CN113304159A - Nanometer diagnosis and treatment agent loaded with adriamycin/banoanthraquinone and preparation method thereof - Google Patents
Nanometer diagnosis and treatment agent loaded with adriamycin/banoanthraquinone and preparation method thereof Download PDFInfo
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- CN113304159A CN113304159A CN202110489071.2A CN202110489071A CN113304159A CN 113304159 A CN113304159 A CN 113304159A CN 202110489071 A CN202110489071 A CN 202110489071A CN 113304159 A CN113304159 A CN 113304159A
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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
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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
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
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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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- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
Abstract
The invention discloses a nano diagnosis and treatment agent loaded with adriamycin/banoanthraquinone and a preparation method thereof, and the method comprises the following steps: (1) dissolving the carnosol-anthraquinone dihydrochloride and the doxorubicin hydrochloride in water, and stirring for reaction; (2) dropwise adding a manganese dichloride solution, stirring for reaction, dropwise adding triethylamine, and stirring for reaction to remove HCl; (3) and (3) slowly dripping the reaction liquid obtained in the step (2) into water, stirring for reaction, and finally dialyzing to remove uncoordinated banoanthraquinone and adriamycin to obtain the nano diagnosis and treatment agent. The invention utilizes the nano diagnosis and treatment agent to provide a light absorption substance, namely the paranthraquinone, for the tumor tissue in a targeted manner, so as to realize the photoacoustic radiography imaging of the tumor; by utilizing the response characteristic of the metal coordination bond to acid, the anticancer drugs adriamycin and the banoanthraquinone can be effectively released in tumor tissues and can be used for synergistic treatment, so that the antitumor effect is enhanced.
Description
Technical Field
The invention relates to the technical field of tumor nano diagnosis and treatment, in particular to a nano diagnosis and treatment agent loaded with adriamycin/banoanthraquinone and a preparation method thereof.
Background
In recent years, with the rapid development of nano-medicine, a multifunctional nano diagnosis and treatment platform integrating diagnosis and treatment has great potential in precise medical treatment and clinical application of tumors. The Metal-Organic Frameworks (MOFs) combined with antitumor drugs can simultaneously incorporate imaging and treatment into a single nanomaterial, and have a diagnosis and treatment integrated function, so that the Metal-Organic Frameworks (MOFs) are concerned by researchers, but the clinical application of the Metal-Organic Frameworks (MOFs) is still limited at present. The main reason for this is that the following problems are prevalent in the current MOFs for the treatment of tumors:
1. the existing MOFs have the problem of single drug loading, and are difficult to efficiently kill tumor cells with tenacious vitality after entering the body. Xue et al have designed and synthesized the metal organic framework DHA @ HPDA-Fe of load dihydroartemisinin based on the iron coordination hollow polydopamine nanosphere [ "Journal of Materials Chemistry B", volume 7 16172-.
2. The existing MOFs have the problem of single function, Zhang Da et al prepare a deeply permeable pH/NIR/hypoxia activated copper-based MOFs [ "Advanced Science", volume 5, page 1700648 (2018) ], and the system loads double drugs, but does not report the function of contrast imaging.
Disclosure of Invention
In view of the defects of the prior art, the invention aims to provide adriamycin/paranthraquinone loaded nano diagnosis and treatment agents (ADMOPs for short) and a preparation method thereof, which are used for solving the problems of single function of MOFs and poor single drug loading curative effect in the prior art.
In order to achieve the above objects and other related objects, a first aspect of the present invention provides a method for preparing a nano diagnostic agent loaded with doxorubicin/banoanthraquinone, comprising the steps of:
(1) dissolving the carnosol-anthraquinone dihydrochloride (AQ4N & HCl) and the doxorubicin hydrochloride (DOX & HCl) in water, and stirring for reaction;
(2) dropwise adding a manganese dichloride solution into the reaction liquid obtained in the step (1), stirring for reaction, dropwise adding triethylamine, and stirring for reaction to remove HCl;
(3) and (3) slowly dripping the reaction liquid obtained in the step (2) into water, stirring for reaction, and finally dialyzing to remove uncoordinated banoanthraquinone and adriamycin to obtain the adriamycin/banoanthraquinone-loaded nano diagnosis and treatment agent.
Further, in the steps (1) and (2), the mass ratio of the carnosoquinone dihydrochloride to the doxorubicin hydrochloride to the manganese dichloride is 10-20:10-20:1, and preferably 10:10: 1.
Further, in the step (1), the concentration of the bacoanthraquinone dihydrochloride and the concentration of the doxorubicin hydrochloride are both 1 mg/mL.
