CN103520720B - Folacin coupled nanometer carboxymethyl chitosan particle is as the method for making of light-operated release NO carrier - Google Patents
Folacin coupled nanometer carboxymethyl chitosan particle is as the method for making of light-operated release NO carrier Download PDFInfo
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Abstract
The present invention relates to the method for making of folacin coupled nanometer carboxymethyl chitosan particle as light-operated release N0 carrier, the method specifically comprises the following steps: first, and carboxymethyl chitosan and folic acid generation coupling reaction generate carboxymethyl chitosan-folate conjugate; Then, there is the conjugate nanoparticle issuing this sodium salt of raw physical crosslinking generation load in this conjugate, i.e. carboxymethyl chitosan-folic acid-RBS composite nano-granule at Roussin black salt sodium salt (RBS).Compared with prior art, the inventive method is simple, fast, cost is low, prepare product and there is biocompatibility, coupling pharmaceutical carrier active targeting factor folic acid, load illumination discharges nitric oxide production donor, and this product can develop into the nanoparticulate carriers having light-operated release nitric oxide function in folacin receptor targeting and cell concurrently, and the research for efficient chitin medicine carrier and other nanometer medicine-carried system is provided a kind of new developing direction by the present invention.
Description
Technical field
The invention belongs to the crossing domain of chemistry, biology and material, be specifically related to the method for making of a kind of folacin coupled nanometer carboxymethyl chitosan particle as light-operated release NO carrier.
Back of the body base technology
Nitric oxide (NO) can be synthesized by human endothelial cells, is a kind of important physiological regulation agent, is distributed widely in the multiple organ of whole body, is also considered to important biological messenger molecule.NO can effectively prevent coagulating platelets and activation, reduces bacterial adhesion, and has the function of killing cancerous cell.The shortage of NO can cause dysfunction of organ, causes hypertension, heart disease, respiratory system disease etc.For the various diseases that treatment causes because NO lacks, correlational study person has designed and synthesized multiple NO donor, especially with azo dienol nucleophic NO donor for representative, they are the NO donors of a kind of function admirable grown up in recent years, normally the nucleophilic compound containing secondary amine group and NO gas are reacted obtained under a certain pressure, can in physiological environment spontaneous release NO.In view of this type of NO donor preparation condition harshness (high pressure) and prepare product release NO and be difficult to control the problem such as (release conditions and speed), inhibit their using value to a certain extent, the more efficient NO donor of development one, have preparation method concurrently simple, product stable and NO discharge the advantages such as controlled, have become one of important goal in research of current NO donor association area.
Carboxymethyl chitosan (CMC) is a kind of soluble derivative that chitosan generates after carboxymethylation reaction, stable in properties, and biocompatibility is high, and degradability is good and toxicity is little.It is both containing alkaline kation (-NH
3 +) group, again containing acidulous anion (-COO
-) group, be a kind of amphipathic electrolyte, CMC developed into nanoparticle pharmaceutical (as NO) carrier and will have applications well prospect.Nano-granule medicine carrier is divided into passive target and active targeting, passive target utilizes that the parent/hydrophobicity of carrier, Electrostatic Absorption, carrier dimensions/chemical factors such as quality, pH value is easily positioned at liver, spleen, the monokaryon of lung and bone marrow, macrophage system absorb, and strengthens antitumor drug to the chemotherapy of tumors effect being positioned at Monocytes/Macrophages system.Comparatively speaking, the more remarkable effect of active targeting, it is combined with cell surface specific receptor by targeted molecular, makes medicine accurately send in tumor cell, realize the targeted therapy of malignant cell.Because folacin receptor is in the overexpression of tumor cell adventitia, illustrate to there is substantial connection between tumor cell and folic acid (FA), when FA is connected to CMC carboxyl (CMC-FA) by side base, it still keeps normal receptor affinity, by receptor endocytosis by internalization.Folacin receptor is that the targeting of specific medicament to tumor provides a kind of effective means in the overexpression of multiple human body tumour cell, folacin receptor mediated cell takes the photograph a process, be the selectivity active targeting effect (K.Sumanta of FA, et a1., J. Mater.Sci.: Mater.Med., 2010,21,1587).
