CN109513009B - Modification method of biological activity glass nano particle physiological environment stability and biomedical application - Google Patents
Modification method of biological activity glass nano particle physiological environment stability and biomedical application Download PDFInfo
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Abstract
A method for modifying the stability of bioactive glass nanoparticles in physiological environment includes dissolving modifier in deionized water or buffer solution, stirring, adding bioactive glass nanoparticles, centrifugal washing, and freeze drying. The modification technology is simple and easy to implement, the reaction condition is mild, the hydrophilic modifier is utilized to modify the bioactive glass nanoparticles for the first time through the ionic interaction force between calcium ions and anionic groups such as phosphate radicals in the modifier and the adsorption effect of the bioactive glass nanoparticles on abundant proteins in serum, the hydrophilicity and the stability of the bioactive glass nanoparticles in different dispersion systems are improved, and the modified bioactive glass nanoparticles not only have good physiological environment stability, but also can effectively inhibit the growth and proliferation of cancer cells, and have great application potential in the biomedical fields such as tissue repair and reconstruction and cancer treatment.
Description
Technical Field
The invention relates to a modification technology of bioactive glass nanoparticles for drug delivery, cancer treatment and tissue repair and regeneration, in particular to a modification method of the physiological environment stability of bioactive glass nanoparticles and biomedical application.
Background
Bioactive glass is a very representative silicate-based biomaterial, and is widely used for bone tissue repair and regeneration in clinic due to its good biocompatibility and osseointegration ability. The most common bioactive glass is made of SiO2-CaO-P2O5Amorphous silicate of composition, in which SiO2And P2O5Forming a base network, SiO4The tetrahedra being connected by bridging oxygen bonds (Si-O-Si), the metal ions acting as network modifiers being connected by non-bridging oxygen bonds (Si-O-M)+) Into which the form of (b) is incorporated. Bioactive glasses exhibit better than silica and other inorganic nanocrystals due to the presence of non-bridging oxygen bondsBiodegradability. Also, the bioactive glass exhibits excellent osteoblast differentiation promoting and drug/gene delivery capabilities due to its gene activation ability and biomolecule loading ability. In particular to monodisperse bioactive glass nanoparticles, which have great application potential in the aspects of drug/gene delivery and the like. However, the heat treatment in the preparation process causes the surface of the bioactive glass nanoparticles to lack rich chemical groups and have poor stability in physiological environment, so that the bioactive glass nanoparticles are easy to agglomerate in clinical application, are easy to generate nonspecific combination with protein in blood, cause immune response reaction and are quickly discharged out of the body. This severely limits the application of bioactive glass nanoparticles in the biomedical field. Therefore, it is necessary to improve the hydrophilicity of the bioactive nanoparticles and improve the physiological stability thereof, so as to promote the wide application thereof in disease treatment and tissue repair.
In order to improve the stability of nanoparticles, a series of methods for improving the stability of the physiological environment of nanoparticles by changing the surface properties of the nanoparticles have been developed. Surface modification by means of chemisorption or chemical reaction is a common modification method, for example, surface modification by reaction between a silane coupling agent and a siloxane bond of a silica surface. The ligand exchange technology is a modification means commonly used for oil-based nanoparticles such as quantum dots. Grafting organic polymers onto the surface of nanoparticles is also a typical modification method. However, because the surface active groups of the bioactive glass nanoparticles are limited, the modification by means of surface grafting is difficult. Other surface modification methods, such as self-assembly of polymers on the surface of nanoparticles to form a hydrophilic surface, have also been reported. However, most of the reported nanoparticle modification methods have complicated steps and the obtained modified nanoparticles have poor biocompatibility. Therefore, there is a need to develop a simple and effective modification technique without affecting the bioactivity and biocompatibility of bioactive glass nanoparticles to improve the physiological stability of bioactive glass nanoparticles and promote the application thereof in the biomedical field.
Disclosure of Invention
The invention aims to provide a modification method of the physiological environment stability of bioactive glass nanoparticles and biomedical application, thereby promoting the application of the bioactive glass nanoparticles in the aspects of drug delivery, gene therapy, bone tissue repair and regeneration and the like. The modification method is simple to operate and mild in reaction conditions.
In order to achieve the purpose, the invention adopts the following technical scheme:
a method for modifying the physiological environment stability of bioactive glass nanoparticles comprises the following steps:
1) preparing a modified system: dissolving a hydrophilic modifier containing phosphate radicals in a solution, and stirring for reaction at room temperature to obtain a solution containing the modifier;
2) the modification process comprises the following steps: adding the bioactive glass nanoparticles into a solution containing a modifier to obtain a mixed solution, performing ultrasonic dispersion on the mixed solution, stirring at room temperature for modification to obtain a modified bioactive glass nanoparticle solution, centrifuging, washing and freeze-drying to obtain the bioactive glass nanoparticles with physiological environment stability.
In a further improvement of the present invention, the bioactive glass nanoparticles are prepared by the following process: the bioactive glass nanoparticles are synthesized by combining a sol-gel method and a template method.
The invention is further improved in that the template agent adopted in the sol-gel method combined template method is dodecylamine or hexadecyl pyridine bromide.
In a further improvement of the invention, the solution in the step 1) is acetic acid buffer solution with pH 4 or deionized water.
The invention further improves that the hydrophilic modifier containing phosphate radical in the step 1) is diphosphate, sodium glycerophosphate, fosfomycin sodium or fetal calf serum.
In a further improvement of the invention, the bisphosphonate is alendronate sodium.
The further improvement of the invention is that in the step 1), the concentration of the diphosphate in the solution containing the modifier is 10-20mg/mL, the concentration of the fosfomycin sodium is 10-40mg/mL, the concentration of the sodium glycerophosphate is 1-3mg/mL, and the volume concentration of the fetal calf serum is 10% -30%.
