CN105434357A - Preparation for amphoteric nanoparticle - Google Patents
Preparation for amphoteric nanoparticle Download PDFInfo
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- CN105434357A CN105434357A CN201510971373.8A CN201510971373A CN105434357A CN 105434357 A CN105434357 A CN 105434357A CN 201510971373 A CN201510971373 A CN 201510971373A CN 105434357 A CN105434357 A CN 105434357A
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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Abstract
The invention provides a preparation method for an amphoteric nanoparticle based on glucan pH and reduction sensitivity and application of the amphoteric nanoparticle to resist tumors, and relates to the technical field of medical materials. The nanoparticle is synthesized by employing glucan, succinic anhydride and cystamine as raw materials, and stable nanoparticles with different particle sizes are prepared according to the following steps: firstly reacting succinic anhydride with glucan to carboxylize glucan, then adding cystamine to perform amidation crosslinking reaction, and controlling the carboxylation degree and crosslinking degree. The nanoparticle possesses amphoteric performance because of carried free amino and carboxyl, and the nanoparticle possesses extremely good protein non-specific adsorption resistance and can be rapidly taken in by cancer cells. The nanoparticle is endowed with reduction sensitivity by a disulfide bond, and is fractured in cancer cells containing reductive glutathione with a relatively high concentration, and therefore the nanoparticle possesses tumor targeting property and controlled release performance, and possesses relatively high application prospect.
Description
Technical field
The present invention relates to biology medical material technical field, particularly relate to a kind of preparation with the nano-particle of zwitterionic character.
Background technology
What cancer was considered to be only second to cardiovascular and cerebrovascular vessel causes people's main causes of death.At present, the important method chemotherapy of Therapeutic cancer.But this method has a lot of defect, many cancer therapy drugs all also exist and are insoluble in the shortcoming such as water, poor stability, and not only have killing action to cancerous cell, also have larger toxic and side effects to Normocellular.And easily removed by reticuloendothelial system, cause Cell uptake poor.
Intelligent nano medicine-carried system brings new hope to treatment of cancer.Nanometer system can strengthen permeability and stop (EPR) effect, and can escape the identification of the RE matter system of human body and catch, and extends drug-loading system circulation time in blood, improves the bioavailability of medicine.Simultaneously, (pH of cancerous cell is lower to utilize cancerous cell and Normocellular difference, the content compared with normal cell of the reduced glutathion in cancerous cell is high, the surface of cell membrane of cancerous cell has the receptor of excessive generation, as folic acid, transferrins) can rapidly by drug release to tumor locus.
At present, the widely used hydrophilic segment preparing nano-particle is Polyethylene Glycol (PEG), but Recent study is thought: PEG also has certain hydrophobicity except hydrophilic, oxidized under oxygen and transition metal ions exist; The immunoreation that the pharmaceutical grade protein of PEG modification is possible is also observed; The PEG housing shroud effect of nano-micelle, is unfavorable for the intracellular picked-up of nano-micelle in addition.And the nano-particle that PEG modifies lacks the reactive group of active targeting.
Succedaneum amphion as PEG shows excellent performance, such as Superhydrophilic, high protein stability and fabulous " stealth " effect.But meanwhile also there are some defects, distinct issues prepare the raw material of amphoteric ion polymer is the most non-Biodegradable.And this will produce a series of problem, the nubbin as the degraded of polymer can cause the incomplete release of medicine and produce bad side reaction.In addition, the method preparing amphion nano-particle be complicated and say take time longer.Thus the bottleneck problem of this type of material practical application is become.
Summary of the invention
For solving these defects, the object of this research design is a kind of biodegradable preparation with the both sexes particle nano-particle of pH and reduction-sensitive.
