nano gel MCB5 in the PBS of different glutathione concentrations
=7.4)
Fig. 6 in the presence of variable concentrations blank nanogel MCB5, the survival rate of 3T3 cells and Hela cells
Specific embodiment：
Embodiment 1：
The preparation of methacryl carboxymethyl chitosan
1g carboxymethyl chitosans are dissolved in into 100mL distilled water, are stirred under the conditions of ice-water bath and is dropwise slowly added to after 30min
A certain amount of methacrylic anhydride, keeps ice-water bath condition mechanical agitation 24h, the synthesis of methacryl carboxymethyl chitosan to match somebody with somebody
Side is as shown in table 1.Reacted product is precipitated with ethanol, filter cake ethanol is crossed and is washed three times, under the conditions of 30 DEG C
It is dried under vacuum to be put into -20 DEG C of Refrigerator stores after constant weight.Feed change weight proportion is obtained 5 methacryl carboxymethyl shells
Glycan samples, are shown in Table 1.
The synthesizing formula of the methacryl carboxymethyl chitosan of table 1
Embodiment 2：
The preparation of nanogel
Addition 80mg methacryls carboxymethyl chitosan and 40mL distilled water in 100mL there-necked flasks, magnetic agitation,
Treat that it is completely dissolved addition 40mg N in backward flask, flask is moved into 80 DEG C of oil bath pans by double (acryloyl) cystamines of N-, and to burning
Nitrogen is passed through in bottle, to be heated and add the persulfate aqueous solution that 1mL concentration is 8mg/mL in flask after 5min, 80 DEG C are continued anti-
Answer 1h.Whole course of reaction is carried out under conditions of magnetic agitation and nitrogen protection.By reacted nanogel solution dress
Enter bag filter (molecular cut off MWCO=8000～14000) to dialyse 5 days by medium of dialysing of distilled water, change once saturating every 8h
Analysis medium, obtains pure nanogel solution.Using N, double (acryloyl) cystamines of N- respectively with CB1, CB2, CB3, CB4, CB5
Reaction, prepared nanogel is respectively designated as MCB1, MCB2, MCB3, MCB4, MCB5, and the ESEM of nanogel shines
Piece is as shown in Figure 2.
Embodiment 3：
The pH sensitivity analyses of nanogel
Nanogel pH value of solution is adjusted with 0.1M NaOH solutions and 0.1M HCl solutions be respectively 4.5,5.8,7.4,8.0,
After pH value of solution is stable, the zeta potential and its particle diameter of nanogel under each pH value are determined using zeta potential and nano-particle size analysis instrument.
As a result as shown in table 2, table 3.As can be seen that as pH value is reduced to 4.5 by 8.0, the zeta potential of nanogel is presented becoming for reduction
Gesture.This mainly due to reducing with pH value, one side particle surface-COO-- COOH is gradually converted into, on the other hand-NH2Turn
It is changed into positively charged-NH3 +With-COO-Produce electrostatic interaction so that negative electrical charge is neutralized, these two aspects reason causes nanogel
- the COO of surface institute band-Amount reduce, surface charge value reduce.As pH value is reduced to 4.5 by 8.0, the particle diameter of nanogel
Overall that the trend for reducing is presented, its main cause has at 2 points：On the one hand, with the reduction of pH value ,-COO in nanogel-Gradually
It is changed into-COOH, the electrostatic repulsion between the carboxylate radical of gel inside reduces, and hydrogen bond action can be also produced between carboxyl.Separately
On the one hand, with unprotonated-NH in the reduction nanogel of pH value3It is changed into positively charged-NH3 +, with-COO-Produce
Electrostatic interaction.Both reasons result in the active force of the molecule interchain inside nanogel jointly to be strengthened, and the particle diameter of gel is received
Contracting.