The further improvement of the invention is that the concentration of the bioactive glass nanoparticles in the mixed solution in the step 2) is as follows: when the hydrophilic modifier is diphosphate or fosfomycin sodium, the concentration of the bioactive glass nanoparticles is 5-10mg/mL, and when the hydrophilic modifier is sodium glycerophosphate or fetal bovine serum, the concentration of the bioactive glass nanoparticles is 1-3 mg/mL.
The further improvement of the invention is that when the modification is carried out by stirring in the step 2), the reaction lasts for 12-24h when the hydrophilic modifier is diphosphonate, fosfomycin sodium or fetal calf serum, and lasts for 1-3h when the hydrophilic modifier is sodium glycerophosphate.
An application of bioactive nanoparticles with physiological environment stability in serving as a load and delivery carrier of anticancer drug adriamycin.
The further improvement of the invention is that the modified biological nanoparticles obtained in the step 2) are washed for 3 times by using deionized water; the bioactive glass was then dried in a lyophilizer at-80 ℃ for 12 h.
Compared with the prior art, the invention has the following beneficial effects:
the bioactive glass nanoparticles contain rich Ca2+The invention takes the biocompatible hydrophilic phosphate molecules containing phosphate radical as a modifier for the first time and utilizes Ca in the structure of bioactive glass nanoparticles2+Under the action of ions between the biological active glass nanoparticles and phosphate radicals in hydrophilic molecules, a hydrophilic modifier is grafted on the surfaces of the biological active glass nanoparticles to improve the stability of the biological active glass nanoparticles; the modification technology of the bioactive glass nanoparticles is simple and easy to implement, the reaction conditions are mild, and the modified bioactive glass has good bioactivity, biocompatibility and physiological stability;
furthermore, the invention firstly utilizes the adsorption capacity of the bioactive glass nanoparticles to abundant proteins in fetal calf serum, and forms a hydrophilic protective layer on the surfaces of the bioactive glass nanoparticles to improve the hydrophilicity and stability of the bioactive glass nanoparticles;
the modified bioactive nanoparticles obtained in the invention have good physiological environment stability, can effectively prolong the dispersion time of bioactive glass nanoparticles in different systems through modification, prevent the aggregation and precipitation of the bioactive nanoparticles, and show long-term stable degradability and bioactivity. Meanwhile, the good drug loading capacity of the recombinant human immunodeficiency virus makes the recombinant human immunodeficiency virus a non-viral gene vector with high potential, and can be used in the biomedical fields of cancer treatment, tissue repair and reconstruction and the like.
Drawings
Fig. 1 is a digital photograph of sodium alendronate diphosphate (AL) modified bioactive glass nanoparticles (AL-BGN) and Bioactive Glass Nanoparticles (BGN) dispersed at a concentration of 1mg/mL in water and phosphate buffer at pH 7.4 for 0h and 48 h. Wherein (a) is a photo that biologically active glass nanoparticles (AL-BGN) modified by sodium alendronate diphosphate (AL) are dispersed in water at the concentration of 1mg/mL for 0 h; (b) a photo of bioactive glass nanoparticles (AL-BGN) modified by alendronate sodium (AL) diphosphate dispersed in water at a concentration of 1mg/mL for 48 h; (c) is a picture of dispersing bioactive glass nano particles (BGN) in water for 0h at the concentration of 1 mg/mL; (d) is a photo that bioactive glass nano-particles (BGN) are dispersed in water for 48h at the concentration of 1 mg/mL; (e) a photograph of bioactive glass nanoparticles (AL-BGN) modified with sodium alendronate diphosphate (AL) dispersed at a concentration of 1mg/mL in phosphate buffer at pH 7.4 for 0 h; (f) a photograph of bioactive glass nanoparticles (AL-BGN) modified with sodium alendronate diphosphate (AL) dispersed at a concentration of 1mg/mL in phosphate buffer at pH 7.4 for 48 h; (g) photograph of Bioactive Glass Nanoparticles (BGN) dispersed in phosphate buffer at pH 7.4 at a concentration of 1mg/mL for 0 h; (h) photograph of Bioactive Glass Nanoparticles (BGN) dispersed at a concentration of 1mg/mL in phosphate buffer at pH 7.4 for 48 h;
FIG. 2 is a digital photograph of sodium fosfomycin (PDS) modified BGN (PDS-BGN) and BGN dispersed in water at a concentration of 1mg/mL for 0h and 48 h. Wherein (a) is a picture of fosfomycin sodium (PDS) modified BGN (PDS-BGN) dispersed in water at a concentration of 1mg/mL for 0 h; (b) photograph of BGN modified with sodium fosfomycin (PDS) (PDS-BGN) dispersed in water at a concentration of 1mg/mL for 48 h; (c) is a picture of BGN dispersed in water at a concentration of 1mg/mL for 0 h; (d) photograph of BGN dispersed in water at a concentration of 1mg/mL for 48 h.
Fig. 3 is a digital photograph of sodium Glycerophosphate (GP) modified BGN (GP-BGN) and BGN dispersed in water at a concentration of 1mg/mL for 0h and 48h and in phosphate buffer at pH 7.4 at a concentration of 1mg/mL for 0h and 2 h. Wherein (a) is a photo of sodium Glycerophosphate (GP) -modified BGN (GP-BGN) dispersed in water at a concentration of 1mg/mL for 0 h; (b) photograph of BGN (GP-BGN) modified with sodium Glycerophosphate (GP) dispersed in water at a concentration of 1mg/mL for 48 h; (c) is a picture of BGN dispersed in water at a concentration of 1mg/mL for 0 h; (d) is a photograph of BGN dispersed in water at a concentration of 1mg/mL for 48 h; (e) photographs of BGN (GP-BGN) modified with sodium Glycerophosphate (GP) dispersed at a concentration of 1mg/mL in phosphate buffer at pH 7.4 for 0 h; (f) photographs of BGN (GP-BGN) modified with sodium Glycerophosphate (GP) dispersed at a concentration of 1mg/mL in phosphate buffer at pH 7.4 for 2 h; (g) photographs showing BGN dispersed at a concentration of 1mg/mL in phosphate buffer at pH 7.4 for 0 h; (h) photograph showing BGN dispersed at a concentration of 1mg/mL in phosphate buffer at pH 7.4 for 2 h.
