CN111388447B - Adriamycin nano-particles, preparation method and application thereof, and medicine for treating tumors by combining acoustic power with chemical therapy - Google Patents
Adriamycin nano-particles, preparation method and application thereof, and medicine for treating tumors by combining acoustic power with chemical therapy Download PDFInfo
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Abstract
The invention provides an adriamycin nanoparticle, a preparation method and application thereof, and a medicament for treating tumors by combining acoustic power with chemical therapy, and relates to the technical field of nano medicaments. The adriamycin nanoparticles provided by the invention can improve the biocompatibility and the cell phagocytosis efficiency of adriamycin by loading the adriamycin on the nanoparticle carrier, and can generate active oxygen clusters under the action of ultrasound to inhibit the efflux of adriamycin by tumor cells, so that the drug resistance of tumor cells is overcome, the antitumor therapy of synergy and attenuation is realized, and the adriamycin nanoparticles have wide application prospects in the fields of biomedicine, disease diagnosis and acoustic-dynamic combined chemotherapy.
Description
Technical Field
The invention relates to the field of nano-drugs, in particular to adriamycin nano-particles, a preparation method and application thereof, and a drug for treating tumors by combining acoustic power with chemical therapy.
Background
Adriamycin is a broad-spectrum antineoplastic drug, can inhibit the synthesis of RNA and DNA, and has killing effect on various tumors and tumor cells in various growth cycles. However, doxorubicin has strong toxic and side effects on normal cells, and easily produces a multidrug resistance effect on tumor cells, thereby limiting the application of doxorubicin in tumor treatment.
The rapid development of nanotechnology provides a new idea for solving the problems faced in the doxorubicin chemotherapy process. The nano drug-carrying system can improve the bioavailability and biocompatibility of the adriamycin and regulate the circulation and distribution in vivo, and becomes one of the most effective ways for reducing the toxic and side effects of chemotherapeutic drugs and improving the curative effect of the drugs. At present, the multi-drug resistance problem of the adriamycin is effectively reduced by combining gene therapy, oxygen supply therapy and other modes, but the modes need to deliver the adriamycin, the gene and oxygen to a tumor part to play a role simultaneously, and the clinical application cost is high and the difficulty is high.
In view of the above, the present invention is particularly proposed.
Disclosure of Invention
The invention aims to provide an adriamycin nanoparticle, which solves the technical problems of high clinical application cost and great difficulty of adriamycin multiple drug resistance in the mode of relieving the existing combined gene therapy, oxygen supply therapy and the like.
The adriamycin nanoparticle provided by the invention comprises adriamycin and a nanoparticle carrier, wherein the adriamycin is loaded on the nanoparticle carrier.
Further, the nanoparticle carrier is selected from at least one of liposome, polyamino acid nanoparticle, polylactic acid-glycolic acid nanoparticle, gold nanocage and mesoporous silicon, and is preferably polyamino acid nanoparticle.
Furthermore, the particle size of the adriamycin nano particles is 20-150nm, preferably 50-100 nm.
The second purpose of the invention is to provide a preparation method of adriamycin nanoparticles, which comprises the following steps:
uniformly mixing adriamycin and the nanoparticle carrier to enable the adriamycin to be loaded on the nanoparticle carrier to obtain adriamycin nanoparticles;
preferably, the nanoparticle carrier is a polyamino acid nanoparticle.
Further, the preparation method of the adriamycin nano particles comprises the following steps: uniformly mixing a polyamino acid salt solution, an adriamycin solution and a cross-linking agent solution, so that polyamino acid and the cross-linking agent react, fold and cross-link to form polyamino acid nanoparticles, and meanwhile, adriamycin is loaded on the polyamino acid nanoparticles to obtain adriamycin nanoparticles;
preferably, a carboxyl activating agent is added into the polyamino acid solution for carboxyl activation, and then the mixture is uniformly mixed with the adriamycin solution and the cross-linking agent solution;
preferably, the carboxyl activating agent is EDC and/or NHS, preferably EDC and NHS;
further preferably, the mass ratio of EDC and NHS is (5-6): (3-4).
Further, the cross-linking agent is a diamino small molecule cross-linking agent, preferably cystamine dihydrochloride;
and/or, the polyamino acid is selected from one or more of polyglutamic acid, polyaspartic acid, polyalanine, polylysine and polyalanine and salts thereof, and is preferably polyglutamate.
Further, the mass ratio of the polyglutamate to the cystamine dihydrochloride to the adriamycin is (1-3): (2-6): (1-3), preferably 1:2: 1.