Further, in the step (1), the stirring reaction time is 1-2h, preferably 1 h.
Further, in the step (2), the concentration of the manganese dichloride solution is 1 mg/mL.
Further, in the steps (1) and (2), the ratio of the total amount of the carnosol-dihydrochloride and the doxorubicin hydrochloride to the amount of triethylamine in the steps (1) and (2) is 1: (0.22-0.23) (mg/mL).
Further, in the step (2), after the manganese dichloride solution is added dropwise, the stirring reaction is continued for 3 to 5 hours, preferably 4 hours.
Further, in the step (2), after the triethylamine is added dropwise, stirring and reacting for not less than 8 hours.
Further, in the step (3), the volume usage ratio of the reaction liquid obtained in the step (2) to water is 1:4-6, preferably 1: 5.
Further, in the step (3), the stirring reaction time is 2-3 h.
Further, in the step (3), the dialysis frequency is not lower than 3 times, and the dialysis time is not lower than 15min each time.
Further, in the steps (1), (2) and (3), the whole reaction process needs to be carried out under the condition of keeping out light.
Further, the steps (1), (2) and (3) are all carried out at room temperature (25 ℃).
Furthermore, the particle size of the nano diagnostic and therapeutic agent is 102.7 +/-20 nanometers. The invention also provides a preparation method of the adriamycin/banoanthraquinone loaded nano diagnosis and treatment agent.
As mentioned above, the adriamycin/banoanthraquinone loaded nano diagnosis and treatment agent and the preparation method thereof have the following beneficial effects:
1. the invention provides a light absorption substance, namely, the kininoxantrone, for targeting tumor tissues by utilizing the nano diagnosis and treatment agent so as to improve the photoacoustic imaging effect.
2. The invention utilizes the response characteristic of metal coordination bond to acid to effectively release the anticancer drugs of adriamycin and banjoxantrone in tumor tissues and carry out synergistic treatment, thereby enhancing the antitumor effect and having the treatment effect.
3. The nano diagnosis and treatment agent is a carrier-free drug delivery system, and has the advantages of simple and easy manufacturing method and low cost.
Drawings
Fig. 1 is a graph showing a distribution of particle sizes of the doxorubicin/banoanthraquinone-loaded nano diagnostic agent in example 1 of the present invention.
FIG. 2 is a confocal view of laser beam uptake by cells according to an embodiment of the present invention.
FIG. 3 shows staining patterns of viable and dead cells obtained by performing a cell viability experiment according to the present invention.
Fig. 4 shows an in vivo photoacoustic imaging graph obtained by performing a tumor-bearing mouse photoacoustic imaging experiment in an embodiment of the present invention.
Detailed Description
The present invention is further described with reference to the following embodiments and drawings, and it is to be understood that other advantages and effects of the present invention can be easily understood by those skilled in the art from the disclosure of the present specification. The invention is capable of other and different embodiments and of being practiced or of being carried out in various ways, and its several details are capable of modification in various respects, all without departing from the spirit and scope of the present invention.
The invention provides a novel nano diagnosis and treatment agent which is loaded with anticancer drugs of adriamycin and banoanthraquinone. Wherein, the adriamycin is an antibiotic generated by actinomycetes var caesius, can penetrate into cells to cross and connect with the DNA of tumor cells, and inhibits the DNA replication; banoxantrone dihydrate (Banoxantrone dihydrate) is a hypoxia-activated prodrug which can be reduced to AQ4 with high toxicity in a hypoxic environment, and effectively inhibits topoisomerase II in DNA.
The preparation method of the adriamycin/banoanthraquinone loaded nano diagnosis and treatment agent comprises the following steps:
(1) adding the carnosol-anthraquinone dihydrochloride (AQ4N & HCl) and the doxorubicin hydrochloride (DOX & HCl) into water, dissolving, and stirring for reaction;
(2) dropwise adding a manganese dichloride solution into the reaction liquid obtained in the step (1), continuously stirring for reaction, dropwise adding triethylamine, and continuously stirring for reaction (overnight) to remove HCl;
(3) and (3) slowly dripping the reaction liquid obtained in the step (2) into water, stirring for reaction, and finally dialyzing to remove uncoordinated banoanthraquinone and adriamycin to obtain the adriamycin/banoanthraquinone-loaded nano diagnosis and treatment agent.
In the preparation process, AQ4N & HCl and DOX & HCl are dissolved in water and stirred for reaction, in order to fully mix AQ4N and DOX, so that a product is better formed after manganese dichloride is added, triethylamine is added dropwise to remove HCl, and finally uncoordinated paradoximen and adriamycin are removed through dialysis, so that the adriamycin/paradoximen-loaded nano diagnosis and treatment agent is obtained.