The invention provides a kind of amphion nano-particle of reducible degraded, include the amphion nano-particle of succinic anhydride, glucosan and cystamine synthesis, wherein glucosan is biodegradable polysaccharide, has a large amount of reactive groups, controlled molecular weight, biodegradable characteristics, bio-compatibility and protein stability etc.In order to make this nano-particle, there is pH and reduction-sensitive, in preparation process, introducing succinic anhydride, is that glucosan has carboxyl in various degree and is combined with cystamine, wherein the mass ratio of glucosan and succinic anhydride is 100:25 ~ 400, and the glucosan of carboxylation and the mass ratio of cystamine are 1:0.2 ~ 3.Thus the quality by designing succinic anhydride and cystamine controls the particle diameter of nano-particle.
The present invention also provides a kind of reducible degraded to gather the preparation method of amphion nano-micelle, comprises the following steps successively:
(1) glucosan of different quality ratio and succinic anhydride carry out carboxylation reaction under the effect of catalyst.Reaction dissolvent is dimethyl sulfoxine.
(2) glucosan after the carboxylation of different quality ratio and 2-aminoethyl disulfide dihydrochloride carry out amidation process under the effect of catalyst.The required solvent of reaction is dimethyl sulfoxine.
(3) product prepared by step (2) is dissolved after purification drying.Solvent needed for dissolving is dimethyl sulfoxine.
(4), after Keep agitation, in solution, ultra-pure water is dripped.
(5) solution of step (4) gained is dialysed.
Concrete, the catalyst in described step (1) needed for carboxylation reaction is DMAP.
Concrete, reaction 60 DEG C of reaction 24h under nitrogen protection in described step (1).
Concrete, in described step (1), mass ratio is 100:25 ~ 400.
Concrete, in described step (2), amidation process catalyst is 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride and I-hydroxybenzotriazole.
Concrete, reaction 25 DEG C of reaction 24h under nitrogen protection in described step (2).
Concrete, in described step (2), mass ratio is 1:0.2 ~ 3.
Concrete, in described step (5), molecular cut off used of dialysing is the bag filter of 3500, and dialysis treatment is no less than 48 hours, obtains amphion nano-particle.The object of bag filter is to remove unreacted micromolecule and oligomer, achieving the goal of selection 3500
The present invention also provides a kind of and biodegradablely has pH and reduction-sensitive amphion nano-particle, is preparing the application in chemotherapeutics carrier.Different (blood pH is 7.4, and lysosome and endosome pH are 5-6) of normal cell and the pH of cancerous cell, medicine can be discharged into target site as much as possible.In addition, the concentration ratio of glutathion in tumor cell is high 100 to 1000 times in body fluid.Drug-loading nanoparticles enters in tumor cell, and under the reduction of glutathion, polymers degrade, discharges medicine.
By such scheme, the present invention at least has the following advantages:
1., because this nano-particle is simultaneously containing construction units such as amino, carboxyl and cystine linkages, have sensitive pH and reduction response, under inside tumor cells environment (faintly acid and reproducibility), nanoparticle structure easy fracture, impels drug release;
2. in nano-particle containing amino and carboxyl, make it have amphion performance, give the anti-protein non-specific adsorption performance of nano-particle excellence;
3. material used is biodegradable, and this nano-particle introduces cystine linkage, and after nano-particle enters tumor cell, rupture under the stimulation of high concentration glutathion, medicine can discharge completely, has actual using value as anti-cancer medicament carrier;
4. nano-micelle no cytotoxicity, meets the safety standards that human body uses;
5. this nano-particle contains a large amount of carboxyl, and by electrostatic interaction and anticancer drugs, doxorubicin, drug loading is higher.
Above-mentioned explanation is only the general introduction of technical solution of the present invention, in order to better understand technological means of the present invention, and can be implemented according to the content of description, coordinates accompanying drawing to be described in detail as follows with preferred embodiment of the present invention.