Further, the polyamino acid solution is a PBS (phosphate buffer solution) solution of polyamino acid, and the concentration of the PBS solution of polyamino acid is (0.5-1.5) mg/mL, preferably 1 mg/mL;
and/or the cystamine dihydrochloride solution is a PBS (phosphate buffered saline) solution of cystamine dihydrochloride, and the concentration of the PBS solution of cystamine dihydrochloride is (0.5-1.5) mg/mL, preferably 1 mg/mL;
and/or the adriamycin solution is a PBS (phosphate buffer solution) of adriamycin, and the concentration of the adriamycin PBS solution is (0.2-0.8) mg/mL, and is preferably 0.5 mg/mL.
The third purpose of the invention is to provide the application of the adriamycin nano-particles or the adriamycin nano-particles obtained by the preparation method provided by the invention in preparing a tumor drug for sonodynamic combination chemotherapy.
The fourth purpose of the invention is to provide a tumor drug for acoustic-dynamic combined chemotherapy, which comprises the adriamycin nano-particles provided by the invention or the adriamycin nano-particles prepared by the preparation method provided by the invention.
The adriamycin nanoparticles provided by the invention can improve the biocompatibility and the cell phagocytosis efficiency of adriamycin by loading the adriamycin on the nanoparticle carrier, can generate active oxygen clusters under ultrasound to inhibit the efflux of adriamycin by tumor cells, and can overcome the drug resistance of the tumor cells without being combined with other substances to be co-delivered to tumor parts, thereby realizing the tumor treatment with synergy and attenuation, reducing the clinical application cost and the treatment difficulty, and having wide application prospects in the fields of biomedicine, disease diagnosis and sound power combined chemical treatment.
The preparation method of the adriamycin nano particles provided by the invention has the advantages of simple process and low raw material cost, and can obviously reduce the preparation cost of the adriamycin nano particles.
Drawings
FIG. 1 is a graph showing the particle size distribution of doxorubicin nanoparticles provided in example 1;
FIG. 2 is a graph of the UV-VIS absorption spectra of doxorubicin nanoparticles provided in example 1 and an aqueous DOX solution provided in comparative example 1;
fig. 3 is a bar graph of the in vitro killing effect detection of U87 cells (brain glioma cells) by doxorubicin nanoparticles provided in example 1 and DOX aqueous solution provided in comparative example 1 at different DOX concentrations;
FIG. 4 is a bar graph of in vitro killing effect of the doxorubicin nanoparticles provided in example 1 and the DOX aqueous solution and the blank control provided in comparative example 1 on U87 cells (glioma cells) under the combined action of ultrasound at different DOX concentrations;
FIG. 5 is a graph of the fluorescence detection effect of the doxorubicin nanoparticles provided in example 1, the DOX aqueous solution provided in comparative example 1, and the deionized water provided in comparative example 2 on the generation of reactive oxygen species under the action of different ultrasonic times;
FIG. 6 is a graph showing the release of doxorubicin nanoparticles provided in example 1 in 24 hours in PBS solution at pH7.4 and PBS solution at pH5.5, respectively.
Detailed Description
Embodiments of the present invention will be described in detail below with reference to examples, but it will be understood by those skilled in the art that the following examples are only illustrative of the present invention and should not be construed as limiting the scope of the present invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
It should be noted that:
in the present invention, all the embodiments and preferred methods mentioned herein can be combined with each other to form a new technical solution, if not specifically stated.
In the present invention, the percentage (%) or parts means the weight percentage or parts by weight with respect to the composition, if not otherwise specified.
In the present invention, the components referred to or the preferred components thereof may be combined with each other to form a novel embodiment, if not specifically stated.
In the present invention, unless otherwise stated, the numerical range "a-b" represents a shorthand representation of any combination of real numbers between a and b, where a and b are both real numbers. For example, a numerical range of "6 to 22" means that all real numbers between "6 to 22" have been listed herein, and "6 to 22" is simply a shorthand representation of the combination of these values.
The "ranges" disclosed herein may have one or more lower limits and one or more upper limits, respectively, in the form of lower limits and upper limits.
In the present invention, unless otherwise specified, the individual reactions or operation steps may be performed sequentially or may be performed in sequence. Preferably, the reaction processes herein are carried out sequentially.
Unless otherwise defined, technical and scientific terms used herein have the same meaning as is familiar to those skilled in the art. In addition, any methods or materials similar or equivalent to those described herein can also be used in the present invention.
According to one aspect of the present invention, the present invention provides an doxorubicin nanoparticle comprising doxorubicin and a nanoparticle carrier, said doxorubicin being supported on said nanoparticle carrier.
In the invention, the adriamycin is loaded on the nanoparticle carrier through a chemical bond or an entrapment mode, wherein the chemical bond comprises a covalent bond, an ionic bond and a metal bond.
