CN107648612B

CN107648612B - Hollow mesoporous gated Mn2+Preparation and application of donor and artemisinin co-transport system

Info

Publication number: CN107648612B
Application number: CN201710962097.8A
Authority: CN
Inventors: 张慧娟; 张振中; 祝杏; 陈俭娇; 张红岭
Original assignee: Zhengzhou University
Current assignee: Zhengzhou University
Priority date: 2017-10-16
Filing date: 2017-10-16
Publication date: 2020-01-10
Anticipated expiration: 2037-10-16
Also published as: CN107648612A

Abstract

The invention relates to hollow mesoporous gated Mn²⁺The preparation and application of the donor and artemisinin cotransport system can effectively solve the problems of low solubility, low oral bioavailability, fast metabolism and instability of artemisinin in the preparation of antitumor drugs, and the technical scheme comprises the following steps: firstly adding sucrose into deionized water, centrifuging after reaction, washing, precipitating and drying, and then dropwise adding Mn (NO)₃)₂Solution, ultrasonic dispersion, centrifugal washing and drying to synthesize HMn₂O₃Of (1); adding deionized water, ultrasonic dissolving with probe, dissolving artemisinin in ethanol, and mixing with HMn₂O₃The preparation method is simple, can greatly improve the solubility and bioavailability of the artemisinin in the preparation of the antitumor drugs, obviously enhances the toxicity of the artemisinin on tumor cells, and provides high-concentration Mn²⁺Can obviously enhance the magnetic resonance imaging and realize the diagnosis and treatment integration of the tumor.

Description

Hollow mesoporous gated Mn2+Preparation and application of donor and artemisinin co-transport system

Technical Field

The invention relates to the field of medicines, in particular to hollow mesoporous gated Mn²⁺Preparation and application of donor and artemisinin co-transport system.

Background

Artemisinin (ART) is a sesquiterpene lactone compound containing peroxy group and having antimalarial effect, and its antimalarial activity is known worldwide, and has the advantages of rapid onset of action, high drug effect, low toxic and side effects, etc. The continuous and intensive research reveals that the compounds have good anti-tumor effects, such as cell cycle arrest induction, cell apoptosis promotion, tumor angiogenesis inhibition, tumor cell invasion and metastasis blocking and the like. However, ART has the defects of difficult dissolution, low oral bioavailability, fast metabolism and instability, so how to enhance the anti-tumor effect of ART and realize the application of ART in anti-tumor drugs is a problem which needs to be solved in the field urgently.

Hollow mesoporous manganese sesquioxide (Hollow Mn)₂O₃，HMn₂O₃) The nanoparticle has a double-layer structure, has a large pore volume inside, can load drugs in hollow and pore channel structures, has a large specific surface area, and has high drug loading capacity. In the neutral environment of human body, HMn₂O₃Can maintain structural integrity, and in a microenvironment with acidity and strong reducibility at the tumor site, HMn₂O₃The structure will gradually erode to generate Mn²⁺On one hand, the loaded medicine is released into tumor cells, and the Mn at the target position of the tumor is realized²⁺The aim of synchronous fixed-point release is fulfilled, and the toxic and side effects of the medicine are reduced; mn on the other hand²⁺The generation of (A) leads to an increase in the osmotic pressure of the tumor cell lysosomes, leading to the phenomenon of lysosome escape, and in addition, Mn²⁺The incubation with ART can destroy the peroxide bridge of ART to generate free radical, and the destruction of free radical on the lysosome membrane of tumor cell can accelerate lysosome escape and cell nucleus targeting, thus obviously enhancing the toxicity of ART on tumor cell. HMn nanoparticles prepared by hollow mesoporous manganese sesquioxide₂O₃Artemisinin (ART) loading, and preparing tumor responsive hollow mesoporous gated Mn²⁺A donor and ART are coordinated to carry out cotransport system, so that the anti-tumor effect of ART can be effectively enhanced, but no related research is found at present.

Disclosure of Invention

In view of the above situation, the present invention aims to overcome the defects of the prior art and provide a hollow mesoporous gated Mn²⁺The preparation and application of the donor and artemisinin cotransport system can effectively solve the problems of low solubility, low oral bioavailability, fast metabolism and instability of artemisinin in the preparation of antitumor drugs.

