CN102698282A - Preparation method for multi-responsive magnetic composite nanoparticles for loading medicament - Google Patents

Preparation method for multi-responsive magnetic composite nanoparticles for loading medicament Download PDF

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CN102698282A
CN102698282A CN2012101781714A CN201210178171A CN102698282A CN 102698282 A CN102698282 A CN 102698282A CN 2012101781714 A CN2012101781714 A CN 2012101781714A CN 201210178171 A CN201210178171 A CN 201210178171A CN 102698282 A CN102698282 A CN 102698282A
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folic acid
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潘长江
董云肖
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Huaiyin Institute of Technology
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Abstract

The invention discloses a preparation method for multi-responsive magnetic composite nanoparticles for loading a medicament. The multi-responsive magnetic composite nanoparticles is prepared by performing functional modification on a substrate material, namely amino-group-containing mesoporous magnetic namoparticles, by using chitosan, folic acid, N-isopropyl-acrylamide; and the magnetic composite nanoparticles prepared by the preparation method have magnetism, pH responsiveness, thermal sensitivity and a targeting property, and can be used for an intelligent targeting medicinal transport system.

Description

The multiple response property magnetic composite nanoparticles method for preparing that is used for carrying medicament
Technical field
The invention belongs to composite Nano biological medicine field of materials, be specifically related to a kind of multiple response property magnetic composite nanoparticles method for preparing that is used for carrying medicament.
Background technology
Magnetic Nano Fe 3O 4Particle (MNP) is with a wide range of applications in various fields because of its unique advantage, and especially the carrier as medicine is used for the big research focus that oncotherapy becomes people.Magnetic Nano Fe with meso-hole structure 3O 4Granule has bigger specific surface area, can carry more medicine, and the meso-porous nano magnetic-particle of process finishing has numerous advantages such as targeting property, intelligent response property, good biocompatibility and in oncotherapy, has broad application prospects.
(Chitosan is good biocompatibility, easily biological-degradable and nontoxic macromolecular material CS) to chitosan, and chitosan has been widely used in biomedical sector, applies film and drug delivery system comprising wound.Because the dissolving of chitosan in aqueous solution has the pH dependency, this graft polymers can be used as the medicine carrying body with pH response and carries out drug conveying.
Folic acid (FA) has good tumor-targeting, can be used for the diagnosis and the treatment of multiple cancer.Because folacin receptor (FR) overexpression in tumor cell utilizes folacin receptor and folic acid (FA) and the bonded characteristic of analog high affinity thereof can realize the targeting of carrier; In addition, folic acid itself has stable high and low immune molecule quality again, need not to modify, and good advantages such as the compatibility is all arranged, the MNP-Fe of modified with folic acid with Organic substance and inorganic salt 3O 4Granule can with loaded drugs targeting property act on the tumor cell that folacin receptor is positive, thereby can realize the selectively targeted of tumor tissues, reduce traditional cancer therapy drug to Normocellular toxic and side effects, improve the selectivity of medicine.
Poly-N-isopropyl acrylamide (PNIPAM); Have temperature sensitivity, when temperature is low, be homogeneous system;, temperature then shows as hydrophobicity when surpassing its lowest critical solution temperature; And produce with on every side disperse medium and to be separated, the transformation behavior of this uniqueness of PNIPAM makes it to be with a wide range of applications in fields such as the concentrating of biomacromolecule, the targeting release of medicine, immunological technique, cytology research, protein antibody antigen are fixing; PNIPAM is coated on magnetic mesoporous nano grain surface; The intelligent response property that can realize carrying medicament transports, thereby avoids the unfavorable release of medicine before arriving lesions position, plays better therapeutic effect.
Yet the particle major part of preparation belongs to single stimulating responsive nanoparticle at present, can not effectively improve the targeting property of medicine, and the seepage that can not effectively reduce medicine improves drug effect.