Figure 4 is a digital photograph of BGN and Fetal Bovine Serum (FBS) modified BGN after 24h dispersion in water and phosphate buffer at pH 7.4. The picture of BGN dispersed in water for 24h, (b) the picture of BGN modified by 10% fetal bovine serum (10% FBS-BGN) dispersed in water for 24h, (c) the picture of BGN modified by 20% fetal bovine serum (20% FBS-BGN) dispersed in water for 24h, and (d) the picture of BGN modified by 30% fetal bovine serum (30% FBS-BGN) dispersed in water for 24 h. (e) The photographs were taken after BGN was dispersed in phosphate buffer at pH 7.4 for 24 hours, (f) the photograph after BGN modified with 10% fetal bovine serum (10% FBS-BGN) was dispersed in phosphate buffer at pH 7.4 for 24 hours, (g) the photograph after BGN modified with 20% fetal bovine serum (20% FBS-BGN) was dispersed in phosphate buffer at pH 7.4 for 24 hours, and (h) the photograph after BGN modified with 30% fetal bovine serum (30% FBS-BGN) was dispersed in phosphate buffer at pH 7.4 for 24 hours.
Figure 5 is a physicochemical characterization and drug release profile of AL-BGN. Wherein, fig. 5(a) is an ultraviolet visible absorption spectrum of AL in a sodium acetate buffer solution with pH 4 before and after modification, fig. 5(b) is a fourier transform infrared absorption spectrum (FTIR) of AL-BGN, BGN and AL, fig. 5(c) is an X-ray diffraction spectrum (XRD) of AL-BGN, BGN and AL, and fig. 5(d) is a cumulative release profile of AL-BGN in a phosphate buffer solution with pH 7.4 releasing AL.
FIG. 6 shows the viability of SJSA-1 cells after incubation of AL-BGN and AL with osteosarcoma cells (SJSA-1) at different AL concentrations for 24h and 72 h; among them, FIG. 6(a) is the survival rate of SJSA-1 cells after AL-BGN and AL were co-cultured with osteosarcoma cells (SJSA-1) at different AL concentrations for 24h, and FIG. 6(b) is the survival rate of SJSA-1 cells after AL-BGN and AL were co-cultured with osteosarcoma cells (SJSA-1) at different AL concentrations for 72 h.
FIG. 7 is a graph showing cell viability showing BGN, BGN loaded with anticancer drug Doxorubicin (DOX) (BGN-DOX), DOX-loaded 10% FBS-BGN (FBS-BGN-DOX) and DOX, which were co-cultured with melanoma cells (A375) at different concentrations for 24h, and survival of A375 cells after co-culturing BGN, BGN-DOX, FBS-BGN-DOX and DOX with A375 at different concentrations for 72h, in FIG. 7 (a).
Detailed Description
The invention is described in detail below with reference to the attached drawing figures:
the invention aims to modify bioactive nanoparticles by taking biocompatible hydrophilic phosphate or fetal calf serum as a surface modifier. On one hand, the invention utilizes the ion interaction force between the abundant calcium ions in the bioactive glass nanoparticles and the anions (phosphate radical) in the modifier or the adsorption capacity of the bioactive glass nanoparticles to the abundant proteins in the fetal calf serum to modify the bioactive glass nanoparticles, and the reaction is simple and easy to implement and has mild conditions. On the other hand, the modified bioactive glass nanoparticles have excellent physiological environment stability, bioactivity and degradability, have long-term stable dispersion capability in different buffer solutions, and can effectively prevent agglomeration and precipitation of nanoparticles through surface modification, so that the in vivo circulation time of the nanoparticles in living body application is prolonged, and the modified bioactive nanoparticles have great application potential in biomedical fields such as tissue engineering, disease treatment and the like.
For better understanding of the present invention, the present invention will be described in detail with reference to the following embodiments, but the present invention is not limited to the following examples.
Example 1
(1) Preparation of bioactive glass nanoparticles: synthesizing bioactive glass nanoparticles by using hexadecyl pyridine bromide as a template and adopting a sol-gel method combined with the template method;
(2) preparing a modified system: dissolving alendronate sodium diphosphate in a sodium acetate buffer solution with the pH value of 4, and after the alendronate sodium is completely dissolved, gently stirring at room temperature for 0.5h, wherein the concentration of the alendronate sodium diphosphate is 20 mg/mL;
(3) the modification process comprises the following steps: adding bioactive glass nanoparticles into a sodium acetate solution of alendronate sodium, wherein the concentration of the bioactive glass nanoparticles is 10mg/mL, and carrying out ultrasonic treatment at 300W for 30min and then carrying out mild stirring at room temperature for 24 h;
(4) and (3) purification and drying: centrifuging the modified bioactive glass nanoparticle solution at 9000rpm for 3min, and washing with deionized water for 3 times to obtain bioactive glass nanoparticles with physiological environment stability;
(5) biomedical applications: the alendronate sodium modified bioactive glass nanoparticles with physiological environment stability are dispersed in a phosphate buffer solution with the pH value of 7.4, and the accumulative release amount of the alendronate sodium is detected. And co-culturing the alendronate sodium modified bioactive glass nanoparticles and osteosarcoma cells, and detecting the killing capability of the nanoparticles on cancer cells.