Further, in the steps (1) and (2), the mass ratio of the carnosoquinone dihydrochloride to the doxorubicin hydrochloride to the manganese dichloride is 10-20:10-20:1, and in the following examples, the mass ratio is 10:10: 1.
Further, in the step (1), the concentration of the carnosol dihydrochloride and the concentration of the adriamycin hydrochloride are both 1 mg/mL.
Further, in the step (1), the stirring reaction time is 1-2h, preferably 1 h.
Further, in the step (2), the concentration of the manganese dichloride solution is 1 mg/mL.
Further, in the step (2), the ratio of the total amount of the carnosoquinone dihydrochloride and the doxorubicin hydrochloride to the amount of triethylamine in the steps (1) and (2) is 1: (0.22-0.23) (mg/mL).
Further, in the step (2), after the manganese dichloride solution is added dropwise, the stirring reaction is continued for 3 to 5 hours, preferably 4 hours.
Further, in the step (2), after the triethylamine is added dropwise, stirring and reacting for not less than 8 hours.
Further, in the step (3), the volume usage ratio of the reaction liquid obtained in the step (2) to water is 1:4-6, preferably 1: 5.
Further, in the step (3), the stirring reaction time is 2-3 h.
Further, in the step (3), the dialysis times are not less than 3, and the dialysis time is not less than 15 min. In the preparation method of the invention, the water used is selected from deionized water and ultrapure water; the dialysis bag used for dialysis was MD44(3500D) from Solarbio; the reactions and operations involved were carried out at room temperature (25 ℃) and were carried out in the absence of light throughout the reaction.
The invention utilizes the response characteristic of metal coordination bond to acid to ensure that the anticancer drugs DOX and AQ4N can be effectively released and synergistically treated in tumor tissues, thereby enhancing the antitumor effect; meanwhile, the AQ4N has a photoacoustic signal and provides a photoacoustic contrast imaging function for the nano diagnosis and treatment agent; the nano diagnosis and treatment agent is a carrier-free drug delivery system, has simple and easy manufacturing method and low cost and has the functions of diagnosis and treatment.
The present invention will be described in detail by way of examples. It is also to be understood that the following examples are illustrative of the present invention and are not to be construed as limiting the scope of the invention, and that certain insubstantial modifications and adaptations of the invention by those skilled in the art may be made in light of the above teachings. The specific process parameters and the like of the following examples are also merely examples of suitable ranges, i.e., those skilled in the art can select from suitable ranges through the description herein and are not limited to the specific values of the following examples.
Example 1
The preparation method of the adriamycin/banoanthraquinone-loaded nano diagnosis and treatment agent comprises the following process steps:
(1) 1mg of paranthraquinone dihydrochloride (AQ4N HCl) and 1mg of doxorubicin hydrochloride (DOX HCl) were dissolved in 1mL of deionized water, and then mixed in a brown glass bottle and stirred magnetically.
(2) After stirring for 1h, 100. mu.L of a 1mg/mL solution of manganese dichloride was added dropwise, stirring was continued for 4h, 450. mu.L of triethylamine was added dropwise, and after the addition was completed, stirring was continued overnight to remove HCl.
(3) And (3) slowly and dropwise adding the reaction liquid obtained in the step (2) into a round-bottom flask containing 10mL of deionized water, and carrying out magnetic stirring for 2 hours.
(4) And (4) finally dialyzing the reaction solution obtained in the step (3) by using a dialysis bag to remove uncoordinated banoanthraquinone and adriamycin to obtain the adriamycin/banoanthraquinone-loaded nano diagnosis and treatment agent.
In the above process, the reaction needs to be protected from light in the whole process, and the rotation speed is controlled at 800rpm, specifically 750rpm, during stirring.
Example 2
The preparation method of the adriamycin/banoanthraquinone-loaded nano diagnosis and treatment agent comprises the following process steps:
(1) 5mg of paranthraquinone dihydrochloride (AQ4N HCl) and 5mg of doxorubicin hydrochloride (DOX HCl) were dissolved in 5mL of deionized water, and mixed in a brown glass bottle, and stirred magnetically.
(2) After stirring for 1h, 0.5mL of a 1mg/mL manganese dichloride solution was added dropwise, after stirring was continued for 4h, 2.25mL of triethylamine was added dropwise, and after the addition was completed, stirring was continued overnight to remove HCl.
(3) And (3) slowly and dropwise adding the reaction liquid obtained in the step (2) into a round-bottom flask containing 50mL of deionized water, and carrying out magnetic stirring for 2 hours.
