CN103143026A - Block copolymer mPEG-PLGA/amorphous calcium silicate hydrate composite nano material as well as preparation method and application thereof - Google Patents
Block copolymer mPEG-PLGA/amorphous calcium silicate hydrate composite nano material as well as preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to a block copolymer mPEG-PLGA/amorphous calcium silicate hydrate composite nano material as well as a preparation method and an application thereof. The composite nano material has a spherical or similar-spherical solid, core-shell or multi-vesicle structure; the size of the composite nano particles is 10-10nm; and the molar ratio of calcium to silicon in the chemical composition of the composite nano material is (0.3:1)-(0.7:1). According to the invention, a degradable block copolymer with good biocompatibility is used as an organic template for preparing a silicate hydrate composite material, and amorphous calcium silicate can be effectively maintained; due to the hydrophobicity of the block copolymer, the composite material can be used as a repository of hydrophobic drugs and proteins, and further can be applied to drug delivery and protein adsorption, and has good application prospect in the field of biological medicine.
Description
Technical field
The invention belongs to the nano meter biomaterial field, relate to a kind of organic/inorganic composite nano materials, especially block copolymer mPEG-PLGA/ calcium silicate hydrate composite nanometer particle and preparation method thereof.
Background technology
At many medical domains such as organizational project, bone defect repair and medicine transmission etc., drug carrier material had huge demand.At present, the organic drug carrier material is widely studied, but organic material has poor heat stability, poor chemical stability and easily the shortcoming such as engulfed by immunocyte in vivo.The composite nano materials of inorganic material/organic polymer is paid close attention at present just widely.This material can be brought up to nanoscale with the compound uniformity of inorganic material and organic polymer, thereby they advantages separately can be merged effectively.At present, take inorganic material as core, polymer is that the composite nanostructure of shell is studied more in materials, and the nanostructured take inorganic material as shell is studied seldom.In inorganic material/polyalcohol nucleocapsid nanostructured, polymer can be used as size and the pattern that template regulates and controls inorganic material, and stable inorganic material shell preferably can prevent that the phenomenon of collapse from appearring in this nucleocapsid structure in drug release process, and this is very important for blood circulation and intracellular drug conveying.In addition, be convenient to clinical practice, the polymer kernel of composite nano materials should not have cytotoxicity, and the inorganic matter shell should have good biocompatibility.Calcium phosphate is often used as the inorganic shell of this type of composite nano materials, and this is because it is the main inorganic composition of people's bone, can not produce immunoreation, good biocompatibility in human body.
Calcium silicates is a kind of emerging biomaterial, it can be converted into osteoid apatite in simulated body fluid, and the osteoblastic differentiation function of inducing is had larger advantage than calcium phosphate material, so its application in field of drug delivery is just receiving increasing researcher concern.Yet, the microscopic appearance of calcium silicate material and size are not easy to control very much, although easily form fibrous and nanostructured (for example CN102923725A discloses a kind of calcium silicates ultrathin nanometer sheet with superhigh specific surface area and preparation method thereof) lamellar, will have a strong impact on its application in drug conveying in blood circulation and cell as long as there is one dimension to exceed nanoscale in its three dimensional structure.
As far as we know, normally hypocrystalline or the crystallization of the calcium silicates of wet chemistry method preparation, and make its microscopic appearance remain lamellar or wire just because of this hypocrystalline and crystallization property, thus make its overall dimensions exceed the nanometer category.With respect to the calcium silicates of hypocrystalline and crystallization, amorphous silicic acid calcium easily forms nutty structure, its overall dimensions is controlled at nanoscale also is easier to realize.Yet the preparation of the amorphous silicic acid calcium of energy stable existence is still a difficult problem at present in aqueous systems.It is reported, because amorphous state is very unstable, the calcium silicates in aqueous systems can experience the fast transition from amorphous to the half hitch crystalline state in its forming process, and this has limited the application of calcium silicates sill as drug carrier material.
Summary of the invention
The object of the present invention is to provide the composite nano materials of a kind of stable Organic substance/amorphous silicic acid calcium.Problem in the face of the prior art existence, the inventor recognizes and can prevent that amorphous silicic acid calcium from changing to half hitch crystalline state or crystalline state by adding a kind of stabilizing agent, further, the inventor recognizes organic polymer, it is amorphous can also keeping calcium silicates when especially the block copolymer mPEG-PLGA template that can be used as calcium silicates/Organic substance composite is controlled the size of composite, is expected to be widely used in amorphous silicic acid calcium synthetic.
