CN102319217B - Polysaccharide coated magnetic nano-particle and preparation method - Google Patents
Polysaccharide coated magnetic nano-particle and preparation method Download PDFInfo
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- CN102319217B CN102319217B CN 201110209763 CN201110209763A CN102319217B CN 102319217 B CN102319217 B CN 102319217B CN 201110209763 CN201110209763 CN 201110209763 CN 201110209763 A CN201110209763 A CN 201110209763A CN 102319217 B CN102319217 B CN 102319217B
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Abstract
The invention provides a chitosan coated magnetic nano-particle which consists of ferroferric oxide magnetic nanopowder, oleic acid, glycerel monostearte, adriamycin and chitosan (or polyethylene glycol chitosan graft). The chitosan coated magnetic nano-particle is prepared by adopting the oleic acid as a surfactant and combining a waterborne solvent diffusion method and an ionic recombination technology, so that controlled release of antitumor medicaments is realized. On the basis of the chitosan coated magnetic nano-particle, the polyethylene glycol chitosan graft is synthesized to prepare the polyethylene glycol modified chitosan coated magnetic nano-particle, so that the passive targeting function of the chitosan coated magnetic nano-particle is improved, and the controlled release ofmedicaments is realized.
Description
Technical field
The invention belongs to magnetic nano particle and preparation method, relate generally to a kind of surperficial chitosan coating ferriferrous oxide nano grain, and preparation method thereof with the controlled release of antitumor drug.
Background technology
Magnetic targeting drug delivery system (magnetic targeting drug delivery system, MTDDS) be to study more a kind of novel targeted drug-supplying system in recent years both at home and abroad, usually formed by magnetic material, carrier material, medicine (mainly being antitumor drug or some diagnostic reagent) and other adjuvant, can pass through administrations such as vein, ductus arteriosus, oral or injection.MTDDS system makes stabilising system with medicine and magnetisable material by appropriate carriers, under enough strong external magnetic field effect, make medicine in vivo directed mobile, locate and concentrate and discharge, bring into play curative effect thereby concentrate on diseased region, have characteristics of high efficiency and low toxicity.At present the magnetic targeting drug delivery system has: magnetic microsphere (magneticmicrospheres, MMS), magnetic nano particle (magneticnanoparticles, MNP), magnetic liposome
[1], magnetic Emulsion, magnetic tablet, magnetic capsule and monoclonal antibody is coupled at the immune magnetic preparation of magnetic dosage surface.The most frequently used magnetic material is Fe at present
3O
4And Fe
2O
3Nano-magnetic powder or magnetic fluid, or claim ferrofluid.
Magnetic nano particle is the focus of studying both at home and abroad in recent years.Magnetic nano particle is used for tumor treatment and mainly has following characteristics: (1) is easily in cancer, tumor locus enrichment, this may be because tumor cell be strong to the phagocytosis of magnetic nano particle, and tumor tissues pathological changes, blood capillary expansion or the leakage of generation crack easily between tissue, nanoparticle passes blood vessel easily and is stranded in the tumor tissues.Because the enrichment of magnetic material, magnetic nano particle also can be applicable in the nmr imaging technique; (2) under the effect in magnetic field, in tumor tissues, cause thromboembolism easily, the blood supply of blocking-up tumor tissues, and cause death of neoplastic cells, and in the non-magnetic field district, the diameter of nanoparticle is littler than the diameter of blood capillary or sinus hepaticus, be single dispersion and exist, generally can not cause thromboembolism; (3) the super-paramagnetism nano grain is in the alternating magnetic field, owing to the magnetic lag effect produces heat, makes the too high and killing tumor cells tissue of local temperature.
Chitosan is the cationic polymer that a class is made up of glucosamine, has good biocompatibility, hypotoxicity and biodegradable.Chitosan is widely used in excipient substance, hemostatic material, tissue engineering bracket etc.It is reported that chitosan has the characteristic that intestinal mucosa adheres to, and is conducive to the oral absorption of medicine as excipient substance.Under the physiological pH condition (7.2 – 7.4) is water insoluble for the macromolecule chitosan, and the low-molecular weight chitoglycan (oligochitosan by enzymatic degradation, Chitosan oligosaccharide CSO) has good water-solubility and lower toxicity, is suitable as excipient substance and uses.