(4) And (4) finally dialyzing the reaction solution obtained in the step (3) by using a dialysis bag to remove uncoordinated banoanthraquinone and adriamycin to obtain the adriamycin/banoanthraquinone-loaded nano diagnosis and treatment agent.
In the above process, the reaction needs to be protected from light in the whole process, and the rotation speed is controlled at 800rpm, specifically 750rpm, during stirring.
Example 3
The preparation method of the adriamycin/banoanthraquinone-loaded nano diagnosis and treatment agent comprises the following process steps:
(1) 20mg of paranthraquinone dihydrochloride (AQ4N HCl) and 20mg of doxorubicin hydrochloride (DOX HCl) were dissolved in 5mL of deionized water, and mixed in a brown glass bottle and stirred magnetically.
(2) After stirring for 2h, 1mL of 1mg/mL manganese dichloride solution was added dropwise, stirring was continued for 5h, 9mL of triethylamine was added dropwise, and after the addition was completed, stirring was continued overnight to remove HCl.
(3) And (3) slowly and dropwise adding the reaction liquid obtained in the step (2) into a round-bottom flask containing 200ml of deionized water, and carrying out magnetic stirring for 3 hours.
(4) And (4) finally dialyzing the reaction solution obtained in the step (3) by using a dialysis bag to remove uncoordinated banoanthraquinone and adriamycin to obtain the adriamycin/banoanthraquinone-loaded nano diagnosis and treatment agent.
In the above process, the reaction needs to be protected from light in the whole process, and the rotation speed is controlled at 800rpm, specifically 750rpm, during stirring.
The nano diagnostic and therapeutic agents (abbreviated as ADMOPs) prepared in example 1 were tested, and the experimental method, experimental results and analysis were as follows:
1. 1mL of the products obtained by dialysis (ADMOPs) were taken, and the average particle size and distribution of the products obtained by dialysis (ADMOPs) were measured by a Marven laser particle sizer, and the results are shown in FIG. 1.
As can be seen from the particle size distribution diagram of fig. 1, the particle size of the adriamycin/paranthraquinone-loaded nano diagnostic agent is 102.7 ± 26.18 nm, the particle size is small, the distribution is narrow, and the targeted distribution in vivo is facilitated.
2. Cellular uptake:
2.0mL of MDA-MB-231 cells (initial density 10)4Per well) were inoculated into a confocal dish. After 24h, each dish was replaced with fresh medium solutions containing free DOX, free AQ4N, and ADMOPs (AQ4N equivalent dose: 25 mg/L; DOX equivalent dose: 16mg/L), and cultured for 4 h. The culture medium was then removed, the cells were washed twice with PBS, fixed with 1mL of methanol for 1min, washed 1 time with PBS, followed by 200ul of DAPI stain for 12min, the cells were washed twice with PBS, 1mL of PBS was added, and fluorescence was observed using confocal laser scanning imaging (CLSM).
FIG. 2 shows the laser confocal image of the cell uptake after 4h incubation in medium containing ADMOPs, i.e., the endocytosis image of ADMOPs, showing the distribution of the drug in tumor cells, wherein the dark blue represents DAPI, the red represents AQ4N, the green represents DOX, and the merge represents the post-fusion image. As shown in fig. 2, after the doxorubicin/paraxantrone-loaded nano diagnostic agent reacts with cancer cells for 4 hours, the drug obviously enters the cell nucleus, which indicates that the drug is effectively released in the cells.
3. Cell death experiment:
2mL of HepG2/mb231 cell suspension (cell density: 2X 10) was added to the confocal dish5Cells/dish), respectively in normoxia (20% O)2) Or hypoxia (1% O)2) Culturing under the condition. After 24 hours, the waste liquid was removed, washed 2 to 3 times, 2mL of free-DOX, free-AQ4N, and ADMOPs (AQ4N equivalent dose: 25 mg/L; DOX equivalent dose: 16mg/L) solution was added, and after 24 hours of culture, the cells were washed 3 times with PBS, and stained with 200. mu.L of PBS solution containing calcein-AM (2.0. mu.M) and 15. mu.L of PI (4.5. mu.M). After incubation for 15min in a 37 ℃ cell incubator, cells were observed with CLSM and photographed.
FIG. 3 is a staining detection image of live and dead cells, and in FIG. 3, (1): blank control; (2): free-DOX group; (3): free-AQ 4N; (4): ADMOPs; (5) the injection concentration of adromps and paradoxin in the solutions of the ADMOPs and the anoxia group is 10 mg/L. The contrast shows that the red fluorescence ratio of the adriamycin/banoanthraquinone-loaded nano diagnosis and treatment agent group is obviously increased compared with the free adriamycin hydrochloride group and the banoanthraquinone group, and the contrast shows that the adriamycin/banoanthraquinone-loaded nano diagnosis and treatment agent can kill tumor cells more effectively under the anoxic condition and shows excellent curative effect.