At first, the invention provides a kind of block copolymer mPEG-PLGA/ amorphous silicic acid hydrate of calcium composite nano materials, wherein, described composite nano materials has spherical or that class is spherical is solid, nucleocapsid or many imitated vesicle structures, described composite nanometer particle is of a size of 10～100nm, and in the chemical composition of described composite nano materials, the mol ratio of calcium and silicon is 0.3:1～0.7:1.
The present invention is used for the calcium silicate hydrate composite manufacture with good biocompatibility, degradable block copolymer as organic formwork agent, can effectively keep amorphous silicic acid calcium, and the hydrophobicity of block copolymer makes composite can be used as storage vault to hydrophobic drug and protein, and then useful as drug conveying and protein adsorption, have a good application prospect at biomedicine field.
Preferably, described composite nano materials comprises amorphous silicic acid calcium network skeleton and Uniform Dispersion block copolymer mPEG-PLGA therein.
Preferably, described composite nano materials comprises amorphous silicic acid calcium nucleocapsid and parcel block copolymer mPEG-PLGA within it.
In the present invention, the BET specific surface area of described composite nano materials can be 30～100m
2/ g.
On the other hand, the invention provides a kind of method for preparing above-mentioned composite nano materials, comprise: the mixed aqueous solution that the mensuration dissolubility silicic saline solution slowly is added dropwise to block copolymer mPEG-PLGA and soluble calcium salt, and control that in final mixed liquor, Ca and Si mol ratio are 0.3:1～3.0:1, stirred described mixed liquor 0～60 minute, and separating obtained precipitation, obtain described block copolymer mPEG-PLGA/ amorphous silicic acid hydrate of calcium composite nano materials after washing, drying.
Preferably, in described mensuration dissolubility silicic saline solution, SiO
3 2-Ion concentration is 0.01～2mol/L; In the mixed aqueous solution of described block copolymer mPEG-PLGA and soluble calcium salt, mPEG-PLGA concentration is 0.5～15g/L, Ca
2+Ion concentration is 0.01～2mol/L.
Preferably, the temperature range of described drying can be room temperature to 100 ℃.
Preparation method environment for use close friend's of the present invention raw material at room temperature carries out, and productive rate is high, and energy savings; Easy to operate, preparation technology is simple, is easy to realize suitability for industrialized production.
On the one hand, the present invention also provides a kind of application in biomedicine field of above-mentioned composite nano materials again.Preferably, described composite nano materials can be used as the pharmaceutical carrier of delivering medicament.For example, described composite nano materials can be for delivery of ibuprofen, and described composite nano materials can be every gram carrier loading 1.8～2.5g ibuprofen pharmaceutical to the useful load of ibuprofen.Again, for example described composite nano materials can be for delivery of Docetaxel, and described composite nano materials can be every gram carrier loading 50～100mg Docetaxel medicine to the medicine useful load of Docetaxel.Described composite nano materials also can be used as protein adsorbent.For example, described composite nano materials is every gram composite nano materials absorption 995 ± 40mg bovine hemoglobin to the high adsorption capacity of bovine hemoglobin.
Description of drawings
Fig. 1 is preparation technology's schematic flow sheet of block copolymer mPEG-PLGA/ calcium silicate hydrate composite nanometer particle of the present invention;
Fig. 2 is a transmission electron microscope (TEM) photo of the block copolymer mPEG-PLGA/ calcium silicate hydrate composite nanometer particle that makes of the embodiment of the present invention 1;
Fig. 3 is another transmission electron microscope (TEM) photo of the block copolymer mPEG-PLGA/ calcium silicate hydrate composite nanometer particle that makes of the embodiment of the present invention 1;
Fig. 4 is X-ray powder diffraction (XRD) spectrogram of the block copolymer mPEG-PLGA/ calcium silicate hydrate composite nanometer particle that makes of the embodiment of the present invention 1;
Fig. 5 be the block copolymer mPEG-PLGA/ calcium silicate hydrate composite nanometer particle that makes of the embodiment of the present invention 1 can spectrogram (EDS);
Fig. 6 is the block copolymer mPEG-PLGA/ calcium silicate hydrate composite nanometer particle powder that makes of the embodiment of the present invention 1 and through the photo in kind after 800 ℃ and 1000 ℃ of calcinings (air atmosphere);