Example 2
(1) Preparation of bioactive glass nanoparticles: synthesizing bioactive glass nanoparticles by using hexadecyl pyridine bromide as a template and adopting a sol-gel method combined with the template method;
(2) preparing a modified system: dissolving fosfomycin sodium in a sodium acetate buffer solution with the pH value of 4, and after the fosfomycin sodium is completely dissolved, gently stirring at room temperature for 0.5h, wherein the concentration of the fosfomycin sodium is 40 mg/mL;
(3) the modification process comprises the following steps: adding bioactive glass nanoparticles into a sodium acetate solution of fosfomycin sodium, wherein the concentration of the bioactive glass nanoparticles is 10mg/mL, and carrying out ultrasonic treatment at 300W for 30min and then carrying out mild stirring at room temperature for 24 h;
(4) and (3) purification and drying: centrifuging the modified bioactive glass nanoparticles at 9000rpm for 3min, and washing with deionized water for 3 times to obtain bioactive glass nanoparticles with physiological environment stability;
(5) biomedical applications: the method comprises the steps of loading an anticancer drug adriamycin on fosfomycin sodium modified bioactive glass nanoparticles with physiological environment stability in an adsorption mode, co-culturing the fosfomycin sodium modified bioactive glass nanoparticles loaded with adriamycin and melanoma cells, and detecting the killing capacity of the nanoparticles on cancer cells.
Example 3
(1) Preparation of bioactive glass nanoparticles: synthesizing bioactive glass nanoparticles by using hexadecyl pyridine bromide as a template and adopting a sol-gel method combined with the template method;
(2) preparing a modified system: dissolving sodium glycerophosphate in deionized water, and stirring at room temperature for 0.5h under mild condition until the sodium glycerophosphate is completely dissolved, wherein the concentration of the sodium glycerophosphate is 3 mg/mL;
(3) the modification process comprises the following steps: adding bioactive glass nanoparticles into an aqueous solution of sodium glycerophosphate, wherein the concentration of the bioactive glass nanoparticles is 1mg/mL, and carrying out ultrasonic treatment at 300W for 30min and then carrying out mild stirring at room temperature for 1 h;
(4) and (3) purification and drying: centrifuging the modified bioactive glass nanoparticles at 9000rpm for 3min, and washing with deionized water for 3 times to obtain bioactive glass nanoparticles with physiological environment stability;
(5) biomedical applications: the method comprises the steps of loading an anticancer drug adriamycin to sodium glycerophosphate modified bioactive glass nanoparticles with physiological environment stability in an adsorption mode, co-culturing the sodium glycerophosphate modified bioactive glass nanospheres loaded with adriamycin and melanoma cells, and detecting the killing capacity of the nanoparticles on cancer cells.
Example 4
(1) Preparation of bioactive glass nanoparticles: synthesizing bioactive glass nanoparticles by using hexadecyl pyridine bromide as a template and adopting a sol-gel method combined with the template method;
(2) preparing a modified system: dissolving fetal calf serum in deionized water, and stirring at room temperature for 0.5h, wherein the volume concentration of fetal calf serum is 10%;
(3) the modification process comprises the following steps: adding bioactive glass nanoparticles into an aqueous solution of fetal calf serum, wherein the concentration of the bioactive glass nanoparticles is 1mg/mL, and carrying out ultrasonic treatment at 300W for 1min and then carrying out mild stirring at room temperature for 24 h;
(4) and (3) purification and drying: centrifuging the modified bioactive glass nanoparticles at 9000rpm for 3min, and washing with deionized water for 3 times to obtain bioactive glass nanoparticles with physiological environment stability;
(5) biomedical applications: the method comprises the steps of loading an anticancer drug adriamycin to fetal calf serum modified bioactive glass nanoparticles with physiological environment stability in an adsorption mode, co-culturing the adriamycin-loaded sodium glycerophosphate modified bioactive glass nanoparticles and melanoma cells, and detecting the killing capacity of the nanoparticles to cancer cells.
Example 5
(1) Preparation of bioactive glass nanoparticles: synthesizing bioactive glass nanoparticles by using hexadecyl pyridine bromide as a template and adopting a sol-gel method combined with the template method;
(2) preparing a modified system: dissolving fetal calf serum in deionized water, and stirring at room temperature for 0.5h, wherein the volume concentration of fetal calf serum is 20%;
(3) the modification process comprises the following steps: adding bioactive glass nanoparticles into an aqueous solution of fetal calf serum, wherein the concentration of the bioactive glass nanoparticles is 1mg/mL, and carrying out ultrasonic treatment at 300W for 1min and then carrying out mild stirring at room temperature for 24 h;
(4) and (3) purification and drying: centrifuging the modified bioactive glass nanoparticles at 9000rpm for 3min, and washing with deionized water for 3 times to obtain bioactive glass nanoparticles with physiological environment stability;
(5) biomedical applications: the method comprises the steps of loading an anticancer drug adriamycin to fetal calf serum modified bioactive glass nanoparticles with physiological environment stability in an adsorption mode, co-culturing the adriamycin-loaded sodium glycerophosphate modified bioactive glass nanoparticles and melanoma cells, and detecting the killing capacity of the nanoparticles to cancer cells.
