CN117298129A - Boration nano targeting preparation and preparation method thereof - Google Patents
Boration nano targeting preparation and preparation method thereof Download PDFInfo
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Health & Medical Sciences (AREA)
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- Animal Behavior & Ethology (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a borated nano-targeting preparation and a preparation method thereof, wherein the borated nano-targeting preparation comprises carbon quantum dots, a drug loaded on the carbon quantum dots and diboron trioxide combined on the carbon quantum dots, and the preparation method comprises the following steps: using rhodamine B as a raw material, using an aqueous solution containing sodium hydroxide as a solvent, and synthesizing rhodamine carbon quantum dots by a solvothermal method; mixing rhodamine carbon quantum dots with an doxorubicin solution, and reacting under the conditions of light shielding and room temperature to obtain a nano preparation loaded with the doxorubicin; dissolving the prepared nano preparation and boric acid with purified water, heating the solution to crack the boric acid, evaporating and dehydrating to obtain a crude product of the nano targeting preparation, and finally removing unbound boric acid to obtain a final product of the nano targeting preparation. The borated nano targeting preparation has an active targeting function, can enrich more medicines at the tumor part, and is favorable for targeted treatment of tumors.
Description
Technical Field
The invention relates to the technical field of medicines, and relates to a borated nano-targeting preparation and a preparation method thereof.
Background
Among non-infectious diseases, cancer remains one of the most important causes of death worldwide, and it is estimated that the global cancer burden will reach 2840 tens of thousands of cancer patients by 2040 years. At present, three major means of drug therapy, radiotherapy and surgery are mainly adopted for treating tumors, wherein the traditional drug therapy is an indispensable means for treating tumors, traditional chemical drugs such as doxorubicin hydrochloride, cisplatin, methotrexate and the like cannot be enriched into tumor tissues due to low targeting property, so that the treatment effect is low, and meanwhile, the chemotherapy drugs can cause fatal damage to normal proliferation cells after long-term use, and in the treatment of solid tumors, the chemotherapy drugs are difficult to quickly infiltrate into cancer cells of the solid tumors, so that the use dose of the chemotherapy drugs is far greater than that required by a patient. With the development of pharmaceutical preparations, the medicines such as doxorubicin hydrochloride liposome, albumin-bound taxol and the like appear successively, wherein the liposome and the albumin are taken as nano-drug carriers, and are considered to realize passive targeting through high permeability and retention (EPR effect) of tumors, so that adverse reactions of traditional chemical medicines are relieved to a certain extent, and great advantages of the nano-carriers are shown. However, passive targeting mechanisms remain controversial compared to active targeting. Recent studies have shown that nanoparticles penetrate tumors primarily through receptor-mediated endocytosis rather than endothelial gaps. The targeting ability can be effectively improved by modifying the nanoparticle to be combined with a specific receptor on the surface of a target cell (such as a tumor cell or an immune cell), so that the research center of gravity is transferred from the EPR effect-mediated passive targeting nanoparticle to the design of an active targeting drug delivery system.
Carbon Dots (CDs) are novel nanomaterials with a size smaller than 10nm, and are widely used in the fields of biosensing, optical imaging, drug delivery and the like due to excellent physicochemical properties such as stable fluorescence, easy surface modification and good biosafety. The CDs are internally provided with a carbon skeleton mainly containing carbon, and the surfaces of the CDs are groups such as-OH, -COOH, -NH2 and the like which are easy to modify. The unique fluorescence property of CDs can be used for positioning cells, tissues, organs and the like, so as to realize the purpose of diagnosis; however, when CDs are used as a diagnosis and treatment platform, the focal site cannot be actively targeted because the CDs alone cannot specifically bind to focal tissues or cells.
Disclosure of Invention
In view of the above, the present invention aims to provide a borated nano-targeting preparation, a preparation method and an application thereof, so as to solve the technical problem of enabling a chemotherapeutic drug to have an active targeting function and further enabling more drugs to be enriched at a tumor part.
The borated nano-targeting preparation comprises carbon quantum dots, a drug loaded on the carbon quantum dots and diboron trioxide combined on the carbon quantum dots.