Accompanying drawing explanation
Fig. 1 is the synthetic route of amphion nano-particle in the present invention
Fig. 2 is the transmission electron microscope photo (a:Dex/SA1-02 of amphion nano-particle in the present invention; B:Dex/SA1-04; C:Dex/SA1-07; D:Dex/SA1-15; E:Dex/SA1-30);
Fig. 3 is the Zeta potential of amphion nano-particle in different pH value and the change of particle diameter in the present invention;
Fig. 4 is the change of size (sample be: Dex/SA1-02) of amphion nano-particle in dithiothreitol, DTT (DTT) solution of variable concentrations, under different time in the present invention;
Fig. 5 is the non-specific adsorption performance of the anti-bovine serum albumin of amphion nano-particle in the present invention;
Fig. 6 is the cytotoxicity result of amphion nano-particle in the present invention.
Detailed description of the invention
Below in conjunction with drawings and Examples, the specific embodiment of the present invention is described in further detail.Following examples for illustration of the present invention, but are not used for limiting the scope of the invention.
Embodiment 1
1) carboxylation of glucosan:
0.500g glucosan is dissolved in the dried dimethyl sulfoxine of 4mL, proceeded in flask dried in advance afterwards, add the DMAP adding the dissolving of 0.5mL dimethyl sulfoxine in flask, then add the succinic anhydride that 1.0mL dimethyl sulfoxine has dissolved, reaction is 60 DEG C of reaction 24h in a nitrogen environment.The cold ethanol extraction of product, with washing with alcohol several times, finally dry in vacuum drying oven.According to the needs of nano-micelle different degree of substitution in concrete use procedure, regulate the proportioning of the quality of glucosan and succinic anhydride.
Table 1 dextran modification formula catalog
2) amidation process of glucosan/succinic anhydride and cystamine:
Glucosan/succinic anhydride (100mg) adds 5.0mL to and contains in 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (2.68mg) and I-hydroxybenzotriazole (4.05mg) dimethyl sulfoxine, stirs 3h at 800 rpm with magnetic stirring apparatus.Subsequently, the dimethyl sulfoxide solution of the 3mL of the Guang containing 20mg is dropwise added dropwise in above-mentioned solution, at room temperature reacts 24h.Finally with the method purified product of dialysis (molecular cut off 3500).Product is obtained by lyophilization.According to the needs of nano-micelle different-grain diameter in concrete use procedure, regulate the proportioning of the quality of glucosan/succinic anhydride and cystamine.
The amidation process formula catalog of table 2 glucosan/succinic anhydride and cystamine
3) preparation of amphion nano-particle
(glucosan/succinic anhydride)/cystamine is made into the dimethyl sulfoxide solution of 0.5wt%, the distilled water of 6mL is dropwise instilled in above-mentioned solution, the mixed solution obtained is stable under magnetic stirring to spend the night, after solution is transferred in bag filter (molecular cut off 3500), dialyse 3 days.As shown in Figure 2, the transmission electron microscope photo of amphion nano-particle in the present invention, in figure, a-e distinguishes the shape appearance figure of the amphion nano-particle of a-e five kinds of formula in corresponding table 2, this nano-particle pattern visible is spherical substantially, particle size distribution is more homogeneous, but when the quality of cystamine in component increases, the particle diameter of nano-particle increases gradually.
Embodiment 2
The pH sensitivity of amphion nano-particle:
Gained amphion nano-particle (Dex/SA1-02) in embodiment 1 is placed in the buffer solution of pH2 ~ 10.0 respectively, zeta potential change is observed with zeta potential measurement instrument, meanwhile, with the particle diameter of nano particle size instrument test nano-particle, the results are shown in Figure 3, when pH value is 7.4, solution alkalescence, the amino in micelle is difficult to absorb proton, and electropositive is suppressed, in micelle, negatively charged ions accounts for mainly, therefore in negative Zeta potential value.When acid condition pH2 ~ 6, the amino picked-up proton in micelle forms ammonium cation, and acidity is stronger, and protonation increases, and therefore Zeta potential value is larger.As seen from Figure 3 as pH=7.4, the particle diameter of nano-particle is minimum, and pH reduces particle diameter and increases.