Ferrum/sulfur/nitrosyl radical ion cluster Roussin black salt salt anionic Fe
4s
3(NO)
7 -(RBS, Na
+salt) NO precursor can be used as, early stage research confirms that RBS under ultraviolet/light visible wavelengths is irradiated, can produce NO release in biology under related concentrations, but in darkroom, water solublity RBS is stable (F.W. Fliteny, et al., Br.J.Pharmacol., 1992,107,842; F.W. Fliteny, et al., Br.J. Pharmacol., 1996,117,1549).Therefore, RBS load is entered CMC-FA nanoparticle system, can obtain and have in bio-compatible, active targeting and tumor cell light-operated release NO character concurrently in the high-quality nano-granule medicine carrier of one.
So far, preparation method about CMC-FA nano-granule medicine carrier has Chinese patent report, as Qian Xiuzhen etc. devises pH sensitive doxorubicin and the Paclitaxel liposome (publication number: CN102225051A and CN102488658A) of the modification of a kind of folic acid-carboxymethyl chitosan, but there is not yet and form CMC-FA-RBS composite nano-granule NO carrier (i.e. novel NO donor) based on CMC-FA nanoparticle load RBS, and report based on relevant Chinese patent prepared by the light-operated release NO system of CMC-FA nanoparticle.
Summary of the invention
Object of the present invention is exactly provide a kind of method simple to overcome defect that above-mentioned prior art exists, and fast, the low folacin coupled nanometer carboxymethyl chitosan particle of cost is as the method for making of light-operated release NO carrier.
Object of the present invention can be achieved through the following technical solutions: a kind of folacin coupled nanometer carboxymethyl chitosan particle is as the method for making of light-operated release NO carrier, and it is characterized in that, the method specifically comprises the following steps:
(1) matter average molecular weight 400kDa is taken, deacetylation 90%, the carboxymethyl chitosan powder (CMC) of carboxymethyl degree 1.112 is dissolved in deionized water, CMC aqueous solution is made with after 0.22 μM of filter paper filtering, drip NaOH solution wherein, adjust ph is alkalescence, adds folic acid (FA) under lucifuge, magnetic agitation is even, reacts under being increased to uniform temperature;
(2) reaction afterproduct is cooled to room temperature, be separated with gel column, in a certain wavelength place monitoring elution process, the solution of the primary peak flowed out when collecting eluting, then by its lyophilization, folacin coupled carboxymethyl chitosan (CMC-FA) conjugate is obtained;
(3) gained CMC-FA conjugate is dissolved in 1% aqueous acetic acid, the acetum of obtained CMC-FA, adds Roussin black salt salt Fe
4s
3(NO)
7 -(RBS, Na
+salt), drip polyphosphoric acids sodium water solution under magnetic stirring, then continue stirring reaction, obtain the CMC-FA nanoparticle suspension of load RBS;
(4) gained suspension is by ultracentrifugation, reject supernatant, collecting precipitation thing, and in deionized water, lyophilization, lyophilizing sample is ground to Powdered, is CMC-FA-RBS nanoparticle in dispersion.
CMC concentration 1 ~ 10mg/mL described in step (1), pH7 ~ 9, CMC and FA mass ratio 5 ~ 10: 1, reaction temperature 50 ~ 100 DEG C, response time 30 ~ 120min.
Monitoring wavelength described in step (2) is 360 ~ 370nm, sublimation drying 12 ~ 24h.
The acetum concentration 5 ~ 10mg/mL of the CMC-FA described in step (3), RBS sodium salt concentration 0.1 ~ 0.5mmol/L, polyphosphoric acids na concn 0.5 ~ 1.0mg/mL, response time 30 ~ 120min.
Centrifugal speed 5000 ~ 14000rpm/min described in step (4), centrifugation time 30 ~ 60mmin, sublimation drying 12 ~ 24h.