The adriamycin nanoparticles provided by the invention can improve the biocompatibility and the cell phagocytosis efficiency of adriamycin by loading the adriamycin on the nanoparticle carrier, can generate active oxygen clusters under ultrasound to inhibit the efflux of adriamycin by tumor cells, and can overcome the drug resistance of the tumor cells without being combined with other substances to be co-delivered to tumor parts, thereby realizing the tumor treatment with synergy and attenuation, reducing the clinical application cost and the treatment difficulty, and having wide application prospects in the fields of biomedicine, disease diagnosis and sound power combined chemical treatment.
In a preferred embodiment of the present invention, the nanoparticle carrier includes, but is not limited to, one or more of liposome, polyamino acid nanoparticle, polylactic-glycolic acid nanoparticle, gold nanocage and mesoporous silicon. Especially, when the nano-particle carrier is the polyamino acid nano-particle, the nano-particle carrier has higher drug encapsulation rate and entrapment rate, better stability, quick degradation in an acid environment, realization of response release of the drug, good biocompatibility and sound sensitivity, effective reduction of organism toxicity, overcoming of drug resistance of tumor cells and improvement of anti-tumor curative effect.
In a preferred embodiment of the present invention, the adriamycin nanoparticles have a particle size of 20 to 150 nm. The particle size of the adriamycin nano particles is controlled to be 20-100nm, so that the adriamycin nano particles are favorably targeted to tumor cells. If the particle size of the adriamycin nanoparticles is less than 20nm, the adriamycin nanoparticles are easy to agglomerate to form large particles, which are not beneficial to targeting tumor cells, and if the particle size of the adriamycin nanoparticles is more than 150nm, the adriamycin nanoparticles are not beneficial to targeting tumor cells. Especially, when the particle size of the adriamycin nano particles is 50-100nm, the adriamycin nano particles have better targeting property.
Typically, but not by way of limitation, the doxorubicin nanoparticles have a particle size of, for example, 20, 30, 40, 50, 60, 70, 80, 90, 100, 120, or 150 nm.
According to a second aspect of the present invention, the present invention provides a method for preparing doxorubicin nanoparticles, comprising the steps of: uniformly mixing the adriamycin and the nanoparticle carrier to load the adriamycin on the nanoparticle carrier to obtain the adriamycin nanoparticles.
In the invention, the adriamycin is loaded on the nanoparticle carrier through chemical bonds or in an entrapment mode, wherein the chemical bonds comprise covalent bonds, ionic bonds and metal bonds.
The preparation method of the adriamycin nano particles provided by the invention is simple in process and low in raw material cost, and can obviously reduce the preparation cost of the adriamycin nano particles.
In a preferred embodiment of the invention, the nanoparticle carrier is a polyamino acid nanoparticle. The selected polyamino acid nano-particles as the adriamycin carrier have the following beneficial effects:
(1) the adriamycin can be efficiently loaded on the polyamino acid nanoparticles to form stable drug-loaded nanoparticles with high encapsulation efficiency and high loading capacity;
(2) the polyamino acid nano-particles have good biocompatibility and biodegradability, and can effectively reduce the toxicity of the adriamycin to organisms;
(3) the polyamino acid nanoparticles can be rapidly degraded under an acidic condition, so that the response control release of the adriamycin is realized;
(4) after the adriamycin is loaded, the compound has sound sensitivity, can generate active oxygen clusters under ultrasonic, overcomes the drug resistance of cancer cells to the adriamycin, and improves the anti-tumor curative effect.
In a preferred embodiment of the present invention, the preparation method of the doxorubicin nanoparticles comprises the following steps: and uniformly mixing the polyamino acid solution, the adriamycin solution and the cross-linking agent solution, so that the polyamino acid and the cross-linking agent react, fold and cross-link to form polyamino acid nanoparticles, and meanwhile, the adriamycin is loaded on the polyamino acid nanoparticles to obtain the adriamycin nanoparticles.
In a preferred embodiment of the present invention, the polyamino acid contains both carboxyl groups and amino groups, and the crosslinking agent crosslinks the amino groups, crosslinks the carboxyl groups, or crosslinks the amino groups and the carboxyl groups, so that the segments of the polyamino acid are folded to form the polyamino acid nanoparticles. The adriamycin has an amino group which can interact with the carboxyl group of polyamino acid and is contained in the polyamino nanoparticles.
In a preferred embodiment of the present invention, the carboxyl activating agent is added to the polyamino acid solution to activate the carboxyl, and then the mixture is uniformly mixed with the adriamycin solution and the cross-linking agent.
Because the polyamino acid contains both amino and carboxyl, a carboxyl activating agent is added into the polyamino acid solution, so that the carboxyl in the polyamino acid is activated to facilitate the crosslinking reaction of the polyamino acid and a crosslinking agent, the polyamino acid nanoparticles are formed by crosslinking and folding, and meanwhile, the activated carboxyl is also easy to react with the amino in adriamycin, so that the adriamycin is loaded on the polyamino acid nanoparticles through an amido bond.