Embodiment 3
The reduction-sensitive of amphion nano-particle:
Gained amphion nano-particle (Dex/SA1-02) in embodiment 1 is placed in the different dithiothreitol, DTT of concentration (DTT) solution, in the change of size of different time with nano particle size instrument test nano-particle, observes reduction response; As shown in Figure 4, nano-micelle, not containing in the PBS buffer solution of dithiothreitol, DTT, experiences particle diameter after 48 hours and does not change result; But nano-particle, containing in dithiothreitol, DTT solution, increases in time, and particle diameter increases gradually, illustrate that cystine linkage ruptures, at this moment after fracture, fragment is assembled, and particle diameter increases.Along with dithiothreitol, DTT concentration increases, change of size trend is larger.
Embodiment 4
The non-specific adsorption performance of the anti-bovine serum albumin of amphion nano-particle:
Being placed in gained amphion nano-particle (Dex/SA1-02) in embodiment 1 containing concentration is respectively the PBS buffer solution of the pH=7.4 of the bovine serum albumin of 0.25mg/mL, hatch the different time, utilize ultraviolet spectrometer to monitor the amount of nano-particle adsorbed proteins, observe anti-bovine serum albumin non-specific adsorption performance.Result as shown in Figure 5, for the amount of nano-particle adsorbed proteins is no more than 10%; As seen from Figure 5: 5 kinds of synthesized nanoparticle sample, under the condition of pH7.4, without mutual adsorption between nano-particle and protein, demonstrate the anti-bovine serum albumin non-specific adsorption performance of nano-particle.
Embodiment 5
The biocompatibility of amphion nano-particle:
Be in the water-bath of 37 DEG C in temperature, thaw rapidly-80 DEG C of frozen 3T3 cells and Hela cell, be moved in the centrifuge tube of the RPMI-1640 culture fluid containing 7mL, with 800rpm centrifugation, single cell suspension is made with the RPMI-1640 culture fluid piping and druming cell containing 10% calf serum, be moved in the culture bottle of 50mL, at 37 DEG C, 5%CO
2cultivate in incubator.
With amphion nanoparticle sample (Dex/SA1-02) for object of study, the cytotoxicity of mtt assay to the nanoparticle that it is formed is adopted to test, with about 2.4 × 10
4/ mL is by l cell and be inoculated in 96 orifice plates, every hole 100 μ L, cultivate 24h, original fluid in the every hole of sucking-off, every hole adds negative controls (the RPMI-1640 culture fluid of 10% calf serum of pH=7.4 and pH=6.5), positive control solution (0.64% phenol culture medium), the sample sets (sample sets is respectively containing the RPMI-1640 culture fluid of 10% calf serum of pH=7.4 and pH=6.5) of 100 μ L, continues to be placed in 37 DEG C, 5%CO
2cultivate in incubator, cultivate 48h.Often group establishes 4 parallel holes.Observed by inverted microscope after taking out culture plate, evaluate cell growth condition.After add MTT20 μ L, continue to cultivate after 4h, after being exhausted by the liquid in the aperture in culture plate, add dimethyl sulfoxine, survey its absorbance (A) by microplate reader in 570nm place, calculating cell survival rate.As shown in Figure 6, the survival rate of 3T3 and Hela two kinds of cells in the nanoparticles solution of variable concentrations is all greater than 95%, meets the standard of biocompatibility.
The above is only the preferred embodiment of the present invention; be not limited to the present invention; should be understood that; for those skilled in the art; under the prerequisite not departing from the technology of the present invention principle; can also make some improvement and modification, these improve and modification also should be considered as protection scope of the present invention.