Compared with prior art, the present invention selects biocompatible carboxymethyl chitosan to be carrier, coupling folic acid thereon, prepare the conjugate with tumor cell folacin receptor targeting, then under RBS sodium salt exists, carry out physical crosslinking, obtain the carboxymethyl chitosan-folic acid composite nanoparticulate carriers of load RBS.Compared with prior art, the inventive method is simple, fast, cost is low, prepares product and can develop into and have the nitric oxide production nanoparticulate carriers of light-operated release in folacin receptor targeting and cell concurrently, for efficient chitin medicine carrier research provides a kind of new developing direction.
Accompanying drawing explanation
Fig. 1 is the structural representation of carboxymethyl chitosan-folate conjugate (CMC-FA);
Fig. 2 is the chemical constitution of CMC-FA conjugate (CMC-FA-RBS) nanoparticle of load RBS sodium salt anion and the schematic diagram as nano-carrier light-operated release NO.
Detailed description of the invention
Below in conjunction with the drawings and specific embodiments, the present invention is described in detail.
Embodiment 1
The structural representation of CMC-FA conjugate (CMC-FA-RBS) nanoparticulate carriers of carboxymethyl chitosan-folate conjugate (CMC-FA) and load RBS sodium salt anion is see Fig. 1 and 2, detailed preparation process is as follows: the CMC aqueous solution of (1) configuration 5mg/mL, be 8.0 by NaOH solution adjust ph, add FA and regulate concentration to 1mg/mL, mix homogeneously under magnetic stirring, reacts 60mmin after mixed liquor being warming up to 60 DEG C.(2) product is crossed gel column separation after terminating by reaction, and collect eluent at 363nm wavelength place, lyophilization 12h, obtains CMC-FA conjugate.(3) configure the aqueous solution 5mg/mL of CMC-FA, add RBS sodium salt under magnetic stirring and regulate concentration to 0.1mmol/L, then add sodium polyphosphate and regulate concentration to be 0.5mg/mL, the system of mix homogeneously continues stirring reaction 60min.(4) reaction terminate after by product high speed centrifugation 30min under 10000rpm/min, remove supernatant, collecting precipitation thing, obtains CMC-FA-RBS composite nano-granule after lyophilization 12h.
Adopt the composition of hydrogen nuclear magnetic resonance spectrum and infrared spectrum characterization product, adopt the pattern of transmission and sem observation product, dynamic light scattering is adopted to measure size and the distribution of product, adopt 550nm radiation of visible light product to make it discharge NO, adopt Griess reagent method to measure the NO content of product release.
Embodiment 2
The CMC aqueous solution of configuration 6mg/mL, is 8.0 by NaOH solution adjust ph, adds FA and regulate concentration to 1.2mgg/mmL, mix homogeneously under magnetic stirring, reacting 60min after mixed liquor being warming up to 60 DEG C.After reaction terminates, product is crossed gel column to be separated, collect eluent at 363nm wavelength place, lyophilization 12h, obtains CMC-FA conjugate.The aqueous solution 6mg/mL of configuration CMC-FA, adds RBS sodium salt under magnetic stirring and regulates concentration to 0.12mmol/L, then add sodium polyphosphate and regulate concentration 0.6mg/mL, and the system of mix homogeneously continues stirring reaction 60min.By product high speed centrifugation 30min under 10000rpm/min after reaction terminates, remove supernatant, collecting precipitation thing, obtains CMC-FA-RBS composite nano-granule after lyophilization 12h.The characterization method of product and research method are with embodiment 1.