Fig. 7 is a transmission electron microscope (TEM) photo of the block copolymer mPEG-PLGA/ calcium silicate hydrate composite nanometer particle that makes of the embodiment of the present invention 2;
Fig. 8 is another transmission electron microscope (TEM) photo of the block copolymer mPEG-PLGA/ calcium silicate hydrate composite nanometer particle that makes of the embodiment of the present invention 2;
Fig. 9 is transmission electron microscope (TEM) photo of the block copolymer mPEG-PLGA/ calcium silicate hydrate composite nanometer particle that makes of the embodiment of the present invention 3;
Figure 10 be the block copolymer mPEG-PLGA/ calcium silicate hydrate composite nanometer particle that makes of the embodiment of the present invention 3 can spectrogram (EDS);
Figure 11 is that in the embodiment of the present invention 7, block copolymer mPEG-PLGA/ calcium silicate hydrate composite nanometer particle loads before and after shipwreck soluble drug ibuprofen, the uv-visible absorption spectra comparison diagram of ibuprofen hexane solution (during mensuration, the ibuprofen hexane solution has diluted 50 times);
Figure 12 is the medicament slow release curve of block copolymer mPEG-PLGA/ calcium silicate hydrate composite nanometer particle in simulated body fluid that has loaded shipwreck soluble drug ibuprofen in the embodiment of the present invention 7;
Figure 13 is X-ray powder diffraction (XRD) spectrogram that has loaded block copolymer mPEG-PLGA/ calcium silicate hydrate composite nanometer particle last product after contained ibuprofen pharmaceutical discharges fully with it of shipwreck soluble drug ibuprofen in the embodiment of the present invention 7;
Figure 14 is the block copolymer mPEG-PLGA/ calcium silicate hydrate composite nanometer particle that loaded the water soluble drug Docetaxel in the embodiment of the present invention 8 is medicament slow release comparison diagram in 7.4 and 5.5 phosphate buffer at pH value;
Figure 15 is that in the embodiment of the present invention 8, block copolymer mPEG-PLGA/ calcium silicate hydrate composite nanometer particle affects figure (composite nanometer particle concentration is 500mg/L) to the gastric carcinoma cells form before loaded with water-soluble medicine Docetaxel;
Figure 16 is that in the embodiment of the present invention 8, block copolymer mPEG-PLGA/ calcium silicate hydrate composite nanometer particle affects figure (concentration of composite nanometer particle medicament carrier system is 500mg/L) to the gastric carcinoma cells form after loaded with water-soluble medicine Docetaxel;
Figure 17 be in the embodiment of the present invention 9 block copolymer mPEG-PLGA/ calcium silicate hydrate composite nanometer particle in aqueous systems to the adsorption curve of the bovine hemoglobin of variable concentrations.
The specific embodiment
Further illustrate the present invention below in conjunction with accompanying drawing and the following specific embodiment, should be understood that following embodiment and/or accompanying drawing only are used for explanation the present invention, and unrestricted the present invention.
The present invention provides a kind of block copolymer mPEG-PLGA/ amorphous silicic acid hydrate of calcium composite nanometer particle in can be applicable to biomedicine field at this.
Composite nanometer particle of the present invention is spherical or spherical particle (solid, nucleocapsid or many imitated vesicle structures), and pattern and size be homogeneous relatively, and three-dimensional dimension is 10-100nm; In its chemical composition, the mol ratio of calcium and silicon is 0.3:1-0.7:1; The BET specific surface area is 30-100m
2/ g; There is no cytotoxicity, and have good biocompatibility and biological activity.
The process flow diagram of the method for preparing block copolymer mPEG-PLGA/ amorphous silicic acid hydrate of calcium composite nanometer particle provided by the invention as shown in Figure 1, at first, with the mensuration dissolubility silicic saline solution of soluble silicate formation homogeneous soluble in water, with block copolymer mPEG-PLGA and soluble calcium salt formation mixed liquor soluble in water.The mensuration dissolubility silicic saline solution slowly is added dropwise in the mixed aqueous solution of block copolymer mPEG-PLGA and soluble calcium salt and forms suspension, the addition of controlling calcium saline solution makes that in final mixed liquor, Ca and Si mol ratio are 0.3:1-3.0:1; Stir described mixed liquor certain hour, for example 0-60 minute, get white precipitate, the precipitation separation product, washing obtains described block copolymer mPEG-PLGA/ amorphous silicic acid hydrate of calcium composite nanometer particle after drying.
Wherein, in final mixed liquor, Ca and Si mol ratio are preferably 0.5-2.0; Mixing time is preferably 10-30 minute.