Claims (9)
1., based on a preparation method for the pH of glucosan and the amphion nano-particle of reduction-sensitive, it is characterized in that preparation process experienced by following steps:
(1) glucosan of different quality ratio and succinic anhydride carry out carboxylation reaction under the effect of catalyst;
(2) glucosan after the carboxylation of different quality ratio and 2-aminoethyl disulfide dihydrochloride carry out amidation process under the effect of catalyst;
(3) product prepared by step (2) is dissolved after purification drying;
(4), after Keep agitation, in solution, ultra-pure water is dripped;
(5) solution of step (4) gained is dialysed.
2. an amphion nanometer grain preparation method for the pH based on glucosan according to claim 1 and reduction-sensitive, is characterized in that: the solvent in described step (1) needed for carboxylation reaction is dimethyl sulfoxine.
3. an amphion nanometer grain preparation method for the pH based on glucosan according to claim 1 and reduction-sensitive, is characterized in that: the catalyst in described step (1) needed for carboxylation reaction is DMAP.
4. an amphion nanometer grain preparation method for the pH based on glucosan according to claim 1 and reduction-sensitive, is characterized in that: reaction 60 DEG C of reaction 24h under nitrogen protection in described step (1).
5. an amphion nanometer grain preparation method for the pH based on glucosan according to claim 1 and reduction-sensitive, is characterized in that: in described step (1), and glucosan and succinic anhydride mass ratio are 100:25 ~ 400.
6. an amphion nanometer grain preparation method for the pH based on glucosan according to claim 1 and reduction-sensitive, is characterized in that: in described step (2), amidation process solvent is dimethyl sulfoxine.
7. prepared by the amphion nano-particle of the pH based on glucosan according to claim 1 and reduction-sensitive, it is characterized in that: in described step (2), amidation process catalyst is 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride and I-hydroxybenzotriazole.
8. an amphion nanometer grain preparation method for the pH based on glucosan according to claim 1 and reduction-sensitive, is characterized in that: reaction 25 DEG C of reaction 24h under nitrogen protection in described step (2).
9. an amphion nanometer grain preparation method for the pH based on glucosan according to claim 1 and reduction-sensitive, is characterized in that: in described step (2), and the glucosan after carboxylation and the mass ratio of 2-aminoethyl disulfide dihydrochloride are 1:0.2 ~ 3.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109030450A (en) * | 2018-05-25 | 2018-12-18 | 苏州大学 | A method of in the two-way controllable self assembly difference charged metal nanoparticle of substrate surface |
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| CN103120797A (en) * | 2012-12-24 | 2013-05-29 | 深圳先进技术研究院 | Nano-drug carrier for reductive response, nano-drug particle, nano-drug particle preparation and preparation methods thereof |
| CN104491871A (en) * | 2014-12-02 | 2015-04-08 | 江南大学 | PH/reduction-sensitive nano microgel based on polyglutamic acid and cystamine |
| CN104644559A (en) * | 2014-11-04 | 2015-05-27 | 江南大学 | Nano particles with double pH/oxidation reduction sensitivities |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103120797A (en) * | 2012-12-24 | 2013-05-29 | 深圳先进技术研究院 | Nano-drug carrier for reductive response, nano-drug particle, nano-drug particle preparation and preparation methods thereof |
| CN104644559A (en) * | 2014-11-04 | 2015-05-27 | 江南大学 | Nano particles with double pH/oxidation reduction sensitivities |
| CN104491871A (en) * | 2014-12-02 | 2015-04-08 | 江南大学 | PH/reduction-sensitive nano microgel based on polyglutamic acid and cystamine |
Non-Patent Citations (1)
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| LUYAN WU等: "Zwitterionic pH/redox nanoparticles based on dextran as drug carriers for enhancing tumor intercellular uptake of doxorubicin", 《MATERIALS SCIENCE AND ENGINEERING C》 * |
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| CN109030450A (en) * | 2018-05-25 | 2018-12-18 | 苏州大学 | A method of in the two-way controllable self assembly difference charged metal nanoparticle of substrate surface |
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Application publication date: 20160330 |