Summary of the invention
The objective of the invention is to: propose a kind of multiple response property magnetic composite nanoparticles method for preparing that is used for carrying medicament; The composite nanoparticle that adopts this method for preparing to obtain has multiple functions such as magnetic, pH response, thermal sensitivity and targeting property; Can realize the multiple intelligent response performance of drug-loading system, effectively improve the targeting property and the intelligent response property of drug delivery system.
Technical solution of the present invention is: select for use and contain amidized magnetic mesoporous nano-particle as base material; With folic acid, chitosan, poly-N-isopropyl acrylamide substrate material surface is carried out functionalization; Get the magnetic composite nanoparticles of multiple response property, and mesopore orbit inside can be used for carrying medicament.
Wherein, the method for preparing of the magnetic nanoparticle of surface amination does, with FeCl 36H 2O is dissolved in the ethylene glycol and adds sodium acetate, bases and diamine compound, and dispersed with stirring evenly back slowly cools to room temperature in 160-200 ℃ of reaction after 4～16 hours, centrifugalize behind the thorough washing repeatedly, and vacuum drying 48 hours obtains the surface and contains-NH 2Fe 3O 4Magnetic mesoporous nano-particle (NH 2-MNP).
Wherein, in the method for the amidized magnetic nanoparticle of synthetic surface, described bases is NaOH, KOH or ammonia.
Wherein, in the method for the amidized magnetic nanoparticle of synthetic surface, described diamine compounds is ethylenediamine, butanediamine or hexamethylene diamine.
Wherein, in the method for the amidized magnetic nanoparticle of synthetic surface, the ratio of the quality of various materials is FeCl 36H 2O: ethylene glycol: diamidogen: sodium acetate: bases=1:40:20:9: (1.5～3.0).
Wherein, The method of modified with folic acid magnetic nanoparticle is: dicyclohexylcarbodiimide (DCC) and N-maloyl imines (NHS) are dissolved in anhydrous dimethyl sulphoxide (DMSO), dimethyl formamide (DMF) or the distilled water; Add NH2-MNP and excessive folic acid (FA); Stirring reaction is 24 hours under the room temperature, and centrifugalize nanoparticle and thorough washing obtain the magnetic mesoporous nanoparticle (FA-NH-MNP) of modified with folic acid.
Wherein, in the method for modified with folic acid magnetic nanoparticle, the amount of substance of folic acid, DCC, NHS ratio is: 1: (1.5 ~ 4): (2～4).
Wherein, The method of modified with folic acid nanoparticle surface coupled chitosan is: with chitosan (CS) join among the anhydrous DMSO or acetic acid-sodium-acetate buffer (pH 4.7) in; The DMSO suspension that adds FA-NH-MNP again; Stirred 24 hours under the room temperature, centrifugalize and thorough washing obtain CS-FA-NH-MNP.
Wherein, in the method for modified with folic acid nanoparticle surface coupled chitosan, the mass ratio of CS, FA-NH-MNP is: (0.5 ~ 2): 1.
Wherein, The method of modifying of folic acid chitosan magnetic nano grain surface poly-N-isopropyl acrylamide is: to containing N-Isopropylacrylamide, N, carry out ultraviolet light irradiation after the logical nitrogen deoxygenation of the aqueous solution of the magnetic nanoparticle that N'-methylene-bisacrylamide (MBA) and folic acid are chitosan-modified.
Wherein, in the method for modifying of folic acid chitosan magnetic nano grain surface poly-N-isopropyl acrylamide, the mass ratio of each material is CS-FA-NH-MNP:N-Isopropylacrylamide: MBA=2:10 ~ 50:1.
Wherein, in the method for modifying of folic acid chitosan magnetic nano grain surface poly-N-isopropyl acrylamide, exposure time is 4-24 hour.