In a preferred embodiment of the invention, the carboxyl activating agent is EDC and/or NHS.
In a preferred embodiment of the invention, EDC is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride; NHS for N-hydroxy succinimide.
In a further preferred embodiment of the present invention, when the carboxyl activating agent is a mixture of EDC and NHS, it has a better activating effect on the carboxyl groups in the polyamino acid, and is more favorable for the reaction of the carboxyl groups.
In a further preferred embodiment of the present invention, when the carboxyl activating agent is a mixture of EDC and NHS, and the mass ratio of EDC to NHS is (5-6): (3-4), the activation efficiency of the carboxyl group activator is higher.
Typically, but not by way of limitation, the mass of EDC and NHS in the carboxy activating agent is, for example, 5:3, 5.2:3, 5.5:3, 5.8:3, 5:3.2, 5.2:3.2, 5.5:3.2, 5.8:3.2, 5:3.5, 5.2:3.5, 5.5:3.5, 5.8:3.5, 6:3.5, 5:3.8, 5.2:3.8, 5.5:3.8, 5.8:3.8, 6:3.8, 5:4, 5.2:4, 5.5:4, 5.8:4, or 6: 4.
In a preferred embodiment of the invention, the cross-linking agent is a diamino small molecule cross-linking agent. The diamino micromolecules are selected as the cross-linking agent, so that the crosslinking reaction between the diamino micromolecules and activated carboxyl in the polyamino acid is facilitated, and the polyamino acid is folded and crosslinked to form the polyamino acid nano-particles.
In a further preferred embodiment of the present invention, the crosslinking agent is cystamine dihydrochloride, including but not limited to sodium cystamine dihydrochloride, potassium cystamine dihydrochloride, and the like.
In a preferred embodiment of the present invention, the polyamino acid is selected from one or more of polyglutamic acid, polyaspartic acid, polyalanine, polylysine, polyalanine, polyglutamate, polyaspartate, polyalaninate, polylysine salt and polyalanine salt. Especially, when the polyamino acid is polyglutamate, the raw material source is wider, the cost is lower, and the polyamino acid nanoparticles are easier to form.
In a preferred embodiment of the present invention, polyglutamates include, but are not limited to, sodium polyglutamate and potassium polyglutamate, more preferably sodium polyglutamate.
In a preferred embodiment of the present invention, the mass ratio of polyglutamate, cystamine dihydrochloride and doxorubicin is (1-3): (2-6): (1-3), by controlling the mass ratio of the three components, the adriamycin nanoparticles with the particle size of 20-150nm can be conveniently prepared, the encapsulation efficiency and the drug loading rate of the adriamycin can be improved, and particularly, when the mass ratio of the polyglutamate to the cystamine dihydrochloride to the adriamycin is 1:2:1, the drug encapsulation efficiency and the drug loading rate of the prepared adriamycin nanoparticles are higher.
Typically, but not by way of limitation, the masses of polyglutamate, cystamine dihydrochloride and doxorubicin are, for example, 1:2:1, 1:2:2, 1:3:1, 1:3:2, 1:4:1, 1:4:2, 2:2:1, 2:2:2, 2:3:1, 2:3:2, 2:4:1 or 2:4: 2.
In a preferred embodiment of the present invention, the solution of the polyamino acid is a PBS solution of the polyamino acid, the concentration of the PBS solution of the polyamino acid being 0.5-1.5 mg/mL.
The concentration of PBS of the polyamino acid is controlled to be favorable for the reaction with the cross-linking agent, so that the polyamino acid nanoparticles are prepared, and particularly, when the concentration of the PBS solution of the polyamino acid is 1mg/mL, the polyamino acid nanoparticles are more favorable for generation. Typically, but not by way of limitation, the concentration of the polyamino acid in PBS is, for example, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, or 1.5 mg/mL.
In a preferred embodiment of the invention, the pH of the PBS solution of the polyamino acid is 5 to 6, preferably 5.5.
The pH value of the PBS solution of the polyamino acid is controlled to be 5-6, so that the crosslinking reaction of the polyamino acid is facilitated to generate polyamino acid nanoparticles, and the crosslinking reaction is easier to perform especially when the pH value is 5.5. Typically, but not by way of limitation, the pH of the PBS solution of the polyamino acid is, e.g., 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, or 6.
In a preferred practice of the invention, the cystamine dihydrochloride solution is cystamine dihydrochloride PBS solution having a concentration of (0.5-1.5) mg/mL.