Further, the drug is doxorubicin.
Further, the carbon quantum dots are synthesized by a solvothermal method by taking rhodamine B as a raw material.
The invention also discloses a preparation method of the borated nano-targeting preparation, which comprises the following steps:
(1) using rhodamine B as a raw material, using an aqueous solution containing sodium hydroxide as a solvent, and synthesizing rhodamine carbon quantum dots by a solvothermal method;
(2) mixing the rhodamine carbon quantum dots prepared in the step (1) with an doxorubicin solution, and reacting under the conditions of light shielding and room temperature to obtain a nano preparation loaded with the doxorubicin;
(3) dissolving the nano preparation prepared in the step (2) and boric acid by adopting purified water, heating the solution to crack the boric acid and combine the boric acid with the surface of the carbon quantum dots, and then evaporating and dehydrating the solution to obtain a crude product of the nano targeting preparation of which the surface of the carbon quantum dots is combined with the diboron trioxide;
(4) dialyzing the crude product of the nano targeting preparation obtained in the step (3) in a buffer solution to remove unbound boric acid, thereby obtaining a final product of the borated nano targeting preparation.
Further, the solvent temperature for synthesizing rhodamine carbon quantum dots by adopting a solvothermal method in the step (1) is 150-200 ℃.
Further, in the step (3), the solution is heated to lead the temperature of the solution for boric acid pyrolysis to be 150-200 ℃.
The invention has the beneficial effects that:
1. the borated nano-targeting preparation can be loaded with a drug, such as Doxorubicin (DOX) which is a traditional chemotherapeutic drug, and the boron trioxide combined with the carbon quantum dots can be specifically combined with Sialic Acid (SA) which is overexpressed on the surface of a tumor through oxygen anions on the structure of the preparation, so that the chemotherapeutic drug has an active targeting function, so that more drugs can be enriched at the tumor part, and the targeted treatment of the tumor is facilitated.
2. The boron is uniformly distributed throughout the whole body of the human body in the form of B (OH) 3, so that the boric acid nano targeting preparation takes the diboron trioxide as a modification material, the toxicity problem of the modification material after degradation is not required to be considered, and the safety is good.
3. The borated nano-targeting preparation has the advantages of easily available raw materials and low cost.
4. The preparation method of the borated nano-targeting preparation is simple and controllable, and the physical properties such as particle size, potential and the like of the nano-preparation can be adjusted by adjusting reaction conditions (time, temperature, feeding proportion and the like).
5. The solvent used in the preparation method of the borated nano-targeting preparation is green and nontoxic, and compared with an organic solvent, the preparation method of the borated nano-targeting preparation is safe and green in purified water and low in cost.
Drawings
FIG. 1 is a schematic representation of the preparation of a borated nano-targeting formulation (RCD@DOX/BA). Rhodamine B carbon quantum dots (RCD) load model medicine DOX through electrostatic interaction, and the DOX is delivered to tumors in a targeted manner through the specific combination of oxyanions on a boron trioxide structure decomposed by Boric Acid (BA) and sialic acid SA overexpressed on the surfaces of the tumors, so that the targeted therapeutic effect is exerted.
FIG. 2 is a Transmission Electron Microscope (TEM) image of RCD@DOX/BA described in example II, and it is clear from the results of the image that RCD@DOX/BA is uniform in size, good in dispersibility and about 12nm in particle size.
FIG. 3 is a narrow spectrum of boron element in the electron energy spectrum of RCD@DOX/BA X-ray in example II, and the result shows that the surface of RCD@DOX/BA has B element and contains a diboron trioxide structure, and the surface modification is successful.
FIG. 4 is an SEM image of cells after uptake of RCD@DOX/BA of example two, and from the results, the cell surface was roughened after the introduction of RCD@DOX/BA, suggesting that more drug was enriched on the tumor cell surface.
FIG. 5 is a graph showing the effect of RCD@DOX/BA of example two on treatment of a mouse subcutaneous tumor model, and from the graph results, the tumor volume of the mice in the RCD@DOX/BA treatment group is obviously smaller than that of the RCD@DOX treatment group and DOX group after a period of time, because the RCD@DOX/BA group has an active targeting effect, and the treatment effect is superior to that of other groups.