Wherein, the response path of the magnetic mesoporous nanoparticle of synthesizing aminoization is as shown in the formula I, II, shown in the III:
Figure 255917DEST_PATH_IMAGE002
Wherein, folic acid (Folic acid, FA), the response path modified of chitosan (chitosan), PNIPAM (PNIPAM) is shown in IV:
Figure 2012101781714100002DEST_PATH_IMAGE004
The present invention has the following advantages:
1, at magnetic mesoporous Fe 3O 4The preparation process in, utilize ethylenediamine to Fe 3O 4Complexing strong, form comparatively stable liquid, temperature rising Fe 3+Discharge, high-temperature lower part is divided and glycol reaction is reduced to Fe 2+, sodium acetate (NaAc) discharges OH -, Fe 3+With Fe 2+Under alkali condition, form Fe 3O 4, because the viscosity of liquid is higher, can effectively control the crystalline speed of growth of Fe3O4 again, obtain homogeneity magnetic nano-particle preferably;
2, the Fe of magnetic mesoporous structure 3O 4The surface of nanoparticle forms amino in the hydro-thermal building-up process of particle again, and the amino further modification that helps particle surface avoids the use of the conventional surface self-assembling method;
3, chitosan has abundant amino, has the pH response, and the chitosan parcel particle that combines with biological targeting molecule folic acid behind the encapsulated drug, makes medicine obtain discharging at lower pH environment, therefore can realize the pH intelligent response property of drug-loading system;
4, the particle after poly-N-isopropyl acrylamide is modified under normal body temperature, possess hydrophilic property, degradability, when temperature is higher (40 ℃ of T ≈), this molecule is rolled up, and has temperature sensitive characteristic;
5, before particle arrives the target location, under the parcel of responsive to temperature type molecule PNIPAM, can effectively prevent the seepage of medicine, reduce the side effect of medicine to normal structure;
6, under externally-applied magnetic field, have magnetic responsiveness, can combine, the composite nano-granule targeting is positioned lesions position with the folic acid targeting;
7, after arriving tumor locus, the hysteresis effect heat production that adds alternating magnetic field also can make responsive to temperature type molecule PNIPAM shrinkage when suppressing tumor promotion, thereby discharges medicine;
8, the amino that enriches on the chitosan makes it be prone to swelling at the lower tumor locus of pH (pH＜6.5), discharges to be encapsulated in the medicine in the particle duct;
9, with the thermotherapy of tumor and chemotherapy in one, utilize the alternating magnetic field heat production to carry out thermotherapy when suppressing activity of tumor cells, the shrinkage of responsive to temperature type molecule realizes the further release of medicine.
10, the present invention is combined in magnetic mesoporous nano-material surface with the molecule of multiple response characteristic, can realize the intelligent response property of tumor-targeting and drug release, is expected in novel intelligent targeted drug transport system, to obtain to use.
The specific embodiment
In order further to explain technical scheme of the present invention, come the present invention is discussed in more detail below by specific embodiment, these embodiment can not be interpreted as it is the restriction to technical scheme.
Embodiment 1:
(1) prepares amidized mesoporous ferriferrous oxide nano particle: the FeCl that takes by weighing 5g 36H 2O places beaker, adds ethylene glycol (EG) 100ml, is stirred to transparent; Add sodium acetate (NaAc) 15g and ethylenediamine (ETH) 50ml, at room temperature be stirred well to and be uniformly dispersed, behind the 30min, liquid is transferred in the agitated reactor; 200 ℃ of reactions 4 hours are cooled to room temperature then, with redistilled water and dehydrated alcohol cyclic washing three times; Centrifugalize, 40 ℃ of vacuum dryings 48 hours obtain amidized Fe 3O 4Magnetic mesoporous nanoparticle (NH 2-MNP);