Preferably, SiO in the mensuration dissolubility silicic saline solution
3 2-Ion concentration is 0.01-2mol/L, and in the mixed aqueous solution of block copolymer mPEG-PLGA and soluble calcium salt, mPEG-PLGA concentration is 0.5-15g/L, Ca
2+Ion concentration is 0.01-2mol/L.More preferably, the SiO in the mensuration dissolubility silicic saline solution
3 2-Ion concentration is 0.1-0.8mol/L, and the mPEG-PLGA concentration in the mixed aqueous solution of block copolymer mPEG-PLGA and soluble calcium salt is 2-8g/L, Ca
2+Ion concentration is 0.03-0.3mol/L.
And soluble calcium salt is preferably Ca (NO
3)
2, CaCl
2, calcium acetate etc.Soluble silicate is preferably Na
2SiO
3, K
2SiO
3Deng.
In addition, in the method for the invention, the baking temperature scope is room temperature to 100 ℃.
The preparation method of block copolymer mPEG-PLGA/ amorphous silicic acid hydrate of calcium composite nanometer particle of the present invention, environment for use close friend's raw material at room temperature carries out, and productive rate is high, and energy savings; Easy to operate, preparation technology is simple, is easy to realize suitability for industrialized production.
Composite nanometer particle useful as drug carrier of the present invention, the drug loading, efficiency of loading and the good medicament slow release performance that poorly water soluble drugs are had superelevation, the peak load of ibuprofen is that every gram carrier loads the 1.8-2.5g ibuprofen pharmaceutical, and the efficiency of loading of ibuprofen is near 100%; The medicament slow release performance that water soluble drug is had higher drug loading and pH controlled release, the useful load of Docetaxel (Docetaxel) is that every gram carrier loads 50-100mg Docetaxel medicine, and gastric carcinoma cells complete lethal concentration is 200-600mg/L(to load the composite nanometer particle after Docetaxel).Composite nanometer particle of the present invention also can be used as protein adsorbent, has high adsorbance: the high adsorption capacity of bovine hemoglobin is that every gram carrier loads 995mg ± 40mg bovine hemoglobin.
The preparation method, the medicine that further describe block copolymer mPEG-PLGA/ amorphous silicic acid hydrate of calcium composite nanometer particle of the present invention below by specific embodiment load release performance and protein adsorption performance.Should understand equally; following examples only are used for the present invention is further illustrated; and can not be interpreted as limiting the scope of the invention, some nonessential improvement that those skilled in the art's foregoing according to the present invention is made and adjustment all belong to protection scope of the present invention.The reaction temperature that following example is concrete, time, inventory etc. are only also examples in OK range, namely, those skilled in the art can do by the explanation of this paper and select in suitable scope, and not really want to be defined in the hereinafter concrete numerical value of example.
Embodiment 1: preparation block copolymer mPEG-PLGA/ calcium silicate hydrate composite nanometer particle
Prepare respectively the Na of 0.5mol/L
2SiO
3Aqueous solution, and comprise 6g/L block copolymer mPEG-PLGA and 0.06mol/L CaCl
2Mixed aqueous solution.Under the condition of room temperature, stirring, slowly drip the above-mentioned Na of 6mL in the above-mentioned mixed aqueous solution of 50mL
2SiO
3Aqueous solution, to be addedly the suspension that obtains is continued to stir 30 minutes after complete, then use the centrifuging separated product, the product of separation washs respectively several with deionized water and ethanol, 60 ℃ of air atmosphere dryings obtain block copolymer mPEG-PLGA/ calcium silicate hydrate composite nanometer particle.
The BET specific surface area of the block copolymer mPEG-PLGA/ calcium silicate hydrate composite nanometer particle that the present embodiment makes is 68m after measured
2/ g(determining instrument: Micromeritics ASAP-2010 specific surface instrument; Assay method: after 100 ℃ of dry 6h of sample, calculate the BET specific surface area by the nitrogen molecular absorption method).
Fig. 2 and Fig. 3 are two transmission electron microscope photos of the block copolymer mPEG-PLGA/ calcium silicate hydrate composite nanometer particle that makes of the present embodiment, illustrate that this composite nanometer particle is of a size of 20-80nm, and have two kinds of nanostructureds concurrently: the solid nano-particle that (1) class is spherical, wherein block copolymer mPEG-PLGA probably is scattered in the network structure of calcium silicate hydrate more equably; (2) the composite Nano ball take block copolymer mPEG-PLGA as core with take calcium silicate hydrate as shell.
Fig. 4 is the X-ray powder diffraction spectrogram of the block copolymer mPEG-PLGA/ calcium silicate hydrate composite nanometer particle that makes of the present embodiment, illustrates that this composite nanometer particle is the amorphous state structure.