The concentration of the PBS solution of the cystamine dihydrochloride is controlled to be 0.5-1.5mg/mL so as to be beneficial to the crosslinking reaction with the polyamino acid, and the crosslinking efficiency is improved, especially when the concentration of the PBS solution with the pH value of cystamine dihydrochloride is 0.5-1.5mg/mL, the crosslinking efficiency with the polyamino acid is higher. Typically, but not by way of limitation, the concentration of cystamine dihydrochloride in PBS is, e.g., 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, or 1.5 mg/mL.
In a preferred embodiment of the invention, the doxorubicin solution is a PBS solution of doxorubicin, and the concentration of the doxorubicin PBS solution is (0.2-0.8) mg/mL, preferably 0.5 mg/mL.
In a preferred embodiment of the invention, doxorubicin is reacted with a polyamino acid and a cross-linking agent in a slight excess to facilitate increased drug loading of the doxorubicin nanoparticles. If the concentration of the doxorubicin PBS solution is lower than 0.2mg/mL, the preparation of doxorubicin nanoparticles with high drug loading rate is not facilitated, and if the concentration of the doxorubicin PBS solution is higher than 0.8mg/mL, the doxorubicin is greatly wasted, so that the doxorubicin PBS solution with the concentration of 0.2-0.8mg/mL is selected to prepare the doxorubicin nanoparticles, and particularly, when the concentration of the doxorubicin PBS solution is 0.5mg/mL, the doxorubicin nanoparticles with high drug loading rate are more easily obtained. Typically, but not by way of limitation, the doxorubicin in PBS may be at a concentration of, for example, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, or 0.8 mg/mL.
According to a third aspect of the present invention, the present invention provides the use of the doxorubicin nanoparticles described above or the doxorubicin nanoparticles obtained according to the above preparation method in the preparation of a medicament for sonodynamic combination chemotherapy of tumors.
Such tumors include, but are not limited to, brain glioma, ovarian cancer, endometrial cancer, renal cancer, breast cancer, lung cancer, colon cancer, and nasopharyngeal carcinoma.
According to a fourth aspect of the present invention, the present invention provides an acoustodynamic combined chemotherapy tumor drug, which comprises the doxorubicin nanoparticles provided by the present invention or the doxorubicin nanoparticles obtained according to the preparation method described above.
Such tumors include, but are not limited to, brain glioma, ovarian cancer, endometrial cancer, renal cancer, breast cancer, lung cancer, colon cancer, and nasopharyngeal carcinoma.
The technical solution provided by the present invention is further described below with reference to examples and comparative examples.
Example 1
The embodiment provides an adriamycin nanoparticle, which is prepared according to the following steps:
(1) respectively preparing a PBS (phosphate buffer solution) solution of sodium Polyglutamate (PGA), an EDC (EDC) aqueous solution, an NHS (NHS) aqueous solution, a PBS solution of cystamine dihydrochloride (Cys) and a PBS solution of adriamycin, wherein the concentration of the PBS solution of PGA is 1mg/mL, and the pH value is 5.5; the concentration of EDC aqueous solution is 5.2mg/mL, the concentration of NHS aqueous solution is 3.2mg/mL, the concentration of Cys PBS solution is 1mg/mL, the concentration of DOX PBS solution is 0.5mg/mL, and the pH value is 7.4;
(2) taking 1mL of PBS solution of PGA, and quickly dropwise adding 0.5mL of EDC aqueous solution and 0.5mL of NHS aqueous solution into the solution, and stirring at room temperature for 15 min;
(3) dripping 1mL of DOX PBS solution and 1mL of Cys PBS solution into the solution obtained in the step (2), and stirring for 4h at room temperature to obtain a nanoparticle solution;
(4) and (4) loading the nanoparticle solution obtained in the step (3) into a dialysis bag with a molecular weight of 3500, and dialyzing with water for 24 hours to obtain the purified adriamycin polyamino acid nanoparticles.
Example 2
This example provides doxorubicin nanoparticles, which are different from example 1 in that in step (1), the concentration of the prepared PBS solution of PGA is 0.5mg/mL, and the rest of the steps are the same as those in example 1, and are not repeated herein.
Example 3
This example provides doxorubicin nanoparticles, which are different from example 1 in that in step (1), the concentration of the prepared PBS solution of PGA is 1.5mg/mL, and the rest of the steps are the same as those in example 1, and are not repeated herein.
Example 4
The present example provides doxorubicin nanoparticles, which are different from example 1 in that in step (1), the concentration of the prepared PBS solution of Cys is 0.5mg/mL, and the rest of the steps are the same as example 1, and are not repeated herein.
Example 5
This example provides an doxorubicin nanoparticle, which is different from example 1 in that in step (1), the concentration of the prepared Cys PBS solution is 1.5mg/mL, and the rest of the steps are the same as example 1, and are not repeated herein.