Example 6
(1) Preparation of bioactive glass nanoparticles: synthesizing bioactive glass nanoparticles by using hexadecyl pyridine bromide as a template and adopting a sol-gel method combined with the template method;
(2) preparing a modified system: dissolving fetal calf serum in deionized water, and stirring at room temperature for 0.5h, wherein the volume concentration of fetal calf serum is 30%;
(3) the modification process comprises the following steps: adding bioactive glass nanoparticles into an aqueous solution of fetal calf serum, wherein the concentration of the bioactive glass nanoparticles is 1mg/mL, and carrying out ultrasonic treatment at 300W for 1min and then carrying out mild stirring at room temperature for 24 h;
(4) and (3) purification and drying: centrifuging the modified bioactive glass nanoparticles at 9000rpm for 3min, and washing with deionized water for 3 times to obtain bioactive glass nanoparticles with physiological environment stability;
(5) biomedical applications: the method comprises the steps of loading an anticancer drug adriamycin to fetal calf serum modified bioactive glass nanoparticles with physiological environment stability in an adsorption mode, co-culturing the adriamycin-loaded sodium glycerophosphate modified bioactive glass nanoparticles and melanoma cells, and detecting the killing capacity of the nanoparticles to cancer cells.
Example 7
(1) Preparation of bioactive glass nanoparticles: synthesizing bioactive glass nanoparticles by using dodecylamine as a template and adopting a sol-gel method combined with a template method;
(2) preparing a modified system: dissolving alendronate sodium diphosphate in a sodium acetate buffer solution with the pH value of 4 until the alendronate sodium is completely dissolved, and stirring the solution for 0.5 hour at room temperature in a mild way, wherein the concentration of the alendronate sodium is 20 mg/mL;
(3) the modification process comprises the following steps: adding the bioactive glass nanoparticles into a sodium acetate solution of alendronate sodium, wherein the concentration of the bioactive glass nanoparticles is 10mg/mL, and carrying out ultrasonic treatment at 300W for 30min and then carrying out mild stirring at room temperature for 24 h;
(4) and (3) purification and drying: centrifuging the modified bioactive glass nanoparticles at 9000rpm for 3min, and washing with deionized water for 3 times to obtain bioactive glass nanoparticles with physiological environment stability;
(5) biomedical applications: the alendronate sodium modified bioactive glass nanoparticles with physiological environment stability are dispersed in a phosphate buffer solution with the pH value of 7.4, and the accumulative release amount of the alendronate sodium is detected. And co-culturing the alendronate sodium modified bioactive glass nanoparticles and osteosarcoma cells, and detecting the killing capability of the nanoparticles on cancer cells.
Example 8
(1) Preparation of bioactive glass nanoparticles: synthesizing bioactive glass nanoparticles by using dodecylamine as a template and adopting a sol-gel method combined with a template method;
(2) preparing a modified system: dissolving fosfomycin sodium in a sodium acetate buffer solution with the pH value of 4, and after the fosfomycin sodium is completely dissolved, gently stirring at room temperature for 0.5h, wherein the concentration of the fosfomycin sodium is 40 mg/mL;
(3) the modification process comprises the following steps: adding bioactive glass nanoparticles into a sodium acetate solution of fosfomycin sodium, wherein the concentration of the bioactive glass nanoparticles is 10mg/mL, and carrying out ultrasonic treatment at 300W for 30min and then carrying out mild stirring at room temperature for 24 h;
(4) and (3) purification and drying: centrifuging the modified bioactive glass nanoparticles at 9000rpm for 3min, and washing with deionized water for 3 times to obtain bioactive glass nanoparticles with physiological environment stability;
(5) biomedical applications: the method comprises the steps of loading an anticancer drug adriamycin on fosfomycin sodium modified bioactive glass nanoparticles with physiological environment stability in an adsorption mode, co-culturing the fosfomycin sodium modified bioactive glass nanoparticles loaded with adriamycin and melanoma cells, and detecting the killing capacity of the nanoparticles on cancer cells.
Example 9
(1) Preparation of bioactive glass nanoparticles: synthesizing bioactive glass nanoparticles by using dodecylamine as a template and adopting a sol-gel method combined with a template method;
(2) preparing a modified system: dissolving sodium glycerophosphate in deionized water, and stirring at room temperature for 0.5h under mild condition until the sodium glycerophosphate is completely dissolved, wherein the concentration of the sodium glycerophosphate is 3 mg/mL;
(3) the modification process comprises the following steps: adding bioactive glass nanoparticles into an aqueous solution of sodium glycerophosphate, wherein the concentration of the bioactive glass nanoparticles is 1mg/mL, and carrying out ultrasonic treatment at 300W for 30min and then carrying out mild stirring at room temperature for 1 h;
(4) and (3) purification and drying: centrifuging the modified bioactive glass nanoparticles at 9000rpm for 3min, and washing with deionized water for 3 times to obtain bioactive glass nanoparticles with physiological environment stability;
(5) biomedical applications: the method comprises the steps of loading an anticancer drug adriamycin to sodium glycerophosphate modified bioactive glass nanoparticles with physiological environment stability in an adsorption mode, co-culturing the sodium glycerophosphate modified bioactive glass nanoparticles loaded with adriamycin and melanoma cells, and detecting the killing capacity of the nanoparticles to cancer cells.
Example 10
(1) Preparation of bioactive glass nanoparticles: synthesizing bioactive glass nanoparticles by using dodecylamine as a template and adopting a sol-gel method combined with a template method;
(2) preparing a modified system: dissolving fetal calf serum in deionized water, and stirring at room temperature for 0.5h, wherein the volume concentration of fetal calf serum is 10%;
(3) the modification process comprises the following steps: adding bioactive glass nanoparticles into an aqueous solution of fetal calf serum, wherein the concentration of the bioactive glass nanoparticles is 1mg/mL, and carrying out ultrasonic treatment at 300W for 1min and then carrying out mild stirring at room temperature for 24 h;
(4) and (3) purification and drying: centrifuging the modified bioactive glass nanoparticles at 9000rpm for 3min, and washing with deionized water for 3 times to obtain bioactive glass nanoparticles with physiological environment stability;
(5) biomedical applications: the method comprises the steps of loading an anticancer drug adriamycin to fetal calf serum modified bioactive glass nanoparticles with physiological environment stability in an adsorption mode, co-culturing the adriamycin-loaded sodium glycerophosphate modified bioactive glass nanoparticles and melanoma cells, and detecting the killing capacity of the nanoparticles to cancer cells.