Fig. 5 be the block copolymer mPEG-PLGA/ calcium silicate hydrate composite nanometer particle that makes of the present embodiment can spectrogram, illustrate that the component of this composite nanometer particle has calcium, silicon, oxygen etc., and calcium and element silicon molar content are than being 0.53:1.
Fig. 6 is the block copolymer mPEG-PLGA/ calcium silicate hydrate composite nanometer particle powder that makes of the present embodiment and through the photo in kind after 800 ℃ and 1000 ℃ of calcinings (air atmosphere); as can be seen from the figure; after calcining, carbonization phenomenon can appear in composite nanometer particle; even temperature increase to 1000 ℃ can not be removed carbon fully; explanation is in composite nanometer particle; block copolymer mPEG-PLGA molecule is wrapped in the calcium silicate hydrate nanostructured well, and this and Fig. 2 and result shown in Figure 3 match.
Embodiment 2: preparation block copolymer mPEG-PLGA/ calcium silicate hydrate composite nanometer particle
Prepare respectively the Na of 0.5mol/L
2SiO
3Aqueous solution, and comprise 6g/L block copolymer mPEG-PLGA and 0.06mol/L Ca (NO
3)
2Mixed aqueous solution.Under the condition of room temperature, stirring, slowly drip the above-mentioned Na of 6mL in the above-mentioned mixed aqueous solution of 50mL
2SiO
3Aqueous solution, to be addedly the suspension that obtains is continued to stir 30 minutes after complete, then use the centrifuging separated product, the product of separation washs respectively several with deionized water and ethanol, 60 ℃ of air atmosphere dryings obtain block copolymer mPEG-PLGA/ calcium silicate hydrate composite nanometer particle.
Fig. 7 and Fig. 8 are two transmission electron microscope photos of the block copolymer mPEG-PLGA/ calcium silicate hydrate composite nanometer particle that makes of the present embodiment, illustrate that this composite nanometer particle is of a size of 15-45nm, and have two kinds of nanostructureds concurrently: (1) class spherical composite nano granule take block copolymer mPEG-PLGA as core with take calcium silicate hydrate as shell; (2) the spherical many vesicles nano-particle of class, wherein the vesicle of block copolymer mPEG-PLGA formation is scattered in the network structure of calcium silicate hydrate more equably.
Embodiment 3: preparation block copolymer mPEG-PLGA/ calcium silicate hydrate composite nanometer particle
Prepare respectively the Na of 0.25mol/L
2SiO
3Aqueous solution, and comprise 3g/L block copolymer mPEG-PLGA and 0.06mol/L CaCl
2Mixed aqueous solution.Under the condition of room temperature, stirring, slowly drip the above-mentioned Na of 6mL in the above-mentioned mixed aqueous solution of 50mL
2SiO
3Aqueous solution, to be addedly the suspension that obtains is continued to stir 30 minutes after complete, then use the centrifuging separated product, the product of separation washs respectively several with deionized water and ethanol, 60 ℃ of air atmosphere dryings obtain block copolymer mPEG-PLGA/ calcium silicate hydrate composite nanometer particle.
Fig. 9 is a transmission electron microscope photo of the block copolymer mPEG-PLGA/ calcium silicate hydrate composite nanometer particle that makes of the present embodiment, illustrate that this composite nanometer particle is of a size of 10-25nm, and have two kinds of nanostructureds concurrently: the solid nano-particle that (1) class is spherical, wherein block copolymer mPEG-PLGA probably is scattered in the network structure of calcium silicate hydrate more equably; (2) the class spherical composite nano granule take block copolymer mPEG-PLGA as core with take calcium silicate hydrate as shell.
Figure 10 be the block copolymer mPEG-PLGA/ calcium silicate hydrate composite nanometer particle that makes of the present embodiment can spectrogram (EDS), illustrate that the component of this composite nanometer particle has calcium, silicon, oxygen etc., and calcium and element silicon molar content are than being 0.55:1.
Condition and the embodiment 1 of following examples 4～6 preparation block copolymer mPEG-PLGA/ calcium silicate hydrate composite nanometer particles are slightly different, but should understand, the block copolymer mPEG-PLGA/ calcium silicate hydrate composite nanometer particle of its preparation is similar to embodiment 1, be amorphous state, be of a size of 20-80nm, and have two kinds of nanostructureds concurrently: the solid nano-particle that (1) class is spherical, wherein block copolymer mPEG-PLGA probably is scattered in the network structure of calcium silicate hydrate more equably; (2) the composite Nano ball take block copolymer mPEG-PLGA as core with take calcium silicate hydrate as shell.From can spectrogram may confirm that product is elementary composition by calcium, silicon, oxygen etc., and calcium and element silicon mol ratio are 0.3:1-0.7:1.