The nanogel of table 2 zeta potential at various ph values
| Nanogel title | pH4.5 | pH5.8 | pH7.4 | pH8.0 |
| MCB1 | -10.3±1.9 | -13.8±0.9 | -20.9±1.7 | -25.8±2.3 |
| MCB2 | -10.1±0.8 | -16.3±1.5 | -22.7±1.4 | -25.5±1.3 |
| MCB3 | -13.7±1.3 | -16.5±2.3 | -18.0±2.8 | -23.6±1.4 |
| MCB4 | -12.0±1.3 | -15.1±1.0 | -23.2±2.2 | -25.9±3.1 |
| MCB5 | -13.5±2.4 | -14.9±1.6 | -21.7±0.9 | -23.4±2.5 |
The nanogel of table 3 particle diameter at various ph values
| Nanogel title | pH4.5 | pH5.8 | pH7.4 | pH8.0 |
| MCB1 | 293 | 330 | 446 | 485 |
| MCB2 | 287 | 326 | 423 | 461 |
| MCB3 | 224 | 306 | 392 | 453 |
| MCB4 | 220 | 289 | 331 | 360 |
| MCB5 | 205 | 231 | 249 | 300 |
Embodiment 4：
The anti-protein adsorption analysis of nanogel
The nanogel solution (pH 7.4) of 1mg/mL is taken, precision weighs a certain amount of bovine serum albumin and is added thereto, makes
The concentration of bovine serum albumin is 0.5mg/mL, is placed in be incubated respectively after 24h in 37 DEG C of thermostatic control oscillator vibrations after being well mixed and takes
Go out, 12000r/min centrifugation 30min take supernatant liquor, absorbance at 279nm are determined, according to the standard of bovine serum albumen solution
Curve calculates adsorbance of the nanogel to bovine serum albumin.As a result such as table 4.In 24h, nanogel is to bovine serum albumin
Adsorbance very little.Known by table 2, when pH is 7.4, the zeta potential of nanogel is -20mV or so, now nanogel surface
Substantial amounts of carboxyl is in the form of carboxylate radical so that its surface carries negative electrical charge.The isoelectric point of most of protein in human body
pI<6, therefore (work as pH in normal human's physiological environment protein belt negative electrical charge<During pI, protein belt positive charge；During pH=pI,
Protein shows electroneutral, neutral；pH>During pI, protein belt negative electrical charge).Isoelectric point pI=4.7 of bovine serum albumin, because
This, when pH is 7.4, bovine serum albumin carries negative electrical charge, there is electrostatic repulsion with nanogel so that nanogel
It is difficult to adsorb bovine serum albumin.It is certain that the ability of this anti-protein adsorption of nanogel can cause it to have in blood
" stealthy " performance, it is to avoid removed by reticuloendothelial system, extends nanogel circulation time in blood.
Absorption (%) of the nanogel of table 4 to bovine serum albumin in 24 hours
Embodiment 5：
The reduction-sensitive analysis of nanogel
It is research object to choose nanogel MCB5, and in 1mg/mL nanogel solution GSH is added, and makes the concentration of GSH
For 10mM, 37 DEG C of incubations, particles size and distribution during incubation 0,5,12,24h is determined respectively using nano particle size instrument, as a result as schemed
Shown in 3, with the prolongation of incubation time in reproducibility environment, the particle diameter of nanogel becomes big, and the dispersion of distribution broadens, this be due to
GSH causes the disulfide bonds in nanogel, nanogel internal cross-linked structure to be destroyed, and the swellability of particle increases.
Embodiment 6：
Nanogel is used to load adriamycin and its release in vitro
It is research object to choose nanogel MCB5, takes the nanogel solution of the 1mg/mL of 50mL pH=8, is added
10mg ADMhs, after lucifuge magnetic agitation 5h bag filter is loaded, and dialyse 24h in distilled water, is changed every 8h and is once dialysed
Liquid, removes free ADMh, you can obtain medicament-carried nano gel solution, can be with according to the calibration curve of ADMh
The carrying drug ratio and envelop rate for calculating nanogel is respectively 18.17% and 90.86%.