Detailed Description
The invention is further described below with reference to the drawings and examples.
Embodiment one: the borated nano-targeting preparation of the embodiment comprises carbon quantum dots, a drug loaded on the carbon quantum dots and diboron trioxide combined on the carbon quantum dots. In this embodiment, the drug loaded on the carbon quantum dots is doxorubicin; of course, in different embodiments, the drug loaded on the carbon quantum dots may also be other drugs. In this embodiment, the carbon quantum dot is synthesized by using rhodamine B as a raw material and adopting a solvothermal method.
Embodiment two: the preparation method of the borated nano-targeting preparation in the preparation embodiment I comprises the following steps:
(1) rhodamine B is used as a raw material, an aqueous solution containing sodium hydroxide is used as a solvent, and a solvothermal method is adopted to synthesize the rhodamine carbon quantum dot. Specifically, rhodamine B is added into a sodium hydroxide solution and stirred uniformly to form a mixture, the concentration of the sodium hydroxide solution is 0.67M, every 6.4mg of rhodamine B is dissolved in 1mL of the sodium hydroxide solution, and the concentration of the sodium hydroxide solution and the dissolution amount of the rhodamine B can be properly adjusted; then placing the solution in a muffle furnace, and reacting for 8 hours at 150 ℃ to obtain a yellow-brown rhodamine carbon quantum dot RCD crude product; slowly adding dilute hydrochloric acid (the concentration of the dilute hydrochloric acid is 37%, and of course, other concentrations of dilute hydrochloric acid can be used in different embodiments) into the crude product solution to remove unreacted sodium hydroxide until a large amount of precipitation occurs, stopping adding the dilute hydrochloric acid dropwise, standing for 12 hours, separating the supernatant by adopting a centrifugal mode to obtain a brown precipitate, and slowly drying the brown precipitate by using an oven to obtain the rhodamine B carbon quantum dots RCD.
(2) Mixing the rhodamine carbon quantum dots prepared in the step (1) with an doxorubicin solution, and feeding the RCD solution and the doxorubicin DOX solution according to a volume ratio of 2:1 in specific implementation. Stirring for 24 hours at the condition of light shielding and room temperature, centrifuging to remove free DOX, and freeze-drying to obtain the nanometer preparation RCD@DOX loaded with doxorubicin.
(3) And (3) dissolving the nano preparation prepared in the step (2) and boric acid by adopting purified water, wherein specific RCD and boric acid BA can be fed according to a mass ratio of 1:10. Heating the solution to crack boric acid and combine the boric acid with the surface of the carbon quantum dots, controlling the temperature of the solution at 150 ℃ and reacting for 5 hours; and then evaporating and dehydrating the solution to obtain a crude product of the nano targeting preparation with the surface of the carbon quantum dot combined with the diboron trioxide.
(4) Dialyzing the crude product of the nano targeting preparation obtained in the step (3) in a buffer solution to remove unbound boric acid, thereby obtaining a final product RCD@DOX/BA of the borated nano targeting preparation.
Embodiment III: the preparation method of the borated nano-targeting preparation in the preparation embodiment I comprises the following steps:
(1) rhodamine B is used as a raw material, an aqueous solution containing sodium hydroxide is used as a solvent, and a solvothermal method is adopted to synthesize the rhodamine carbon quantum dot. Specifically, rhodamine B is added into sodium hydroxide solution, and the mixture is formed by stirring uniformly, wherein the concentration of the sodium hydroxide solution is 0.67M, and each 6.4mg of rhodamine B is dissolved in 1mL of sodium hydroxide solution; then placing the solution in a muffle furnace, and reacting for 6 hours at 180 ℃ to obtain a yellow-brown rhodamine carbon quantum dot RCD crude product; slowly adding dilute hydrochloric acid into the crude product solution to remove unreacted sodium hydroxide until a large amount of precipitation appears, stopping dripping the dilute hydrochloric acid, standing for 12 hours, separating the supernatant by adopting a centrifugal mode to obtain brown precipitate, and slowly drying the brown precipitate by using an oven to obtain the rhodamine B carbon quantum dot RCD.