Embodiment 4: preparation block copolymer mPEG-PLGA/ calcium silicate hydrate composite nanometer particle
Prepare respectively the K of 0.5mol/L
2SiO
3Aqueous solution, and comprise 6g/L block copolymer mPEG-PLGA and 0.06mol/L CaCl
2Mixed aqueous solution.Under the condition of room temperature, stirring, slowly drip the above-mentioned Na of 6mL in the above-mentioned mixed aqueous solution of 50mL
2SiO
3Aqueous solution, to be addedly the suspension that obtains is continued to stir 30 minutes after complete, then use the centrifuging separated product, the product of separation washs respectively several with deionized water and ethanol, 60 ℃ of air atmosphere dryings obtain block copolymer mPEG-PLGA/ calcium silicate hydrate composite nanometer particle.
Embodiment 5: preparation block copolymer mPEG-PLGA/ calcium silicate hydrate composite nanometer particle
Prepare respectively the Na of 0.5mol/L
2SiO
3Aqueous solution, and comprise 6g/L block copolymer mPEG-PLGA and 0.06mol/L (CH
3COO)
2The mixed aqueous solution of Ca.Under the condition of room temperature, stirring, slowly drip the above-mentioned Na of 6mL in the above-mentioned mixed aqueous solution of 50mL
2SiO
3Aqueous solution, to be addedly the suspension that obtains is continued to stir 30 minutes after complete, then use the centrifuging separated product, the product of separation washs respectively several with deionized water and ethanol, 60 ℃ of air atmosphere dryings obtain block copolymer mPEG-PLGA/ calcium silicate hydrate composite nanometer particle.
Embodiment 6: preparation block copolymer mPEG-PLGA/ calcium silicate hydrate composite nanometer particle
Prepare respectively the Na of 0.5mol/L
2SiO
3Aqueous solution, and comprise 6g/L block copolymer mPEG-PLGA and 0.06mol/L CaCl
2Mixed aqueous solution.Under the condition of room temperature, stirring, slowly drip the above-mentioned Na of 6mL in the above-mentioned mixed aqueous solution of 50mL
2SiO
3Aqueous solution, to be addedly the suspension that obtains is continued to stir 10 minutes after complete, then use the centrifuging separated product, the product of separation washs respectively several with deionized water and ethanol, 60 ℃ of air atmosphere dryings obtain block copolymer mPEG-PLGA/ calcium silicate hydrate composite nanometer particle.
Embodiment 7: block copolymer mPEG-PLGA/ calcium silicate hydrate composite nanometer particle is used for loading and the slow release of the anti-inflammation and analgesic drugs ibuprofen of slightly water-soluble
load: 1.0 embodiment 1 gained block copolymer mPEG-PLGA/ calcium silicate hydrate composite nanometer particles are joined in the ibuprofen hexane solution that 50mL concentration is 40mg/mL, rocked 24 hours under 37 ℃ of conditions after sealing, then the composite nanometer particle after medicine carrying is separated, get and carry out the uv-visible absorption spectra test after supernatant dilutes 50 times, by contrasting the uv-visible absorption spectra of ibuprofen normal hexane mother solution under same test condition, as shown in figure 11, and the visible absorbance peak intensity that wavelength is the 460nm place is analyzed, draw the efficiency of loading of ibuprofen pharmaceutical near 100%.Be pressed into tablet (every 0.2g) after the product drying that separation is obtained, draw this composite nanometer particle of every gram by thermogravimetry and can load approximately 1.9g(determining instrument of ibuprofen pharmaceutical: Netzsch STA-409PC thermal analyzer; Near assay method: the loss in weight of this composite nanometer particle 900 ℃ before and after loading by drugs compared, calculate the medicine useful load, heating rate used is 10 ℃/min, and atmosphere used is moving air atmosphere), this is far above present other known material.