4. Tumor-bearing mouse photoacoustic imaging experiment:
tumor-bearing nude mice were divided into two groups, and 200. mu.l of AQ4N and ADMOPs (AQ4N equivalent dose: 25mg/L) were injected into caudal vein, respectively, and then photoacoustic imaging (PA) images of 8h and 12h were collected by 690nm Laser irradiation on a Vevo Laser photoacoustic imaging system, as shown in FIG. 4.
In fig. 4, red represents the photoacoustic imaging effect, which indicates that the ADMOPs of the present invention have the photoacoustic imaging effect, and the ADMOPs reached the tumor region after 8 h.
The foregoing embodiments are merely illustrative of the principles and utilities of the present invention and are not intended to limit the invention. Any person skilled in the art can modify or change the above-mentioned embodiments without departing from the spirit and scope of the present invention. Accordingly, it is intended that all equivalent modifications or changes which can be made by those skilled in the art without departing from the spirit and technical spirit of the present invention be covered by the claims of the present invention.
Claims (10)
1. A nanometer diagnosis and treatment agent loaded with adriamycin/banoanthraquinone and a preparation method thereof are characterized by comprising the following steps:
(1) dissolving the carnosol-anthraquinone dihydrochloride and the doxorubicin hydrochloride in water, and stirring for reaction;
(2) dropwise adding a manganese dichloride solution into the reaction liquid obtained in the step (1), stirring for reaction, dropwise adding triethylamine, and stirring for reaction to remove HCl;
(3) and (3) slowly dripping the reaction liquid obtained in the step (2) into water, stirring for reaction, and finally dialyzing to remove uncoordinated banoanthraquinone and adriamycin to obtain the adriamycin/banoanthraquinone-loaded nano diagnosis and treatment agent.
2. The method of claim 1, wherein: in the steps (1) and (2), the mass ratio of the carnosoquinone dihydrochloride to the doxorubicin hydrochloride to the manganese dichloride is 10-20:10-20: 1.
3. The method of claim 1, wherein: in the step (1), the concentrations of the carnosol anthraquinone dihydrochloride and the adriamycin hydrochloride are both 1 mg/mL;
and/or, in the step (2), the concentration of the manganese dichloride solution is 1 mg/mL.
4. The method of claim 1, wherein: in the step (1), the stirring reaction time is 1-2 h.
5. The method of claim 1, wherein: in the steps (1) and (2), the dosage ratio of the total amount of the paraminoquinone dihydrochloride and the doxorubicin hydrochloride to the triethylamine is 1: (0.22-0.23) (mg/mL).
6. The method of claim 1, wherein: in the step (2), after the manganese dichloride solution is dripped, continuously stirring and reacting for 3-5 h;
and/or in the step (2), after the triethylamine is added dropwise, continuously stirring and reacting for not less than 8 hours.
7. The method of claim 1, wherein: in the step (3), the volume usage ratio of the reaction liquid obtained in the step (2) to water is 1: 4-6;
and/or in the step (3), stirring for 2-3 h;
and/or in the step (3), the dialysis times are not less than 3, and the dialysis time is not less than 15 min.
8. The method of claim 1, wherein: in the steps (1), (2) and (3), the whole reaction process needs to be carried out under the condition of keeping out of the sun;
and/or, the steps (1), (2) and (3) are all carried out at room temperature.
9. The method of claim 1, wherein: the particle size of the nano diagnostic agent is 102.7 +/-20 nanometers.
10. The nanometer diagnosis and treatment agent loaded with the adriamycin/banoanthraquinone prepared by the preparation method of any one of the claims 1 to 9.
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| CN109790519A (en) * | 2016-06-22 | 2019-05-21 | 塞尔丽思股份公司 | The pharmaceutically active substance or marker delivery system of cell-targeting |
| CN111909384A (en) * | 2020-07-02 | 2020-11-10 | 南方医科大学南方医院 | Mesoporous metal organic framework and preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109790519A (en) * | 2016-06-22 | 2019-05-21 | 塞尔丽思股份公司 | The pharmaceutically active substance or marker delivery system of cell-targeting |
| CN111909384A (en) * | 2020-07-02 | 2020-11-10 | 南方医科大学南方医院 | Mesoporous metal organic framework and preparation method and application thereof |
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