Embodiment 3
The CMC aqueous solution of configuration 7mg/mL, is 8.5 by NaOH solution adjust ph, adds FA and regulate concentration to 1.4mg/mL, mix homogeneously under magnetic stirring, reacting 90min after mixed liquor being warming up to 70 DEG C.After reaction terminates, product is crossed gel column to be separated, collect eluent at 363nm wavelength place, lyophilization 18h, obtains CMC-FA conjugate.The aqueous solution 7mg/mL of configuration CMC-FA, adds RBS sodium salt under magnetic stirring and regulates concentration to 0.14mmol/L, then add sodium polyphosphate and regulate concentration 0.7mg/mL, and the system of mix homogeneously continues stirring reaction 90min.By product high speed centrifugation 45min under 12000rpm/min after reaction terminates, remove supernatant, collecting precipitation thing, obtains CMC-FA-RBS composite nano-granule after lyophilization 24h.The characterization method of product and research method are with embodiment 1.
Embodiment 4
The CMC aqueous solution of configuration 8mg/mL, is 8.5 by NaOH solution adjust ph, adds FA and regulate concentration to 1.6mg/mL, mix homogeneously under magnetic stirring, reacting 90min after mixed liquor being warming up to 70 DEG C.After reaction terminates, product is crossed gel column to be separated, collect eluent at 363nm wavelength place, lyophilization 18h, obtains CMC-FA conjugate.The aqueous solution 8mg/mL of configuration CMC-FA, adds RBS sodium salt under magnetic stirring and regulates concentration to 0.16mmol/L, then add sodium polyphosphate and regulate concentration 0.8mg/mL, and the system of mix homogeneously continues stirring reaction 90min.By product high speed centrifugation 45min under 12000rpm/min after reaction terminates, remove supernatant, collecting precipitation thing, obtains CMC-FA-RBS composite nano-granule after lyophilization 24h.The characterization method of product and research method are with embodiment 1.
Embodiment 5
The CMC aqueous solution of configuration 10mg/mL, is 9.0 by NaOH solution adjust ph, adds FA and regulate concentration to 2.0mg/mL, mix homogeneously under magnetic stirring, reacting 120min after mixed liquor being warming up to 80 DEG C.After reaction terminates, product is crossed gel column to be separated, collect eluent at 363nm wavelength place, lyophilization 24h, obtains CMC-FA conjugate.The aqueous solution 10mg/mL of configuration CMC-FA, adds RBS sodium salt under magnetic stirring and regulates concentration to 0.2mmol/L, then add sodium polyphosphate and regulate concentration 1.0mg/mL, and the system of mix homogeneously continues stirring reaction 120min.By product high speed centrifugation 45min under 12000rpm/min after reaction terminates, remove supernatant, collecting precipitation thing, obtains CMC-FA-RBS composite nano-granule after lyophilization 24h.The characterization method of product and research method are with embodiment 1.
Embodiment 6
The CMC aqueous solution of configuration 10mg/mL, is 7.0 by NaOH solution adjust ph, adds FA and regulate concentration to 1.0mg/mL, mix homogeneously under magnetic stirring, reacting 30min after mixed liquor being warming up to 100 DEG C.After reaction terminates, product is crossed gel column to be separated, collect eluent at 370nm wavelength place, lyophilization 12h, obtains CMC-FA conjugate.The aqueous solution 5mg/mL of configuration CMC-FA, adds RBS sodium salt under magnetic stirring and regulates concentration to 0.1mmol/L, then add sodium polyphosphate and regulate concentration 0.5mg/mL, and the system of mix homogeneously continues stirring reaction 30min.By product high speed centrifugation 30min under 14000rpm/min after reaction terminates, remove supernatant, collecting precipitation thing, obtains CMC-FA-RBS composite nano-granule after lyophilization 12h.The characterization method of product and research method are with embodiment 1.
Embodiment 7
The CMC aqueous solution of configuration 5mg/mL, is 9.0 by NaOH solution adjust ph, adds FA and regulate concentration to 1.0mg/mL, mix homogeneously under magnetic stirring, reacting 120min after mixed liquor being warming up to 50 DEG C.After reaction terminates, product is crossed gel column to be separated, collect eluent at 360nm wavelength place, lyophilization 24h, obtains CMC-FA conjugate.The aqueous solution 10mg/mL of configuration CMC-FA, adds RBS sodium salt under magnetic stirring and regulates concentration to 0.5mmol/L, then add sodium polyphosphate and regulate concentration 1mg/mL, and the system of mix homogeneously continues stirring reaction 120mmin.By product high speed centrifugation 60min under 5000rpm/min after reaction terminates, remove supernatant, collecting precipitation thing, obtains CMC-FA-RBS composite nano-granule after lyophilization 24h.The characterization method of product and research method are with embodiment 1.