Example 6
This example provides doxorubicin nanoparticles, which are different from example 1 in that in step (1), the concentration of the prepared DOX PBS solution is 0.2mg/mL, and the rest of the steps are the same as example 1, and are not repeated herein.
Example 7
This example provides doxorubicin nanoparticles, which are different from example 1 in that in step (1), the concentration of the prepared DOX PBS solution is 0.8mg/mL, and the rest of the steps are the same as example 1, and are not repeated herein.
Example 8
This example provides doxorubicin nanoparticles, which are different from example 1 in that in step (1), the concentration of the prepared PBS solution of PGA is 0.2mg/mL, and the rest of the steps are the same as those in example 1, and are not repeated herein.
Example 9
This example provides doxorubicin nanoparticles, which are different from example 1 in that in step (1), the concentration of the prepared PBS solution of PGA is 3mg/mL, and the remaining steps are the same as example 1, and are not repeated herein.
Example 10
This example provides an doxorubicin nanoparticle, which is different from example 1 in that in step (1), the concentration of the prepared Cys PBS solution is 0.2mg/mL, and the rest of the steps are the same as example 1, and are not repeated herein.
Example 11
This example provides an doxorubicin nanoparticle, which is different from example 1 in that in step (1), the concentration of the prepared Cys PBS solution is 3mg/mL, and the rest of the steps are the same as example 1, and are not repeated herein.
Example 12
This example provides doxorubicin nanoparticles, which are different from example 1 in that in step (1), the concentration of the prepared DOX PBS solution is 0.1mg/mL, and the rest of the steps are the same as example 1, and are not repeated herein.
Comparative example 1
This comparative example 1 provides an aqueous solution of DOX.
Comparative example 2
This comparative example 2 provides deionized water.
Test example 1
0.5mL of the doxorubicin nanoparticle solutions provided in examples 1 to 12 were taken, diluted to appropriate concentrations with PBS solutions, and analyzed with an ultraviolet spectrophotometer to calculate the drug content; meanwhile, 0.5mL of the doxorubicin nanoparticle solutions provided in examples 1 to 12 was precisely measured and lyophilized, and the weights of the nanoparticles were weighed and recorded, respectively, and the drug loading rates were calculated.
Respectively and precisely weighing 0.5mL of the doxorubicin nanoparticles provided in examples 1 to 12, diluting the doxorubicin nanoparticles to appropriate concentrations with PBS solutions, analyzing the diluted doxorubicin nanoparticles with an ultraviolet spectrophotometer, calculating the total drug content, and calculating the encapsulation efficiency.
The doxorubicin nanoparticle solutions provided in examples 1-12 were each diluted to the appropriate concentration and the particle size was measured in a malvern laser particle sizer. The results are shown in Table 1.
TABLE 1 doxorubicin nanoparticles data sheet
| Drug Loading Rate (%) | Encapsulation efficiency (%) | Particle size (nm)/PDI | |
| Example 1 | 29.35 | 87.96 | 69.27/0.31 |
| Example 2 | 26.96 | 51.36 | 53.86/0.50 |
| Example 3 | 20.48 | 80.77 | 114.11/0.58 |
| Example 4 | 20.43 | 61.84 | 43.32/0.48 |
| Example 5 | 22.82 | 78.61 | 115.56/0.59 |
| Example 6 | 20.25 | 81.17 | 65.44/0.25 |
| Example 7 | 21.01 | 56.33 | 119.47/0.59 |
| Example 8 | 15.24 | 68.14 | 56.92/0.24 |
| Example 9 | 11.21 | 80.21 | 504.81/0.83 |
| Example 10 | 9.41 | 43.27 | 28.11/0.30 |
| Example 11 | 17.01 | 80.67 | 251.48/0.56 |
| Example 12 | 6.94 | 80.67 | 31.02/0.45 |
As can be seen from table 1, the doxorubicin nanoparticles provided in examples 1 to 7 all have a drug loading rate higher than 20%, an encapsulation rate higher than 50%, a particle size between 50 and 120nm, and PDI less than 0.6, which indicates that the doxorubicin nanoparticles provided in examples 1 to 7 have higher drug loading rate and encapsulation rate, and a particle size between 50 and 120nm, have good biofilm penetration, and are beneficial for targeting tumor cells.
As can be seen from the comparison of examples 1 to 7 and examples 8 to 12, when the mass ratio of PGA, Cys and DOX is (1 to 3): (2-6): and (1-3), the adriamycin nano-particles with excellent comprehensive performance can be obtained more favorably. In addition, the particle size distribution diagram of the adriamycin nanoparticles provided in example 1 detected in a malvern laser particle sizer is shown in fig. 1, and as can be seen from fig. 1, the particle size distribution of the adriamycin nanoparticles provided in example 1 is 50-100nm, so that the adriamycin nanoparticles have excellent tumor cell targeting property.