(2) Mixing the rhodamine carbon quantum dots prepared in the step (1) with an doxorubicin solution, and feeding the RCD solution and the doxorubicin DOX solution according to a volume ratio of 1.5:1 in specific implementation. Stirring for 24 hours at the condition of light shielding and room temperature, centrifuging to remove free DOX, and freeze-drying to obtain the nanometer preparation RCD@DOX loaded with doxorubicin.
(3) Dissolving the nano preparation prepared in the step (2) and boric acid by adopting purified water, and feeding the specific RCD and boric acid BA according to the mass ratio of 1:9. Heating the solution to crack boric acid and combine the boric acid with the surface of the carbon quantum dots, controlling the temperature of the solution at 180 ℃ and reacting for 4.5h; and then evaporating and dehydrating the solution to obtain a crude product of the nano targeting preparation with the surface of the carbon quantum dot combined with the diboron trioxide.
(4) Dialyzing the crude product of the nano targeting preparation obtained in the step (3) in a buffer solution to remove unbound boric acid, thereby obtaining a final product RCD@DOX/BA of the borated nano targeting preparation.
Embodiment III: the preparation method of the borated nano-targeting preparation in the preparation embodiment I comprises the following steps:
(1) rhodamine B is used as a raw material, an aqueous solution containing sodium hydroxide is used as a solvent, and a solvothermal method is adopted to synthesize the rhodamine carbon quantum dot. Specifically, rhodamine B is added into sodium hydroxide solution, and the mixture is formed by stirring uniformly, wherein the concentration of the sodium hydroxide solution is 0.67M, and each 6.4mg of rhodamine B is dissolved in 1mL of sodium hydroxide solution; then placing the solution in a muffle furnace, and reacting for 7 hours at 180 ℃ to obtain a yellow-brown rhodamine carbon quantum dot RCD crude product; slowly adding dilute hydrochloric acid into the crude product solution to remove unreacted sodium hydroxide until a large amount of precipitation appears, stopping dripping the dilute hydrochloric acid, standing for 12 hours, separating the supernatant by adopting a centrifugal mode to obtain brown precipitate, and slowly drying the brown precipitate by using an oven to obtain the rhodamine B carbon quantum dot RCD.
(2) Mixing the rhodamine carbon quantum dots prepared in the step (1) with an doxorubicin solution, and feeding the RCD solution and the doxorubicin DOX solution according to a volume ratio of 1.5:1 in specific implementation. Stirring for 24 hours at the condition of light shielding and room temperature, centrifuging to remove free DOX, and freeze-drying to obtain the nanometer preparation RCD@DOX loaded with doxorubicin.
(3) Dissolving the nano preparation prepared in the step (2) and boric acid by adopting purified water, and feeding the specific RCD and boric acid BA according to the mass ratio of 1:9. Heating the solution to crack boric acid and combine the boric acid with the surface of the carbon quantum dots, controlling the temperature of the solution at 150 ℃ and reacting for 5 hours; and then evaporating and dehydrating the solution to obtain a crude product of the nano targeting preparation with the surface of the carbon quantum dot combined with the diboron trioxide.
(4) Dialyzing the crude product of the nano targeting preparation obtained in the step (3) in a buffer solution to remove unbound boric acid, thereby obtaining a final product RCD@DOX/BA of the borated nano targeting preparation.