Example 11
(1) Preparation of bioactive glass nanoparticles: synthesizing bioactive glass nanoparticles by using dodecylamine as a template and adopting a sol-gel method combined with a template method;
(2) preparing a modified system: dissolving fetal calf serum in deionized water, and stirring at room temperature for 0.5h, wherein the volume concentration of fetal calf serum is 20%;
(3) the modification process comprises the following steps: adding bioactive glass nanoparticles into an aqueous solution of fetal calf serum, wherein the concentration of the bioactive glass nanoparticles is 1mg/mL, and carrying out ultrasonic treatment at 300W for 1min and then carrying out mild stirring at room temperature for 24 h;
(4) and (3) purification and drying: centrifuging the modified bioactive glass nanoparticles at 9000rpm for 3min, and washing with deionized water for 3 times to obtain bioactive glass nanoparticles with physiological environment stability;
(5) biomedical applications: the method comprises the steps of loading an anticancer drug adriamycin to fetal calf serum modified bioactive glass nanoparticles with physiological environment stability in an adsorption mode, co-culturing the adriamycin-loaded sodium glycerophosphate modified bioactive glass nanoparticles and melanoma cells, and detecting the killing capacity of the nanoparticles to cancer cells.
Example 12
(1) Preparation of bioactive glass nanoparticles: synthesizing bioactive glass nanoparticles by using dodecylamine as a template and adopting a sol-gel method combined with a template method;
(2) preparing a modified system: dissolving fetal calf serum in deionized water, and stirring at room temperature for 0.5h, wherein the volume concentration of fetal calf serum is 30%;
(3) the modification process comprises the following steps: adding bioactive glass nanoparticles into an aqueous solution of fetal calf serum, wherein the concentration of the bioactive glass nanoparticles is 1mg/mL, and carrying out ultrasonic treatment at 300W for 1min and then carrying out mild stirring at room temperature for 24 h;
(4) and (3) purification and drying: centrifuging the modified bioactive glass nanoparticles at 9000rpm for 3min, and washing with deionized water for 3 times to obtain bioactive glass nanoparticles with physiological environment stability;
(5) biomedical applications: the method comprises the steps of loading an anticancer drug adriamycin to fetal calf serum modified bioactive glass nanoparticles with physiological environment stability in an adsorption mode, co-culturing the adriamycin-loaded sodium glycerophosphate modified bioactive glass nanoparticles and melanoma cells, and detecting the killing capacity of the nanoparticles to cancer cells.
Example 13
(1) Preparation of bioactive glass nanoparticles: synthesizing bioactive glass nanoparticles by using hexadecyl pyridine bromide as a template and adopting a sol-gel method combined with the template method;
(2) preparing a modified system: dissolving alendronate sodium diphosphate in a sodium acetate buffer solution with the pH value of 4, and after the alendronate sodium is completely dissolved, gently stirring at room temperature for 0.5h, wherein the concentration of the alendronate sodium diphosphate is 10 mg/mL;
(3) the modification process comprises the following steps: adding bioactive glass nanoparticles into a sodium acetate solution of alendronate sodium, wherein the concentration of the bioactive glass nanoparticles is 5mg/mL, and carrying out ultrasonic treatment at 300W for 30min and then carrying out mild stirring at room temperature for 12 h;
(4) and (3) purification and drying: centrifuging the modified bioactive glass nanoparticle solution at 9000rpm for 3min, and washing with deionized water for 3 times to obtain bioactive glass nanoparticles with physiological environment stability;
(5) biomedical applications: the alendronate sodium modified bioactive glass nanoparticles with physiological environment stability are dispersed in a phosphate buffer solution with the pH value of 7.4, and the accumulative release amount of the alendronate sodium is detected. And co-culturing the alendronate sodium modified bioactive glass nanoparticles and osteosarcoma cells, and detecting the killing capability of the nanoparticles on cancer cells.
Example 14
(1) Preparation of bioactive glass nanoparticles: synthesizing bioactive glass nanoparticles by using hexadecyl pyridine bromide as a template and adopting a sol-gel method combined with the template method;
(2) preparing a modified system: dissolving fosfomycin sodium in a sodium acetate buffer solution with the pH value of 4, and after the fosfomycin sodium is completely dissolved, gently stirring at room temperature for 0.5h, wherein the concentration of the fosfomycin sodium is 10 mg/mL;
(3) the modification process comprises the following steps: adding bioactive glass nanoparticles into a sodium acetate solution of fosfomycin sodium, wherein the concentration of the bioactive glass nanoparticles is 6mg/mL, and carrying out ultrasonic treatment at 300W for 30min and then carrying out mild stirring at room temperature for 18 h;
(4) and (3) purification and drying: centrifuging the modified bioactive glass nanoparticles at 9000rpm for 3min, and washing with deionized water for 3 times to obtain bioactive glass nanoparticles with physiological environment stability;
(5) biomedical applications: the method comprises the steps of loading an anticancer drug adriamycin on fosfomycin sodium modified bioactive glass nanoparticles with physiological environment stability in an adsorption mode, co-culturing the fosfomycin sodium modified bioactive glass nanoparticles loaded with adriamycin and melanoma cells, and detecting the killing capacity of the nanoparticles on cancer cells.