The technical proposal for solving is that the hollow mesoporous gate-controlled Mn²⁺The preparation and application of the donor and artemisinin cotransport system comprise the following steps:

（1）HMn₂O₃the synthesis of (2): adding 10-45g of sucrose into 15-180mL of deionized water, reacting for 3-7h at 145-295 ℃, centrifuging for 9-11min at 12500-14000rpm, discarding the supernatant, sequentially washing the precipitate with deionized water and absolute ethanol for 2-3 times, and drying at 55-59 ℃ to obtain the final productBlack carbon powder; weighing 0.5-4.5g of carbon powder, ultrasonically dispersing in 10-45mL of deionized water, and dropwise adding 15-45mL of Mn (NO) with mass concentration of 50%₃)₂Ultrasonic dispersing the solution for 13-16min, soaking for 30-70h, stirring, centrifuging at 12500-₂O₃；

（2）HMn₂O₃Preparation of load artemisinin: weighing 5-20mg of HMn prepared in step (1)₂O₃Adding into 2-40ml deionized water, and ultrasonic dissolving with probe to obtain HMn₂O₃Dissolving 20-40mg of artemisinin in 2-5ml of ethanol, and mixing with HMn₂O₃Mixing the solutions, carrying out ultrasonic treatment for 0.5-1h in ice bath, stirring at room temperature, dialyzing in a dialysis bag with cut-off molecular weight MW =3500Da for 2-3 days, and freeze-drying to obtain the hollow mesoporous gated Mn²⁺And (3) a donor and artemisinin co-transport system.

The hollow mesoporous gated Mn prepared by the method²⁺The particle size of the donor and artemisinin cotransport system is 50-300 nm.

The hollow mesoporous gated Mn prepared by the method²⁺Application of donor and artemisinin co-transport system in preparing antitumor drugs is provided.

The preparation method is simple, the solubility and bioavailability of artemisinin in the preparation of antitumor drugs can be greatly improved, the toxicity of artemisinin to tumor cells is remarkably enhanced, and the high-concentration Mn provided by the hollow mesoporous manganese sesquioxide nanoparticle carrier at tumor parts²⁺Can obviously enhance the magnetic resonance imaging and realize the diagnosis and treatment integration of the tumor.

Detailed Description

The following examples further illustrate embodiments of the present invention in detail.

Example 1

Hollow mesoporous gated Mn²⁺The preparation and application of the donor and artemisinin cotransport system comprise the following steps:

（1）HMn₂O₃the synthesis of (2): will 10Adding sucrose into 15mL of deionized water, reacting for 7h at 145 ℃, centrifuging for 11min at 12500rpm, discarding the supernatant, sequentially washing the precipitate with deionized water and absolute ethyl alcohol for 2 times respectively, and drying at 55 ℃ to obtain black carbon powder; 0.5g of carbon powder is weighed, ultrasonically dispersed in 10mL of deionized water, and 15mL of Mn (NO) with the mass concentration of 50 percent is dropwise added₃)₂Ultrasonically dispersing the solution for 13min, soaking for 70h, stirring, centrifuging at 12500rpm for 33min, discarding the supernatant, sequentially washing the precipitate with deionized water and anhydrous ethanol for 2 times, drying at 55 deg.C, and calcining at 350 deg.C for 9h to obtain HMn₂O₃；

（2）HMn₂O₃Preparation of load artemisinin: weighing 5mg of HMn prepared in step (1)₂O₃Adding into 2ml deionized water, and ultrasonic dissolving with probe to obtain HMn₂O₃Dissolving 20mg of artemisinin in 2ml of ethanol, and mixing with HMn₂O₃Mixing the solutions, carrying out ultrasonic treatment for 0.5h in ice bath, stirring at room temperature, putting into a dialysis bag with molecular weight cutoff MW =3500Da, dialyzing for 2 days, and freeze-drying to obtain the hollow mesoporous gated Mn²⁺And (3) a donor and artemisinin co-transport system.

Example 2

（1）HMn₂O₃the synthesis of (2): adding 30g of sucrose into 100mL of deionized water, reacting for 4h at 200 ℃, centrifuging for 10min at 13000rpm, discarding the supernatant, sequentially washing the precipitate with deionized water and absolute ethyl alcohol for 3 times respectively, and drying at 57 ℃ to obtain black carbon powder; weighing 2.0g of carbon powder, ultrasonically dispersing the carbon powder in 30mL of deionized water, and dropwise adding 30mL of Mn (NO) with the mass concentration of 50%₃)₂Ultrasonically dispersing the solution for 15min, soaking for 48h, stirring, centrifuging at 13000rpm for 30min, discarding the supernatant, sequentially washing the precipitate with deionized water and anhydrous ethanol for 3 times, drying at 60 deg.C, and calcining at 500 deg.C for 5h to obtain HMn₂O₃；

（2）HMn₂O₃Preparation of load artemisinin: weighing 10mg of HMn prepared in step (1)₂O₃Adding into 20ml deionized water, and probe treatingDissolving by sound to obtain HMn₂O₃Dissolving 25mg of artemisinin in 3ml of ethanol, and mixing with HMn₂O₃Mixing the solutions, carrying out ultrasonic treatment for 0.5h in ice bath, stirring at room temperature, dialyzing in a dialysis bag with molecular weight cutoff MW =3500Da for 2 days, and freeze-drying to obtain the hollow mesoporous gated Mn²⁺And (3) a donor and artemisinin co-transport system.