Other has report to point out, carries out hydrophilic polyethyleneglycol modifiedly in pharmaceutical carrier, can reduce plasma protein to the adsorption of carrier, can reduce macrophage to the phagocytosis of pharmaceutical carrier simultaneously, and the half-life of carrier in blood circulation prolonged.The targeting that is conducive to medicine.Carry out polyethyleneglycol modified based on this to chitosan, can reduce plasma protein to chitosan coating magnetic nano particle opsonic action in vivo, thereby reduce macrophage to the picked-up of chitosan coating magnetic nano particle, delay the process that chitosan coating magnetic nano particle is eliminated from blood plasma, and by " seeing through and retention effect of enhancing ", further improve the passive target function of chitosan coating magnetic nano particle.
The present invention is by the combination of aqueous solvent diffusion technique and ion complex technique, preparation chitosan coating magnetic nano particle, realization is to the controlled release of antitumor drug, synthesizing polyethylene glycol chitosan grafting on this basis, and prepare polyethyleneglycol modified chitosan coating magnetic nano particle, to improve the passive target function of chitosan coating magnetic nano particle.
Summary of the invention
An object of the present invention is to provide a kind of chitosan coating magnetic nano particle.This magnetic nano particle is made up of ferriferrous oxide nano magnetic powder, oleic acid, monoglyceride, amycin and chitosan (or Polyethylene Glycol chitosan grafting).The ferriferrous oxide nano magnetic powder (mean diameter 30nm) of consisting of of chitosan coating magnetic nano particle: 1mg, the oleic acid of 2mg, the monoglyceride of 6.5mg, the amycin of 0.5mg and the chitosan of 1mg (or Polyethylene Glycol chitosan grafting).Wherein, the weight average molecular weight of chitosan is 18 KDa, and deacetylation is 95%; The weight average molecular weight of Polyethylene Glycol is 2KDa, and the grafting ratio of Polyethylene Glycol and chitosan is 1:1 (mol:mol)
Another object of the present invention provides the preparation method of chitosan coating magnetic nano particle, specifically realizes by following approach:
(1) takes by weighing ferroso-ferric oxide (Fe
3O
4) nano-magnetic powder body (mean diameter 30nm) 5mg, be added in the 50ml pure water, pop one's head in ultrasonic (600W; Work 2s stops 3s) the 40min dispersion; Take by weighing 10 mg oleic acid, be dissolved in 1 ml dehydrated alcohol after, slowly add in the above-mentioned dispersion liquid,, ultrasonic (600W pops one's head in; Work 2s stops 3s) 10min obtains through the stable Fe of oleic acid
3O
4Nano-magnetic powder dispersion (1);
(2) precision takes by weighing after the monoglyceride of 32.5mg and 2.5mg amycin be dissolved in 1ml dehydrated alcohol and inferior maple (DMSO) mixed solvent of 1ml diformazan, adds through the stable Fe of oleic acid
3O
4In the nano-magnetic powder dispersion, get magnetic nano particle dispersion liquid (2).
(3) get magnetic nano particle dispersion liquid (2) 10 mL, under the water-bath ultrasound condition, dropwise be added dropwise in 10 mL, 100 μ g/mL chitosan aqueous solution or the Polyethylene Glycol chitosan grafting aqueous solution, continue ultrasonic 5 min of water-bath, get chitosan coating magnetic nano particle.
It is surfactant that the present invention at first adopts oleic acid, prepare stable ferriferrous oxide nano dispersion liquid, and the organic solvent that further will be dissolved with matrix material and antitumor drug is injected into through the stable ferriferrous oxide nano dispersion liquid of oleic acid, can prepare the electronegative magnetic nano particle that contains medicine.Cationic chitosan can further be wrapped in electronegative magnetic nano particle surface by the ion compound action, prepares chitosan coating magnetic nano particle, and realizes the controlled release of medicine.
Description of drawings
Fig. 1Transmission electron microscope photo for polyethyleneglycol modified chitosan coating magnetic nano particle (a) and chitosan coating magnetic nano particle (b).
Fig. 2Be the chitosan coating magnetic nano particle (a) for preparing and the doxorubicin in vitro release profiles of polyethyleneglycol modified chitosan coating magnetic nano particle (b).
The specific embodiment
The present invention is further described in conjunction with the accompanying drawings and embodiments.