5mL medicament-carried nano gel solutions are taken, it has been investigated respectively, and (PBS that pH is respectively 5.8,7.4,8.0 is molten in different pH
Liquid) and different reproducibility environment (GSH concentration is respectively 0,10, the PBS solution of 20mM pH=7.4) under release in vitro (37
DEG C, constant temperature oscillation), the volume of initial release medium is 50mL.3mL dissolution mediums are taken at set intervals in ultraviolet spectrometry light
Absorbance of the wavelength at 485nm is determined on degree meter, the concentration of ADMh is calculated by calibration curve, while supplementing every time
Equivalent fresh dissolution medium is maintaining its cumulative volume constant.Release profiles (as shown in Figure 4) under different pH environment can
Go out that pH value is less, nanogel is faster to the rate of release of adriamycin, and preparation is also bigger.After release 24h, pH 5.8
Under the conditions of preparation reach 83.2%, and under the conditions of pH 8.0 be only 57.0%.This is due to nanogel and Ah mould
The structure of element can be affected by pH.During pH 5.8, the amino of adriamycin is protonated completely, and carboxylate radical also can in nanogel
There are Partial protons and be changed into carboxyl, cause the electrostatic interaction between nanogel and adriamycin to reduce, make loaded Ah mould
Element is easier to discharge.With the rising of pH value, the carboxylic acid radical content in nanogel increases, quiet between gel and adriamycin
Electro ultrafiltration increases so that the rate of release of adriamycin slows down, and preparation reduces.The release profiles of different reproducibility environments are such as
It can be found that it is 58.0% that dissolution medium does not add the final preparation of GSH shown in Fig. 5, and GSH concentration point in dissolution medium
Not Wei the finally accumulative release rate of 10mM and 20mM be respectively 66.0% and 83.6%, illustrate that reproducibility environment can substantially accelerate medicine
The release of thing, improves the preparation of medicine.This can make the S -- S in nanogel rupture mainly due to GSH, destruction
The structure of nanogel, the drug molecule inside gel can be released quickly against in medium
Embodiment 7：
Nanogel cytotoxicity test
The cytotoxicity of blank nanogel is estimated using mtt assay, the cell for cytotoxicity test is 3T3
Cell and Hela cells, concrete operation step is as follows：
Take the logarithm the phase growth 3T3 cells or Hela cells, Jing pancreatin digestion after, with containing 10% hyclone RPMI-
1640 culture mediums (RPMI-1640 complete mediums) are diluted to concentration for 6 × 104The cell suspension of individual/mL, is inoculated in the training of 96 holes
Foster plate, 100 μ L are inoculated with per hole, are placed in 37 DEG C, 5%CO2Cultivate in incubator after 24h and discard culture medium.Negative control group, the positive
It is complete that control group and experimental group are separately added into 100 μ L RPMI-1640 complete mediums, the RPMI-1640 containing 0.64% phenol per hole
Full culture medium, the MC5B of nanogel containing variable concentrations RPMI-1640 complete mediums (concentration of nanogel is respectively 10,
20th, 50,100,200 μ g/mL), 4 multiple holes are set per group, continue to be placed in 37 DEG C, 5%CO2Cultivate in incubator after 24h, add per hole
Enter 20 μ L MTT solution, continue to cultivate after 4h, discard the solution in culture plate, 150 μ L DMSO are added per hole, shake up, use enzyme mark
Instrument determines OD values at 570nm, and calculates cell survival rate.
As a result it is as shown in Figure 6, although the survival rate of the concentration versus cell of nanogel has a certain impact, even if nanometer
Gel strength has reached 200 μ g/mL, and the survival rate of two kinds of cells also still reaches more than 85%, illustrates prepared nanogel
No cytotoxicity.
Above-described embodiment is used for illustrating the present invention, rather than limits the invention, the present invention spirit and
In scope of the claims, any modifications and changes made to the present invention both fall within protection scope of the present invention.
Claims (8)
1. a kind of preparation method of modified carboxy methyl chitosan nano gel, comprises the following steps successively：
1) by carboxymethyl chitosan solution and methacrylic acid anhydride reactant, methacryl carboxymethyl chitosan is prepared for, and it is right
It is purified；
2) by methacryl carboxymethyl chitosan and N, N '-bis- (acryloyl) cystamine is dissolved in together in distilled water, and heating is simultaneously
Nitrogen is protected, and adds initiator so that the carbon-carbon double bond in system occurs radical polymerization, obtains modified carboxy methyl chitosan nano
Rice gel；
3) prepared nanogel is dialysed by medium of distilled water, is obtained pure nanogel solution.