Fifth embodiment: the preparation method of the borated nano-targeting preparation in the preparation embodiment I comprises the following steps:
(1) rhodamine B is used as a raw material, an aqueous solution containing sodium hydroxide is used as a solvent, and a solvothermal method is adopted to synthesize the rhodamine carbon quantum dot. Specifically, rhodamine B is added into sodium hydroxide solution, and the mixture is formed by stirring uniformly, wherein the concentration of the sodium hydroxide solution is 0.67M, and each 6.4mg of rhodamine B is dissolved in 1mL of sodium hydroxide solution; then placing the solution in a muffle furnace, and reacting for 5 hours at 200 ℃ to obtain a yellow-brown rhodamine carbon quantum dot RCD crude product; slowly adding dilute hydrochloric acid into the crude product solution to remove unreacted sodium hydroxide until a large amount of precipitation appears, stopping dripping the dilute hydrochloric acid, standing for 12 hours, separating the supernatant by adopting a centrifugal mode to obtain brown precipitate, and slowly drying the brown precipitate by using an oven to obtain the rhodamine B carbon quantum dot RCD.
(2) Mixing the rhodamine carbon quantum dots prepared in the step (1) with an doxorubicin solution, and feeding the RCD solution and the doxorubicin DOX solution according to a volume ratio of 2.5:1 in specific implementation. Stirring for 24 hours at the condition of light shielding and room temperature, centrifuging to remove free DOX, and freeze-drying to obtain the nanometer preparation RCD@DOX loaded with doxorubicin.
(3) And (3) dissolving the nano preparation prepared in the step (2) and boric acid by adopting purified water, wherein specific RCD and boric acid BA can be fed according to a mass ratio of 1:11. Heating the solution to crack boric acid and combine the boric acid with the surface of the carbon quantum dots, controlling the temperature of the solution at 200 ℃, and reacting for 4 hours; and then evaporating and dehydrating the solution to obtain a crude product of the nano targeting preparation with the surface of the carbon quantum dot combined with the diboron trioxide.
(4) Dialyzing the crude product of the nano targeting preparation obtained in the step (3) in a buffer solution to remove unbound boric acid, thereby obtaining a final product RCD@DOX/BA of the borated nano targeting preparation.
Finally, it should be understood that the above embodiments are only for illustrating the technical solution of the present invention, and those skilled in the art should understand that the parameters of solution concentration, feeding ratio, reaction temperature, reaction time, etc. in the above embodiments may be modified, but these modifications or equivalent substitutions are substantially the same as those of the technical solution of the present invention, and therefore, these substantially the same modifications or equivalent substitutions should also be covered in the scope of the claims of the present invention.
Claims (6)
1. A borated nano-targeting formulation characterized by: comprises carbon quantum dots, a drug loaded on the carbon quantum dots and boron trioxide combined on the carbon quantum dots.
2. The borated nano-targeted formulation as claimed in claim 1 characterised in that: the medicine is doxorubicin.
3. The borated nano-targeted formulation as claimed in claim 1 characterised in that: the carbon quantum dots are synthesized by using rhodamine B as a raw material and adopting a solvothermal method.
4. A method of preparing a borated nano-targeting formulation as claimed in claims 1 to 3 characterised in that: the method comprises the following steps:
(1) using rhodamine B as a raw material, using an aqueous solution containing sodium hydroxide as a solvent, and synthesizing rhodamine carbon quantum dots by a solvothermal method;
(2) mixing the rhodamine carbon quantum dots prepared in the step (1) with an doxorubicin solution, and reacting under the conditions of light shielding and room temperature to obtain a nano preparation loaded with the doxorubicin;
(3) dissolving the nano preparation prepared in the step (2) and boric acid by adopting purified water, heating the solution to crack the boric acid and combine the boric acid with the surface of the carbon quantum dots, and then evaporating and dehydrating the solution to obtain a crude product of the nano targeting preparation of which the surface of the carbon quantum dots is combined with the diboron trioxide;
(4) dialyzing the crude product of the nano targeting preparation obtained in the step (3) in a buffer solution to remove unbound boric acid, thereby obtaining a final product of the borated nano targeting preparation.
5. The method for preparing the borated nano-targeting preparation according to claim 4, wherein the method comprises the following steps: the solvent temperature for synthesizing rhodamine carbon quantum dots by adopting a solvothermal method in the step (1) is 150-200 ℃.
6. The method for preparing the borated nano-targeting preparation according to claim 4, wherein the method comprises the following steps: and (3) heating the solution in the step (3) to ensure that the temperature of the solution for boric acid pyrolysis is 150-200 ℃.
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