Embodiment 1:
(1) oleic acid is stablized the preparation of ferriferrous oxide nano magnetic powder
Precision takes by weighing Fe
3O
4Nano-magnetic powder body (mean diameter 30nm) 5mg is added in the 50ml pure water, and ultrasonic (600W pops one's head in; Work 2s stops 3s) the 40min dispersion.Precision takes by weighing 10mg oleic acid, be dissolved in 1 ml dehydrated alcohol after, slowly add in the above-mentioned dispersion liquid,, ultrasonic (600W pops one's head in; Work 2s stops 3s) 5min obtains through the stable Fe of oleic acid
3O
4The nano-magnetic powder dispersion.
(2) precision takes by weighing after the monoglyceride of 32.5mg and 2.5mg amycin be dissolved in 1ml dehydrated alcohol and inferior maple (DMSO) mixed solvent of 1ml diformazan, adds through the stable Fe of oleic acid
3O
4In the nano-magnetic powder dispersion, get magnetic nano particle dispersion liquid (2).
(3) get magnetic nano particle dispersion liquid (2) 10 mL, under the water-bath ultrasound condition, dropwise be added dropwise in 10 mL, 100 μ g/mL chitosans (weight average molecular weight is 18 KDa, and deacetylation the is 95%) aqueous solution, continue ultrasonic 5 min of water-bath, get chitosan coating magnetic nano particle.
The transmission electron microscope picture of gained chitosan coating magnetic nano particle is seen Fig. 1 (b); The number average bead diameter of measuring this nanoparticle through particle diameter potential measurement instrument is that 312.0 ± 19.0nm, current potential are 30.2 ± 0.6mV; Entrapment efficiency through the fluorescence spectrophotometry amycin is 70.20 ± 0.21%, and drug loading is 3.09 ± 0.02%.
Table 1: the physicochemical property of chitosan coating magnetic nano particle and polyethyleneglycol modified chitosan coating magnetic nano particle
| ? | d N(nm) | PI | Zeta potential (mV) | EE (%) | DL(%) |
| CS | 312.0±19.0 | 0.478±0.079 | 30.2±0.6 | 70.20±0.21 | 3.09±0.02 |
| CS-PEG | 259.5±2.5 | 0.424±0.031 | 31.3±0.7 | 78.90±0.20 | 3.46±0.01 |
CS, CS-PEG, d in the table
N, PI, EE, DL be respectively chitosan coating nanoparticle, polyethyleneglycol modified chitosan coating magnetic nano particle, number average bead diameter, the polydispersity coefficient of particle diameter, entrapment efficiency, drug loading
Embodiment 2:
(1) polyethyleneglycol modified chitosan is synthetic
Precision takes by weighing 300 mg chitosans, and (weight average molecular weight is 18 KDa, deacetylation is 95%) with the terminal aldehyde group polyethylene glycol (weight average molecular weight is 2 KDa) of identical molal weight in 40 mL pure water, after lucifuge stirs 24 h under the room temperature, be transferred to (MWCO 7000 Da in the bag filter, Spectrum Laboratories, Laguna Hills, CA) pure water 24 h that dialyse change water one time every 1-2 h.With solution lyophilization in the bag filter, get polyethyleneglycol modified chitosan.
(2) oleic acid is stablized the preparation of ferriferrous oxide nano magnetic powder
Precision takes by weighing Fe
3O
4Nano-magnetic powder body (mean diameter 30nm) 5mg is added in the 50ml pure water, and ultrasonic (600W pops one's head in; Work 2s stops 3s) the 40min dispersion.Precision takes by weighing 10mg oleic acid, be dissolved in 1 ml dehydrated alcohol after, slowly add in the above-mentioned dispersion liquid,, ultrasonic (600W pops one's head in; Work 2s stops 3s) 5min obtains through the stable Fe of oleic acid
3O
4The nano-magnetic powder dispersion.
(3) precision takes by weighing after the monoglyceride of 32.5mg and 2.5mg amycin be dissolved in 1ml dehydrated alcohol and inferior maple (DMSO) mixed solvent of 1ml diformazan, adds through the stable Fe of oleic acid
3O
4In the nano-magnetic powder dispersion, get magnetic nano particle dispersion liquid (2).