Example 15
(1) Preparation of bioactive glass nanoparticles: synthesizing bioactive glass nanoparticles by using hexadecyl pyridine bromide as a template and adopting a sol-gel method combined with the template method;
(2) preparing a modified system: dissolving sodium glycerophosphate in deionized water, and stirring at room temperature for 0.5h under mild condition until the sodium glycerophosphate is completely dissolved, wherein the concentration of the sodium glycerophosphate is 1 mg/mL;
(3) the modification process comprises the following steps: adding bioactive glass nanoparticles into an aqueous solution of sodium glycerophosphate, wherein the concentration of the bioactive glass nanoparticles is 2mg/mL, and carrying out ultrasonic treatment at 300W for 30min and then carrying out mild stirring at room temperature for 2 h;
(4) and (3) purification and drying: centrifuging the modified bioactive glass nanoparticles at 9000rpm for 3min, and washing with deionized water for 3 times to obtain bioactive glass nanoparticles with physiological environment stability;
(5) biomedical applications: the method comprises the steps of loading an anticancer drug adriamycin to sodium glycerophosphate modified bioactive glass nanoparticles with physiological environment stability in an adsorption mode, co-culturing the sodium glycerophosphate modified bioactive glass nanospheres loaded with adriamycin and melanoma cells, and detecting the killing capacity of the nanoparticles on cancer cells.
Example 16
(1) Preparation of bioactive glass nanoparticles: synthesizing bioactive glass nanoparticles by using hexadecyl pyridine bromide as a template and adopting a sol-gel method combined with the template method;
(2) preparing a modified system: dissolving fetal calf serum in deionized water, and stirring at room temperature for 0.5h, wherein the volume concentration of fetal calf serum is 15%;
(3) the modification process comprises the following steps: adding bioactive glass nanoparticles into an aqueous solution of fetal calf serum, wherein the concentration of the bioactive glass nanoparticles is 3mg/mL, and carrying out ultrasonic treatment at 300W for 1min and then carrying out mild stirring at room temperature for 20 h;
(4) and (3) purification and drying: centrifuging the modified bioactive glass nanoparticles at 9000rpm for 3min, and washing with deionized water for 3 times to obtain bioactive glass nanoparticles with physiological environment stability;
(5) biomedical applications: the method comprises the steps of loading an anticancer drug adriamycin to fetal calf serum modified bioactive glass nanoparticles with physiological environment stability in an adsorption mode, co-culturing the adriamycin-loaded sodium glycerophosphate modified bioactive glass nanoparticles and melanoma cells, and detecting the killing capacity of the nanoparticles to cancer cells.
The bioactive glass nanoparticles with stable physiological environment obtained by modification are dried to form white powder.
The stability of the bioactive glass nanoparticles with stable physiological environment prepared by the invention in buffer systems such as deionized water, phosphate buffer solution and the like is obviously improved.
Fig. 1 shows that AL-BGN can be stably dispersed in deionized water and phosphate buffer at pH 7.4 for up to 48h, whereas BGN precipitates almost completely after being dispersed in water or phosphate buffer at pH 7.4 for 48 h.
In FIG. 2, photomicrographs of PDS-BGN and BGN dispersed in water for 0h and 48 h. Obviously, after dispersing in water for 48h, BGN is completely precipitated at the bottom, and PDS-BGN can keep stable dispersion without obvious precipitation.
Fig. 3 is an optical photograph of GP-BGN and BGN after dispersing in water for 48h and in phosphate buffer at pH 7.4 for 2 h. GP-BGN can keep a stable dispersion state in water for 48 hours and in a phosphate buffer solution for 2 hours. BGN was completely precipitated after 48h and 2h dispersion in water and phosphate buffer, respectively.
Fig. 4 is a photo of 10% FBS-BGN, 20% FBS-BGN, 30% FBS-BGN, and BGN after dispersing in water and phosphate buffer at pH 7.4 for 24 h. The FBS-modified bioactive glass nanoparticles can be stably dispersed in water and a phosphate buffer solution for 24 hours without precipitation, while BGN is completely precipitated. Therefore, the modification method of the bioactive glass nanoparticles provided by the invention can effectively improve the stability of the bioactive glass nanoparticles in the physiological environment, and has important significance for prolonging the blood circulation time of materials and reducing immune response in the clinical use process.
Fig. 5(a) shows that the uv absorbance of the solution was significantly decreased after AL modification, indicating that AL was successfully grafted on the surface of the bioactive glass nanoparticle. FIG. 5(b) is a Fourier transform infrared absorption spectrum (FTIR) of AL-BGN, BGN and AL, wherein the characteristic absorption peak (1541 cm) of phosphate group in AL is clearly observed on the IR spectrum of AL-BGN-1) Bending vibration peak of hydroxyl group (930 cm)-1Nearby). FIG. 5(c) is an X-ray diffraction pattern (XRD) of AL-BGN, BGN and AL, and a diffraction peak of AL is clearly observed on the XRD pattern of AL-BGN. Thus, FTIR and XRD characterization both further indicated that AL was successfully grafted onto the surface of the bioactive glass nanoparticles. Fig. 5(d) is a drug cumulative release profile of AL-BGN releasing AL in phosphate buffer at pH 7.4. It can be seen that AL exhibits slow and sustained release behavior, and therefore AL-BGN is useful in bone tissue repair and disease treatmentHas great application potential in treatment. AL, a common bisphosphonate, is used not only to treat osteoporosis and inhibit bone resorption, but also to inhibit cancer cell growth and angiogenesis. Therefore, AL-BGN can be co-cultured with cancer cells to test the application potential of the AL-BGN in cancer treatment.