(2) modified with folic acid magnetic nano-particle (FA-NH-MNP): 0.186g dicyclohexylcarbodiimide (DCC) and 0.155gN-maloyl imines (NHS) are dissolved among the anhydrous DMSO of 20ml; Add 0.3g folic acid and 0.12gNH2-MNP; Stirring reaction is 24 hours under the room temperature; Wash respectively 3 times with deionized water and dehydrated alcohol after the centrifugalize, 60 ℃ are descended dry 6h, obtain the magnetic mesoporous nanoparticle (FA-NH-MNP) of modified with folic acid;
(3) modified with folic acid particle surface coupled chitosan: take by weighing the 0.05g chitosan; Be suspended among the anhydrous DMSO of 15ml, the anhydrous DMSO suspension (10mg/ml) that the back that stirs adds FA-NH-MNP stirred 24 hours under the room temperature; Centrifugalize; And use the dehydrated alcohol thorough washing, vacuum drying in 40 ℃ of baking ovens gets modified product CS-FA-NH-MNP;
(4) at FA-CS-Fe 3O 4Particle surface parcel poly-N-isopropyl acrylamide (PNIPAM): in beaker, successively add the NIPAM of 2.45g, the N of 0.062g, N'-methylene-bisacrylamide (MBA) and 100ml two steam water, and the back that stirs adds the FA-CS-Fe of 4.3g 3O 4, logical N 2Behind the 30min, beginning ultraviolet light irradiation, irradiation are after 24 hours, and permanent magnet separates and thorough washing, gets composite nanoparticle PNIPAM/FA-CS-Fe 3O 4
Embodiment 2:
(1) prepares amidized mesoporous ferriferrous oxide nano particle: the FeCl that takes by weighing 5g 36H 2O places beaker, adds ethylene glycol (EG) 100ml, is stirred to transparent; Add sodium acetate (NaAc) 15g, NaOH 2g and butanediamine 50ml, at room temperature be stirred well to and be uniformly dispersed, behind the 30min; Liquid is transferred in the agitated reactor, and 160 ℃ were reacted 16 hours, and were cooled to room temperature then; With redistilled water and dehydrated alcohol cyclic washing three times, 50 ℃ of following vacuum dryings are 48 hours after the centrifugalize, obtain amidized Fe 3O 4Magnetic mesoporous nanoparticle (NH 2-MNP);
(2) modified with folic acid magnetic nano-particle (FA-NH-MNP): 0.186g dicyclohexylcarbodiimide (DCC) and 0.232gN-maloyl imines (NHS) are dissolved among the anhydrous DMSO of 20ml; Add 0.3g folic acid; 0.12gNH2-MNP stirring reaction is 24 hours under the room temperature, washs respectively 3 times with deionized water and dehydrated alcohol after the centrifugalize; 60 ℃ are descended dry 6h, obtain the magnetic mesoporous nanoparticle (FA-NH-MNP) of modified with folic acid;
(3) modified with folic acid particle surface coupled chitosan (CS-FA-NH-Fe 3O 4): take by weighing the 0.10g chitosan; Be suspended among the anhydrous DMSO of 20ml, the back that stirs adds the anhydrous DMSO suspension (10mg/ml) of FA-NH-MNP, and 30 ℃ were stirred 24 hours down; Centrifugalize; And use the dehydrated alcohol thorough washing, vacuum drying in 40 ℃ of baking ovens gets modified product CS-FA-NH-MNP;
(4) at FA-CS-Fe 3O 4Particle surface parcel poly-N-isopropyl acrylamide (PNIPAM): in beaker, successively add the NIPAM of 1.47g, the N of 0.062g, N'-methylene-bisacrylamide (MBA) and 100ml two steam water, and the back that stirs adds the FA-CS-Fe of 2g 3O 4, logical N 2Behind the 30min, beginning ultraviolet light irradiation, irradiation are after 16 hours, and permanent magnet separates and thorough washing, gets composite nanoparticle PNIPAM/FA-CS-Fe 3O 4
Embodiment 3:
(1) prepares amidized mesoporous ferriferrous oxide nano particle: the FeCl that takes by weighing 5g 36H 2O places beaker, adds ethylene glycol (EG) 140ml; Be stirred well to transparently, add sodium acetate (NaAc) 15g, NaOH 4g and hexamethylene diamine 10ml, be stirred well under the room temperature and liquid be transferred in the agitated reactor after being uniformly dispersed; 180 ℃ of reactions 10 hours are cooled to room temperature then, with redistilled water and dehydrated alcohol cyclic washing three times; 60 ℃ of following vacuum dryings are 48 hours after the centrifugalize, obtain amidized Fe 3O 4Magnetic mesoporous nanoparticle (NH 2-MNP);