The above is only the preferred embodiment of the present invention; it should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (1)
1. folacin coupled nanometer carboxymethyl chitosan particle is as a method for making for light-operated release NO carrier, and it is characterized in that, the method specifically comprises the following steps:
(1) matter average molecular weight 400kDa is taken, deacetylation 90%, the carboxymethyl chitosan powder (CMC) of carboxymethyl degree 1.112 is dissolved in deionized water, CMC aqueous solution is made with after 0.22 μM of filter paper filtering, drip NaOH solution wherein, adjust ph is alkalescence, adds folic acid (FA) under lucifuge, magnetic agitation is even, reacts under being increased to uniform temperature;
(2) reaction afterproduct is cooled to room temperature, be separated with gel column, in a certain wavelength place monitoring elution process, the solution of the primary peak flowed out when collecting eluting, then by its lyophilization, folacin coupled carboxymethyl chitosan (CMC-FA) conjugate is obtained;
(3) gained CMC-FA conjugate is dissolved in 1% aqueous acetic acid, the acetum of obtained CMC-FA, adds Roussin black salt salt Fe
4s
3(NO)
7 -(RBS, Na
+salt), drip polyphosphoric acids sodium water solution under magnetic stirring, then continue stirring reaction, obtain the CMC-FA nanoparticle suspension of load RBS;
(4) gained suspension is by ultracentrifugation, reject supernatant, collecting precipitation thing, and disperse in deionized water, lyophilization, lyophilizing sample is ground to Powdered, is CMC-FA-RBS nanoparticle;
CMC concentration 1 ~ 10mg/mL described in step (1), pH 7 ~ 9, CMC and FA mass ratio 5 ~ 10:1, reaction temperature 50 ~ 100 DEG C, response time 30 ~ 120min;
Monitoring wavelength described in step (2) is 360 ~ 370nm, sublimation drying 12 ~ 24h;
The acetum concentration 5 ~ 10mg/mL of the CMC-FA described in step (3), RBS sodium salt concentration 0.1 ~ 0.5mmol/L, polyphosphoric acids na concn 0.5 ~ 1.0mg/mL, response time 30 ~ 120min;
Centrifugal speed 5000 ~ 14000rpm/min described in step (4), centrifugation time 30 ~ 60min, sublimation drying 12 ~ 24h.
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| CN104188910B (en) * | 2014-06-20 | 2017-03-08 | 华东理工大学 | Targeting light-operated release nitric oxide nano composite material drug system and preparation method thereof |
| CN104829652A (en) * | 2015-03-31 | 2015-08-12 | 华东理工大学 | Near infrared light-controlled nitrogen monoxide release nanosystem, and preparation method and application thereof |
| CN106177987B (en) * | 2016-08-17 | 2020-06-12 | 上海交通大学 | Micromolecule-macromolecule conjugate self-assembly drug-loaded nanoparticle and preparation method thereof |
| CN107638567B (en) * | 2017-09-21 | 2020-10-27 | 深圳大学 | Metal Lawsonia inermis black salt and preparation method and application thereof |
| CN111418596B (en) * | 2020-05-29 | 2021-01-15 | 中国农业科学院植物保护研究所 | Thiofuramide-loaded folic acid/zinc nitrate gel system and preparation method and application thereof |
| CN111603616B (en) * | 2020-06-04 | 2021-04-30 | 青岛大学 | Nano fiber vascular stent material with double-drug loading and step-by-step slow release functions and preparation method thereof |
| CN111743914A (en) * | 2020-07-14 | 2020-10-09 | 上海师范大学 | Exploring the influencing factors of the reaction of the nitroso-iron-sulfur cluster compound and the hydrogen peroxide |
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