FIG. 6 shows the cell viability of osteosarcoma cells (SJSA-1) after 24h and 72h incubation with different concentrations of AL-BGN, where the same concentration of pure AL is used as a control. From FIGS. 6(a) and 6(b), it can be seen that AL-BGN has a concentration dependence on the lethality of the cells. Also, AL-BGN showed more pronounced cytocidal activity than AL when the concentration of AL was lower. This is because, at lower concentrations, AL-BGN is more readily taken up by the cells and efficiently releases the AL molecule than free AL molecule, thereby showing significant cell killing, and at higher concentrations, AL-BGN and AL are both significantly toxic to cancer cells. Therefore, AL-BGN has great potential for use in cancer therapy, particularly in the treatment of osteosarcoma or bone metastasis.
FIG. 7 is a lethality test of BGN-DOX, FBS-BGN-DOX and DOX on melanoma cells (A-375). As can be seen from FIGS. 7(a) and 7(b), BGN-DOX, FBS-BGN-DOX and DOX are concentration-and time-dependent on the lethality of A-375. Moreover, the BGN modified by FBS has no obvious influence on the DOX loading and releasing capacity, and can effectively inhibit the growth and proliferation of cancer cells.
The modification method of the bioactive glass nanoparticles is simple, and the reaction conditions are mild; the prepared bioactive glass nanoparticles have good physiological environment stability, so the modification method provided by the invention effectively improves the hydrophilicity and stability of the bioactive glass nanoparticles, and has important significance for prolonging the blood circulation time of the bioactive glass nanoparticles, reducing the immune reaction, improving the biocompatibility and slowly releasing the medicament in a living experiment. Further in vitro experiments show that the modified bioactive glass nanoparticles with stable physiological environment have strong drug loading capacity, can obviously inhibit the growth and proliferation of cancer cells, and have great application potential in the aspects of drug delivery, disease treatment and the like.
Firstly, preparing bioactive glass nanoparticles, then dissolving a modifier in deionized water or buffer solution, stirring at medium temperature, and adding the bioactive glass nanoparticles after the modifier is completely dissolved to perform modification reaction; and finally, centrifugally washing and freeze-drying the modified bioactive glass nanoparticles to obtain a final product. The modification technology is simple and easy to implement, the reaction condition is mild, the hydrophilic modifier is utilized to modify the bioactive glass nanoparticles for the first time through the ionic interaction force between calcium ions and anionic groups such as phosphate radicals in the modifier and the adsorption effect of the bioactive glass nanoparticles on abundant proteins in serum, the hydrophilicity and the stability of the bioactive glass nanoparticles in different dispersion systems are improved, and the modified bioactive glass nanoparticles not only have good physiological environment stability, but also can effectively inhibit the growth and proliferation of cancer cells, and have great application potential in the biomedical fields such as tissue repair and reconstruction and cancer treatment.
The above-mentioned contents are only for illustrating the technical idea of the present invention, and the protection scope of the present invention is not limited thereby, and any modification made on the basis of the technical idea of the present invention falls within the protection scope of the claims of the present invention.
Claims (10)
1. A method for modifying the physiological environment stability of bioactive glass nanoparticles is characterized by comprising the following steps:
1) preparing a modified system: dissolving a hydrophilic modifier containing phosphate radicals in a solution, and stirring for reaction at room temperature to obtain a solution containing the modifier;
2) the modification process comprises the following steps: adding the bioactive glass nanoparticles into a solution containing a modifier to obtain a mixed solution, performing ultrasonic dispersion on the mixed solution, stirring at room temperature for modification to obtain a modified bioactive glass nanoparticle solution, centrifuging, washing and freeze-drying to obtain the bioactive glass nanoparticles with physiological environment stability.
2. The method for modifying the physiological environment stability of bioactive glass nanoparticles according to claim 1, wherein the bioactive glass nanoparticles are prepared by the following steps: the bioactive glass nanoparticles are synthesized by combining a sol-gel method and a template method.
3. The method for modifying the physiological environment stability of bioactive glass nanoparticles according to claim 2, wherein the template agent used in the combination of the sol-gel method and the template method is dodecylamine or cetylpyridinium bromide.
4. The method for modifying the physiological environment stability of bioactive glass nanoparticles according to claim 1, wherein the solution in step 1) is acetic acid buffer solution with pH =4 or deionized water.
5. The method for modifying the physiological environment stability of bioactive glass nanoparticles according to claim 1, wherein the hydrophilic modifier containing phosphate in step 1) is diphosphate, sodium glycerophosphate or sodium fosfomycin.
6. The method for modifying the physiological environment stability of bioactive glass nanoparticles according to claim 5, wherein the bisphosphonate is alendronate.
7. The method for modifying the physiological environment stability of bioactive glass nanoparticles according to claim 5, wherein in step 1), the concentration of diphosphate, the concentration of fosfomycin sodium and the concentration of sodium glycerophosphate in the solution containing the modifier are respectively 10-20mg/mL, 10-40mg/mL and 1-3 mg/mL.
8. The method for modifying the physiological environment stability of bioactive glass nanoparticles according to claim 1, wherein the concentration of bioactive glass nanoparticles in the mixed solution in the step 2) is as follows: when the hydrophilic modifier is biphosphate or fosfomycin sodium, the concentration of the bioactive glass nano-particle is 5-10 mg/mL.
9. The method for modifying the physiological environment stability of bioactive glass nanoparticles according to claim 1, wherein the modification is performed by stirring in step 2), and the reaction is performed for 12-24h when the hydrophilic modifier is diphosphate or fosfomycin sodium, and for 1-3h when the hydrophilic modifier is sodium glycerophosphate.
10. Use of biologically active nanoparticles having physiological environmental stability obtained according to any one of claims 1 to 9 as a carrier for loading and delivery of the anticancer drug doxorubicin.
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