Slow release: the tablet that is pressed into is immersed in 200mL simulated body fluid (pH7.4), rock in the environment of 37 ℃, take out at set intervals the 2ml release medium, add the fresh simulated body fluid of 2mL simultaneously in former mixed liquor.The release medium of taking out is carried out the ultra-violet absorption spectrum test, and the uv absorption peak intensity that wavelength is the 263nm place is analyzed, obtained loading the medicament slow release curve of composite nanometer particle in simulated body fluid of ibuprofen pharmaceutical, as shown in figure 12, its pharmaceutical release time can reach 288 hours, and finally almost medicine can be discharged fully, illustrate that this composite nanometer particle can make ibuprofen pharmaceutical that slow-release function is preferably arranged.After medicine is discharged fully, last product is carried out X-ray powder diffraction spectrum analysis, as shown in figure 13, through confirmation, its phase changes hydroxyapatite (Ca fully into
10(PO
4)
6(OH)
2), illustrate that the medicament carrier system that this composite nanometer particle forms has good biological activity, has application prospect preferably in field of drug delivery.
Embodiment 8: block copolymer mPEG-PLGA/ calcium silicate hydrate composite nanometer particle is used for loading and the slow release of water miscible anticancer drug docetaxel
Load: 60mg embodiment 1 gained block copolymer mPEG-PLGA/ calcium silicate hydrate composite nanometer particle is joined in the Docetaxel aqueous solution that 2.5mL concentration is 40mg/mL, rocked 24 hours under 37 ℃ of conditions after sealing, then the composite nanometer particle after medicine carrying is separated, with washing with alcohol once, drying has obtained loading the composite nanometer particle of Docetaxel.Draw this composite nanometer particle of every gram by thermogravimetry and can load approximately 82mg(determining instrument of Docetaxel medicine: Netzsch STA-409PC thermal analyzer; Assay method: near the loss in weight of this composite nanometer particle 900 ℃ before and after loading by drugs compared, calculate the medicine useful load, heating rate used is 10 ℃/min, atmosphere used is moving air atmosphere).
Slow release: the composite nanometer particle that 5mg has been loaded Docetaxel immerses 10mL pH and is respectively in 7.4 and 5.5 phosphate buffer, rock in the environment of 37 ℃, take out at set intervals the 0.2ml release medium, add 0.2mL fresh phosphoric salt buffer simultaneously in former mixed liquor.the release medium of taking out is carried out the ultra-violet absorption spectrum test, and the uv absorption peak intensity that wavelength is the 230nm place is analyzed, obtained loading the medicament slow release curve of composite nanometer particle in the phosphate buffer of pH7.4 and pH5.5 of Docetaxel medicine, as shown in figure 14, its pharmaceutical release time was over 72 hours, and the rate of release in the phosphate buffer of pH5.5 is faster than the rate of release in the phosphate buffer of pH7.4, this is significant for treatment of cancer, because the pH value of tumor tissues is generally lower than normal structure, and this medicament carrier system has the potentiality that guide drugs discharges at tumor tissues.
Figure 14 and Figure 15 be respectively block copolymer mPEG-PLGA/ calcium silicate hydrate composite nanometer particle in the present embodiment carry out the Docetaxel medicine load before and afterwards on the figure that affects of gastric carcinoma cells form; can find out; under the condition that has composite nanometer particle or composite nanometer particle medicament carrier system to exist; before medicine loads, cell can be attached in substrate well; and after the medicine loading, cell is killed; break away from substrate and become rounded form, and the killing rate of cell is near 100%.Therefore, block copolymer mPEG-PLGA/ calcium silicate hydrate composite nanometer particle medicament carrier system has application prospect preferably in treatment of cancer.
Embodiment 9: block copolymer mPEG-PLGA/ calcium silicate hydrate composite nanometer particle is used for the absorption of bovine hemoglobin
5.5mg embodiment 1 gained block copolymer mPEG-PLGA/ calcium silicate hydrate composite nanometer particle is dispersed in the aqueous solution (50 of the bovine hemoglobin of 2mL variable concentrations, 100, 200, 300, 500, 700, 1000, 1500, 2000, 3000, 4000, 5000, 6000, 7000mg/L), rocked 2 hours under 37 ℃ of conditions after sealing, then mixture is centrifugal, get supernatant and suitably carry out the uv-visible absorption spectra test after dilution, and the visible absorbance peak intensity that wavelength is the 460nm place is analyzed, obtain the adsorption curve of composite nanometer particle in the aqueous solution of bovine hemoglobin, as shown in figure 17, the adsorbance of bovine hemoglobin is directly proportional basically to its initial concentration, high adsorption capacity is every gram composite nanometer particle absorption 995 ± 40mg bovine hemoglobin, far away higher than other material, and the space with further lifting, illustrate that block copolymer mPEG-PLGA/ calcium silicate hydrate composite Nano has application prospect preferably aspect protein adsorption.