(2) modified with folic acid magnetic nano-particle (FA-NH-MNP): 0.186g dicyclohexylcarbodiimide (DCC) and 0.311gN-maloyl imines (NHS) are dissolved among the anhydrous DMSO of 30ml, add 0.3g folic acid, 0.12gNH 2-MNP, stirring reaction is 24 hours under the room temperature, washs respectively 3 times with deionized water and dehydrated alcohol after the centrifugalize, and 60 ℃ are descended dry 6h, obtain the magnetic mesoporous nanoparticle (FA-NH-MNP) of modified with folic acid;
(3) modified with folic acid particle surface coupled chitosan (CS-FA-NH-Fe 3O 4): take by weighing the 0.10g chitosan; Join in 20ml acetic acid-sodium-acetate buffer (pH 4.7), the anhydrous DMSO suspension (5mg/10ml) that the back that stirs adds FA-NH-MNP stirred 24 hours under the room temperature; Centrifugalize; And use the dehydrated alcohol thorough washing, vacuum drying in 40 ℃ of baking ovens gets modified product CS-FA-NH-MNP;
(4) at FA-CS-Fe 3O 4Particle surface parcel poly-N-isopropyl acrylamide (PNIPAM): in beaker, successively add the NIPAM of 0.49g, the N of 0.062g, two of N'-methylene-bisacrylamide (MBA) and 100ml steams water, and the back that stirs adds the FA-CS-Fe of 4.3g 3O 4, logical N 2Behind the 30min, the beginning ultraviolet light irradiation, irradiation 12 hours, permanent magnet separates and thorough washing, gets composite nanoparticle PNIPAM/FA-CS-Fe 3O 4
Embodiment 4:
(1) prepares amidized mesoporous ferriferrous oxide nano particle: the FeCl that takes by weighing 5g 36H 2O places beaker, adds ethylene glycol (EG) 140ml; Be stirred to transparently, add sodium acetate (NaAc) 15g, NaOH 4g and hexamethylene diamine 10ml, at room temperature be stirred well to and liquid be transferred in the agitated reactor after being uniformly dispersed; 180 ℃ of reactions 10 hours are cooled to room temperature then, with redistilled water and dehydrated alcohol cyclic washing three times; Separate through permanent magnet, 60 ℃ of following vacuum dryings 48 hours obtain amidized Fe 3O 4Magnetic mesoporous nanoparticle (NH 2-MNP);
(2) modified with folic acid magnetic nano-particle (FA-NH-MNP): 0.293g dicyclohexylcarbodiimide (DCC) and 0.310gN-maloyl imines (NHS) are dissolved among the anhydrous DMSO of 30ml, add 0.3g folic acid, 0.12gNH 2-MNP, stirring reaction is 24 hours under the room temperature, washs respectively 3 times with deionized water and dehydrated alcohol after the centrifugalize, and 60 ℃ are descended dry 6h, obtain the magnetic mesoporous nanoparticle (FA-NH-MNP) of modified with folic acid;
(3) modified with folic acid particle surface coupled chitosan (CS-FA-NH-Fe 3O 4): take by weighing the 0.10g chitosan; Be suspended among the anhydrous DMSO of 20ml, the back that stirs adds the anhydrous DMSO suspension (5mg/ml) of FA-NH-MNP, and 40 ℃ were stirred 24 hours down; Centrifugalize; And use the dehydrated alcohol thorough washing, vacuum drying in 40 ℃ of baking ovens gets modified product CS-FA-NH-MNP;
(4) FA-CS-Fe 3O 4Particle surface parcel poly-N-isopropyl acrylamide (PNIPAM): in beaker, successively add the NIPAM of 0.49g, the N of 0.062g, two of N'-methylene-bisacrylamide (MBA) and 100ml steams water, and the back that stirs adds the FA-CS-Fe of 4.3g 3O 4, logical N 2Behind the 30min, beginning ultraviolet light irradiation, irradiation are after 4 hours, and permanent magnet separates nanoparticle and thorough washing, gets composite nanoparticle PNIPAM/FA-CS-Fe 3O 4

Claims (8)

1. the multiple response property magnetic composite nanoparticles method for preparing that is used for carrying medicament; It is characterized in that: successively the amidized magnetic mesoporous nano-particle in surface is carried out functionalization with folic acid, chitosan, poly-N-isopropyl acrylamide, obtain having the magnetic composite nanoparticles of multiple response property.