Test example 2
Ultraviolet absorption spectrum tests were performed on the doxorubicin nanoparticle solution provided in example 1 and an aqueous solution of DOX provided in comparative example 1, respectively, and the obtained spectra are shown in fig. 2, wherein DOX represents the aqueous solution of DOX provided in comparative example 1, and DOX-PGA represents the doxorubicin nanoparticle solution provided in example 1; as can be seen from fig. 2, the doxorubicin nanoparticle solution provided in example 1 retained the characteristic absorption peak typical of doxorubicin, and the absorption peak at 480nm produced a significant red-shift due to the encapsulation of doxorubicin in the polyamino acid nanoparticles.
Test example 3
Brain glioma cells (U87) were seeded in 96-well plates (10)4One/well), the doxorubicin nanoparticle solution provided in example 1 and the aqueous solution of DOX provided in comparative example 1 were prepared into solutions with DOX doses of 0 μ g/mL, 1.25 μ g/mL, 2.5 μ g/mL, 5 μ g/mL, 10 μ g/mL and 20 μ g/mL, respectively, and then the above solutions were added to the brain glioma cells, respectively, for incubation for 24 hours, and then the cell viability was measured by CCK8 reagent and on a microplate reader, respectively, as shown in fig. 3. Wherein DOX represents the aqueous solution of DOX provided in comparative example 1; DOX-PGA represents the doxorubicin nanoparticle solution provided in example 1.
As can be seen from fig. 3, the killing efficiency of the doxorubicin nanoparticles provided in example 1 and the killing efficiency of the doxorubicin solution provided in comparative example 1 are equivalent for the same DOX dose, which indicates that the effect of doxorubicin chemotherapy is not affected by loading doxorubicin in the polyamino acid nanoparticles.
Test example 4
Brain glioma cells (U87) were seeded in 96-well plates (10)4One/well), the doxorubicin nanoparticles provided in example 1 and the aqueous solution of DOX provided in proportion 1 were prepared into solutions with respective doses of DOX of 0 μ g/mL, 1.25 μ g/mL, 2.5 μ g/mL, 5 μ g/mL, 10 μ g/mL and 20 μ g/mL, and the solutions were added to the glioma cells, respectively, and incubated for 3 hours, while the glioma cells without the drug were used as a placebo, and the cells in each well to which the drug was added and the cells in the placebo were sonicated for 3 minutes (power of 1.5W/cm)2) After 24 hours, the cell survival rate is detected by a CCK8 reagent and a microplate reader, and the result is shown in FIG. 4, wherein Control (+) represents the ultrasonic treatment of the blank Control group, and DOX (+) represents the combined ultrasonic treatment of the aqueous solution of DOX provided in the comparative example 1; DOX-PGA (+) represents the doxorubicin nanoparticle solution provided in example 1 in combination with sonication.
As can be seen from fig. 4, by performing ultrasound, the killing efficiency of the doxorubicin nanoparticles provided in example 1 on tumor cells is significantly higher than that of the doxorubicin nanoparticles provided in comparative example 1, which indicates that the doxorubicin nanoparticles provided in example 1 have acoustic sensitivity, can implement acoustic-dynamic combination chemotherapy on tumor cells under the action of ultrasound, overcome the problem of tumor drug resistance, and significantly improve the anti-tumor therapeutic effect.
Test example 5
The doxorubicin nanoparticles provided in example 1 and the aqueous solution of DOX provided in comparative example 1 were prepared as solutions of DOX dose 20 μ g/mL, respectively, and then the above solutions were placed in two 35mm diameter cell culture dishes, while the deionized water provided in comparative example 2 was placed in a third 35mm diameter cell culture dish, and then the active oxygen cluster fluorescent indicator SOSG was added to the three cell culture dishes, respectively, and then the solutions in the three dishes were subjected to sonication for 8 minutes (power 1.5W/cm) respectively (power 1.5W/cm)2) Within a certain ultrasonic time (0min, 0.5min, 1min, 2min, 3min, 5min, 8min), 200. mu.L of the solution was taken out from the three cell culture dishes and placed in a centrifuge tube, and the fluorescence imaging graph is shown in FIG. 5, wherein H is2O represents deionized water provided in comparative example 2 and DOX represents an aqueous solution of DOX provided in comparative example 1; DOX-PGA represents the doxorubicin nanoparticle solution provided in example 1.