Industrial applicability
Block copolymer mPEG-PLGA/ amorphous silicic acid hydrate of calcium composite nano materials good biocompatibility provided by the invention, the medicine useful load is high, and protein adsorption is good, at biomedicine field, good application prospect is arranged.Preparation method environment for use close friend's of the present invention raw material at room temperature carries out, and productive rate is high, and energy savings; Easy to operate, preparation technology is simple, is easy to realize suitability for industrialized production.
Claims (13)
1. block copolymer mPEG-PLGA/ amorphous silicic acid hydrate of calcium composite nano materials, it is characterized in that, described composite nano materials has spherical or that class is spherical is solid, nucleocapsid or many imitated vesicle structures, described composite nanometer particle is of a size of 10～100nm, and in the chemical composition of described composite nano materials, the mol ratio of calcium and silicon is 0.3:1～0.7:1.
2. described composite nano materials according to claim 1, is characterized in that, described composite nano materials comprises amorphous silicic acid calcium network skeleton and Uniform Dispersion block copolymer mPEG-PLGA therein.
3. described composite nano materials according to claim 1, is characterized in that, described composite nano materials comprises amorphous silicic acid calcium nucleocapsid and parcel block copolymer mPEG-PLGA within it.
4. the described described composite nano materials of any one according to claim 1～3, is characterized in that, the BET specific surface area of described composite nano materials is 30～100 m
2/ g.
5. a method for preparing the described composite nano materials of any one in claim 1～4, is characterized in that, comprising:
The mensuration dissolubility silicic saline solution slowly is added dropwise to the mixed aqueous solution of block copolymer mPEG-PLGA and soluble calcium salt, and controls that in final mixed liquor, Ca and Si mol ratio are 0.3:1～3.0:1, stirred described mixed liquor 0～60 minute, and
Separating obtained precipitation obtains described block copolymer mPEG-PLGA/ amorphous silicic acid hydrate of calcium composite nano materials after washing, drying.
6. method according to claim 5, is characterized in that,
In described mensuration dissolubility silicic saline solution, SiO
3 2-Ion concentration is 0.01～2 mol/L;
In the mixed aqueous solution of described block copolymer mPEG-PLGA and soluble calcium salt, mPEG-PLGA concentration is 0.5～15 g/L, Ca
2+Ion concentration is 0.01～2 mol/L.
7. according to claim 5 or 6 described methods, is characterized in that, the temperature range of described drying is room temperature to 100 ℃.
8. the application in biomedicine field of the described composite nano materials of any one in a claim 1～4.
9. application according to claim 8, is characterized in that, described composite nano materials is as the pharmaceutical carrier of delivering medicament.
10. application according to claim 9, is characterized in that, described composite nano materials is for delivery of ibuprofen, and described composite nano materials is that every gram carrier loads 1.8～2.5 g ibuprofen pharmaceuticals to the useful load of ibuprofen.
11. application according to claim 9 is characterized in that, described composite nano materials is for delivery of Docetaxel, and described composite nano materials is that every gram carrier loads 50～100 mg Docetaxel medicines to the medicine useful load of Docetaxel.
12. application according to claim 8 is characterized in that, described composite nano materials is as protein adsorbent.
13. application according to claim 12 is characterized in that, described composite nano materials is every gram composite nano materials absorption 995 ± 40 mg bovine hemoglobin to the high adsorption capacity of bovine hemoglobin.
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| CN101623266A (en) * | 2009-07-24 | 2010-01-13 | 中国科学院上海硅酸盐研究所 | Calcium phosphate/block copolymer composite porous nanoparticles and preparation method thereof |
| CN102923725A (en) * | 2012-11-26 | 2013-02-13 | 中国科学院上海硅酸盐研究所 | Ultrathin calcium silicate nanosheet with ultrahigh specific surface area and preparation method thereof |
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| CN101623266A (en) * | 2009-07-24 | 2010-01-13 | 中国科学院上海硅酸盐研究所 | Calcium phosphate/block copolymer composite porous nanoparticles and preparation method thereof |
| CN102923725A (en) * | 2012-11-26 | 2013-02-13 | 中国科学院上海硅酸盐研究所 | Ultrathin calcium silicate nanosheet with ultrahigh specific surface area and preparation method thereof |
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| CN107162469A (en) * | 2017-05-26 | 2017-09-15 | 中建商品混凝土有限公司 | A kind of ultra-small grain size micellar solution early strength agent and preparation method thereof |
| CN107162469B (en) * | 2017-05-26 | 2019-10-25 | 中建商品混凝土有限公司 | A kind of ultra-small grain size micellar solution early strength agent and preparation method thereof |
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