2. the multiple response property magnetic composite nanoparticles method for preparing that is used for carrying medicament according to claim 1, it is characterized in that: the method for preparing of the magnetic nanoparticle of surface amination is with FeCl 36H 2O is dissolved in the ethylene glycol and adds sodium acetate, bases and diamine compound, and dispersed with stirring evenly back slowly cools to room temperature in 160-200 ℃ of reaction after 4～16 hours, centrifugalize behind the thorough washing repeatedly, and vacuum drying 48 hours obtains the surface and contains-NH 2Fe 3O 4Magnetic mesoporous nano-particle (NH 2-MNP).
3. the multiple response property magnetic composite nanoparticles method for preparing that is used for carrying medicament according to claim 2, it is characterized in that: described bases is NaOH, KOH or ammonia.
4. the multiple response property magnetic composite nanoparticles method for preparing that is used for carrying medicament according to claim 2, it is characterized in that: described diamine compounds is ethylenediamine, butanediamine or hexamethylene diamine.
5. the multiple response property magnetic composite nanoparticles method for preparing that is used for carrying medicament according to claim 2, it is characterized in that: the ratio of the quality of various materials is FeCl 36H 2O: ethylene glycol: diamidogen: sodium acetate: bases=1:40:20:9: (1.5～3.0).
6. the multiple response property magnetic composite nanoparticles method for preparing that is used for carrying medicament according to claim 1; It is characterized in that: the method for modified with folic acid magnetic nanoparticle is that dicyclohexylcarbodiimide (DCC) and N-maloyl imines (NHS) are dissolved in anhydrous dimethyl sulphoxide (DMSO), dimethyl formamide (DMF) or the distilled water; Add amination magnetic nanoparticle and excessive folic acid (FA); Stirring reaction is 24 hours under the room temperature, and centrifugalize nanoparticle and thorough washing obtain the magnetic mesoporous nanoparticle (FA-NH-MNP) of modified with folic acid; Wherein, the amount of substance of folic acid, DCC, NHS ratio is: 1: (1.5 ~ 4): (2～4).
7. the multiple response property magnetic composite nanoparticles method for preparing that is used for carrying medicament according to claim 1; It is characterized in that: the method for nanoparticle surface coupled chitosan is to join among the anhydrous DMSO chitosan (CS) or in acetic acid-sodium-acetate buffer of pH 4.7 behind the modified with folic acid; The DMSO suspension that adds FA-NH-MNP again; Stirred 24 hours under the room temperature, centrifugalize and thorough washing obtain CS-FA-NH-MNP; Wherein, the mass ratio of CS, FA-NH-MNP is: (0.5 ~ 2): 1.
8. the multiple response property magnetic composite nanoparticles method for preparing that is used for carrying medicament according to claim 1; It is characterized in that: the method for modifying of the surperficial poly-N-isopropyl acrylamide of folic acid chitosan magnetic nano-particle (CS-FA-NH-MNP) is to containing N-Isopropylacrylamide (NIPAM), N; Carry out ultraviolet light irradiation after the logical nitrogen deoxygenation of the aqueous solution of the magnetic nanoparticle that N'-methylene-bisacrylamide (MBA) and folic acid are chitosan-modified, obtain NIPAM/CS-FA-NH-MNP after permanent magnet separation and the washing; Wherein, the mass ratio of each material is CS-FA-NH-MNP:N-Isopropylacrylamide: MBA=2:10 ~ 50:1; Wherein, exposure time is 4-24 hour.
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Application publication date: 20121003