2. the preparation method of modified carboxy methyl chitosan nano gel according to claim 1, it is characterised in that：The step
1) for 87.0%, viscosity average molecular weigh is M to the carboxy methylation degree of the carboxymethyl chitosan for adoptingη=6.3 × 105。
3. the preparation method of modified carboxy methyl chitosan nano gel according to claim 1, it is characterised in that：The step
1) carboxymethyl chitosan is respectively 1 with the mass ratio of methacrylic anhydride in:0.5、1:1.0、1:1.5、1:2.0、1:2.5；Carboxylic
Methyl chitosan is made into the 1w% aqueous solution, mixes with methacrylic anhydride, mechanical agitation, and at 0 DEG C 24h is reacted.
4. the preparation method of modified carboxy methyl chitosan nano gel according to claim 1, it is characterised in that：The step
2) in, methacryl carboxymethyl chitosan and N, N ' mass ratio of-bis- (acryloyl) cystamines is 1:0.2～1:2.
5. the preparation method of modified carboxy methyl chitosan nano gel according to claim 1, it is characterised in that：The step
2) reaction temperature is 40～90 DEG C, and the initiator of addition is potassium peroxydisulfate or ammonium persulfate, and initiator amount is methacryl
The 2%～20% of carboxymethyl chitosan quality.
6. the preparation method of modified carboxy methyl chitosan nano gel according to claim 1, it is characterised in that：The step
3) in, the bag filter molecular cut off for using is 8000～14000, and dialysis time is no less than 3 days.
7. a kind of modified carboxy methyl chitosan nano gel, is characterized in that by methacryl carboxymethyl chitosan and N, N '-
The cross-linked copolymer that double (acryloyl) cystamines are prepared according to claim 1 methods described, this copolymer forms nanometer in water and coagulates
Glue, its particle diameter changes with the pH differences of solution, and distribution is between 220 nanometers to 485 nanometers.
8. a kind of application of modified carboxy methyl chitosan nano gel, is characterized in that modified carboxy methyl shell described in claim 7
Glycan nanogel is mixed with ADMh solution, and nanogel loads ADMh by electrostatic interaction, passes through
Dialysis removes free adriamycin, and in vitro in release experiment, medicament-carried nano gel shows preferable pH and reduction-sensitive.
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| CN107541927A (en) * | 2017-09-19 | 2018-01-05 | 安徽阜南县万家和工艺品有限公司 | A kind of processing method for improving Lin's grass dyefastness |
| CN107457855A (en) * | 2017-09-20 | 2017-12-12 | 阜南县星光工艺品有限公司 | A kind of drying means for avoiding Chinese white poplar sheet material from ftractureing |
| CN107955099A (en) * | 2017-12-26 | 2018-04-24 | 安徽省东乾食品有限公司 | A kind of preparation method of the absorbing membrane based on vegetable and fruit packaging |
| CN111001008B (en) * | 2019-12-28 | 2021-09-17 | 湖北大学 | Preparation method and application of double-crosslinked nanogel |
| CN112250887B (en) * | 2020-09-01 | 2022-05-24 | 华南理工大学 | Copper metal organic framework nanoparticle functionalized hydrogel and preparation method and application thereof |
| CN113694176A (en) * | 2021-09-15 | 2021-11-26 | 天津医科大学 | Application of oxytocin-loaded chitosan nanogel in preparation of early intervention drug for Alzheimer's disease |
| CN113713120A (en) * | 2021-09-16 | 2021-11-30 | 浙江海洋大学 | Carboxymethyl chitosan nanogel for delivering antitumor drugs |
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| CN104491871A (en) * | 2014-12-02 | 2015-04-08 | 江南大学 | PH/reduction-sensitive nano microgel based on polyglutamic acid and cystamine |
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| CN104311821A (en) * | 2014-10-15 | 2015-01-28 | 江南大学 | Preparation of polymer medicine-carrying nano micelle with dual responsiveness |
| CN104491871A (en) * | 2014-12-02 | 2015-04-08 | 江南大学 | PH/reduction-sensitive nano microgel based on polyglutamic acid and cystamine |
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