(4) get magnetic nano particle dispersion liquid (2) 10 mL, under the water-bath ultrasound condition, dropwise be added dropwise in 10 mL, the 100 μ g/mL Polyethylene Glycol chitosan grafting aqueous solutions, continue ultrasonic 5 min of water-bath, get polyethyleneglycol modified chitosan coating magnetic nano particle.
The transmission electron microscope picture of the polyethyleneglycol modified chitosan coating of gained magnetic nano particle is seen Fig. 1 (a); The number average bead diameter of measuring this nanoparticle through particle diameter potential measurement instrument is that 259.5 ± 2.5nm, current potential are 31.3 ± 0.7mV; Entrapment efficiency through the fluorescence spectrophotometry amycin is 78.90 ± 0.20%, and drug loading is 3.46 ± 0.01%.
Embodiment 3:
Get 4 mL drug loaded magnetic nanoparticle dispersion liquids and place cillin bottle, Magnet is adsorbed to the solution clarification, abandon supernatant, add the PBS buffer of 1 mL pH 7.4 in the precipitation, behind vortex 90 s, put into bag filter (MWCO 14000 Da, Spectrum Laboratories, Laguna Hills, CA), release medium is PBS (the pH 7. 4) solution of 20 mL.Be to carry out release in vitro under the 60 r/min conditions in 37 ℃ of constant temperature, frequency of oscillation.At 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h, 24 h, 48 h timing samplings, change whole release medium respectively.Adopt the content with fluorescence spectrophotometry release medium Chinese medicine, calculate cumulative release percentage rate (%).
Fig. 2 is the vitro drug release curve of chitosan coating magnetic nano particle and polyethyleneglycol modified chitosan coating magnetic nano particle.By this curve as can be seen, two kinds of drug loaded magnetic nanoparticles all do not have significantly to dash forward releases phenomenon, has the good slow release effect, and sustainable release amycin reached more than 48 hours, and free drug solution all discharges constantly 0; Than chitosan coating magnetic nano particle, polyethyleneglycol modified chitosan coating magnetic nano particle has slower drug release rate.
Claims (3)
1. a chitosan coating magnetic nano particle is characterized in that, by ferriferrous oxide nano magnetic powder, 2mg oleic acid, the 6.5mg monoglyceride of 1mg mean diameter 30nm, 0.5mg amycin and 1mg chitosan are formed, wherein, the weight average molecular weight of chitosan is 18 KDa, and deacetylation is 95%; Described chitosan coating magnetic nano particle is realized by following steps:
(1) takes by weighing the ferriferrous oxide nano magnetic powder 5mg of mean diameter 30nm, be added in the 50ml pure water, the ultrasonic 40min that pops one's head in for the first time disperses, take by weighing 10 mg oleic acid, after being dissolved in 1 ml dehydrated alcohol, slowly add in the above-mentioned dispersion liquid, the ultrasonic 10min that pops one's head in for the second time obtains through the stable ferriferrous oxide nano magnetic powder dispersion liquid (a) of oleic acid;
(2) precision takes by weighing after the monoglyceride of 32.5mg and 2.5mg amycin be dissolved in 1ml dehydrated alcohol and the inferior maple mixed solvent of 1ml diformazan, adds in the dispersion liquid (a), gets magnetic nano particle dispersion liquid (b);
(3) get dispersion liquid (b) 10 mL, under the water-bath ultrasound condition, dropwise add in 10 mL, the 100 μ g/mL chitosan aqueous solution, continue ultrasonic 5 min of water-bath, get chitosan coating magnetic nano particle.
2. chitosan coating magnetic nano particle, it is characterized in that, ferriferrous oxide nano magnetic powder, 2mg oleic acid, 6.5mg monoglyceride by 1mg mean diameter 30nm, 0.5mg amycin and 1mg Polyethylene Glycol chitosan grafting are formed, wherein, the weight average molecular weight of chitosan is 18 KDa, and deacetylation is 95%, the weight average molecular weight of Polyethylene Glycol is 2KDa, and the grafting mol ratio of Polyethylene Glycol and chitosan is 1:1.
3. a kind of chitosan coating magnetic nano particle according to claim 1 is characterized in that, ultrasound condition: the 600W that wherein pops one's head in for the first time in the preparation process (1), and work 2s stops 3s; Ultrasound condition: the 600W that pops one's head in for the second time, work 2s stops 3s.
?
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