As can be seen from fig. 5, when the deionized water provided by comparative example 2 is subjected to short-time ultrasound, fluorescence cannot be generated, and only weak fluorescence can be generated as the ultrasound time is prolonged, whereas when the aqueous solution of DOX provided by comparative example 1 is subjected to short-time ultrasound, fluorescence which is stronger than that of comparative example 2 but weaker than that of example 1 can be generated as the ultrasound time is prolonged, whereas when the doxorubicin nanoparticles provided by example 1 are subjected to short-time ultrasound, fluorescence which is remarkably stronger than that of comparative example 1 can be generated as the ultrasound time is prolonged, which indicates that under the ultrasound action, the doxorubicin nanoparticles provided by example 1 generate a significantly higher number of active oxygen clusters than that of the DOX solution provided by comparative example 1, i.e. the doxorubicin nanoparticles provided by example 1 have significantly improved acoustic sensitivity by supporting doxorubicin on the polyamino acid nanoparticles, thereby effectively improving the anti-tumor curative effect.
Test example 6
2mL of the doxorubicin nanoparticles provided in example 1 were taken and loaded into two dialysis bags having a molecular weight of 3500, 1mL each, and then the two dialysis bags were placed into two centrifuge tubes with caps containing 25mL of a PBS solution having a pH of 7.4 and a PBS solution having a pH of 5.5, respectively. The two centrifuge tubes were placed in an air bath shaker (temperature 37 ℃ and rotation speed 200rpm) respectively and shaken, and 1mL of the dialyzed DOX-containing sample was taken out of the two centrifuge tubes at appropriate time intervals (0.5h, 1h, 2h, 3h, 4h, 6h, 8h, 12h, and 24h) and supplemented with an equal amount of fresh PBS solution. Finally, the collected sample was subjected to quantitative analysis using a fluorescence spectrophotometer, and an doxorubicin release profile was plotted, as shown in fig. 6, in which ph7.4 represents the doxorubicin release profile of the doxorubicin nanoparticles provided in example 1 in a ph7.4 (neutral) PBS solution; ph5.5 represents the doxorubicin release profile of the doxorubicin nanoparticles provided in example 1 in PBS solution ph5.5 (acidic).
As can be seen from fig. 6, the doxorubicin nanoparticles provided in example 1 released almost completely (93% release) at 4h in PBS solution at ph5.5 (acidic), whereas the doxorubicin nanoparticles provided in example 1 released only 33% at 24h in PBS solution at ph 7.4. This shows that the doxorubicin nanoparticles provided in example 1 have significantly higher doxorubicin release efficiency and release amount in the PBS solution at ph7.4 (neutral) than in the PBS solution at ph5.5 (acidic). This demonstrates that the doxorubicin nanoparticles provided in example 1 can be rapidly degraded under acidic conditions, and that a responsive controlled release of doxorubicin is achieved.
Finally, it should be noted that: the above embodiments are only used to illustrate the technical solution of the present invention, and not to limit the same; while the invention has been described in detail and with reference to the foregoing embodiments, it will be understood by those skilled in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some or all of the technical features may be equivalently replaced; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.
Claims (4)
1. A preparation method of adriamycin nanoparticles is characterized by comprising the following steps: uniformly mixing adriamycin and the nanoparticle carrier to enable the adriamycin to be loaded on the nanoparticle carrier to obtain adriamycin nanoparticles;
the nano-particle carrier is a polyamino acid nano-particle;
the carboxyl activating agent is EDC and NHS; the mass ratio of EDC to NHS is (5-6): (3-4);
the cross-linking agent is cystamine dihydrochloride;
the polyamino acid is polyglutamate;
the mass ratio of the polyglutamate to the cystamine dihydrochloride to the adriamycin is 2:2: 1;
also comprises the following steps: uniformly mixing a polyamino acid solution, an adriamycin solution and a cross-linking agent solution, so that polyamino acid and the cross-linking agent react, fold and cross-link to form polyamino acid nanoparticles, and meanwhile, adriamycin is loaded on the polyamino acid nanoparticles to obtain adriamycin nanoparticles;
firstly, adding a carboxyl activating agent into a polyamino acid solution for carboxyl activation, and then uniformly mixing with an adriamycin solution and a cross-linking agent solution.
2. The method according to claim 1, wherein the solution of the polyamino acid is a PBS solution of a polyamino acid having a concentration of (0.5-1.5) mg/mL;
and/or the cystamine dihydrochloride solution is a cystamine dihydrochloride PBS solution, and the concentration of the cystamine dihydrochloride PBS solution is (0.5-1.5) mg/mL;
and/or the adriamycin solution is a PBS (phosphate buffer solution) of adriamycin, and the concentration of the PBS of the adriamycin is (0.2-0.8) mg/mL.
3. Use of the adriamycin nano-particles obtained by the preparation method according to any one of claims 1-2 in preparing a medicament for sonodynamic combination chemotherapy of tumors.
4. An acoustodynamic combined chemotherapy tumor drug, which is characterized by comprising the adriamycin nano-particles obtained by the preparation method of any one of claims 1 to 2.
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