Example 3

（1）HMn₂O₃the synthesis of (2): adding 45g of sucrose into 180mL of deionized water, reacting for 3h at 295 ℃, centrifuging for 9min at 14000rpm, discarding the supernatant, sequentially washing the precipitate with deionized water and absolute ethyl alcohol for 3 times respectively, and drying at 59 ℃ to obtain black carbon powder; weighing 4.5g of carbon powder, ultrasonically dispersing in 45mL of deionized water, and dropwise adding 45mL of Mn (NO) with the mass concentration of 50%₃)₂Ultrasonically dispersing the solution for 16min, soaking for 70h, stirring, centrifuging at 13500rpm for 28min, discarding the supernatant, sequentially washing the precipitate with deionized water and anhydrous ethanol for 3 times, drying at 65 deg.C, and calcining at 650 deg.C for 3h to obtain HMn₂O₃；

（2）HMn₂O₃Preparation of load artemisinin: weighing 20mg of HMn prepared in step (1)₂O₃Adding into 40ml deionized water, and ultrasonically dissolving with probe to obtain HMn₂O₃Dissolving 40mg of artemisinin in 5ml of ethanol, and mixing with HMn₂O₃Mixing the solutions, carrying out ultrasonic treatment for 1h in ice bath, stirring at room temperature, dialyzing in a dialysis bag with molecular weight cutoff MW =3500Da for 3 days, and freeze-drying to obtain hollow mesoporous gated Mn²⁺And (3) a donor and artemisinin co-transport system.

The invention provides hollow mesoporous gated Mn with lysosome escape function and cell nucleus targeting²⁺A donor and Artemisinin (ART) antitumor drug co-transport system; the invention selects Hollow mesoporous manganese sesquioxide nano-particles (Hollow Mn) with higher drug loading capacity and biocompatibility₂O₃，HMn₂O₃) As a base material for the glass substrate,loading an anti-tumor drug ART, and constructing a mesoporous gating type drug transport system with a nuclear magnetic imaging function; the nano system has the particle size of 50-300nm, uniform size and good dispersibility; the system mainly has the following characteristics: 1) ART and HMn₂O₃After entering a target cell, the co-transport system can realize lysosome escape and cell nucleus targeting through two mechanisms, so that the anti-tumor effect of ART is effectively enhanced; 2) the carrier can be used as Mn in specific weak acid and reducibility environment of tumor²⁺Donor with gating effect and realizing ART and Mn²⁺Donor cooperative cotransport to generate free radical to strengthen ART antitumor effect; 3) mn produced at tumor site²⁺The magnetic resonance imaging can be obviously enhanced, and the diagnosis and treatment integration of the tumor is realized; 4) large dose of ART required for antitumor, HMn₂O₃The high drug capacity of the double-layer hollow porous structure can effectively solve the problems of poor solubility and large dosage of ART.

The invention relates to hollow mesoporous gated Mn with a lysosome escape function and cell nucleus targeting²⁺A donor and Artemisinin (ART) antitumor drug co-transport system. Firstly, preparing multifunctional double-layer Hollow mesoporous nanoparticles (Hollow Mn)₂O₃，HMn₂O₃) The material is used as a matrix (large specific surface area, large capacity, small density, Mn)²⁺Donor), internally loaded with ART. In the tumor environment, the carrier structure is destroyed, and a large amount of Mn is generated while the carrier structure is split into small particles²⁺Causing the osmotic pressure in the tumor cell lysosome to increase rapidly, causing lysosome escape and cell nucleus targeting. Then ART with Mn²⁺The reaction produces a large number of free radicals. On one hand, lysosome escape is more obvious by destroying the structure of a lysosome membrane; on the other hand, the antitumor effect of ART can be significantly enhanced. Meanwhile, Mn generated by the system under a tumor specific microenvironment²⁺The magnetic resonance imaging agent can be used as a contrast agent to obviously enhance the magnetic resonance imaging capability of a tumor part. In summary, the delivery system has Mn²⁺The donor and ART are co-transported cooperatively, the tumor responsiveness is synchronously released, and the tumor is treated by a plurality of mechanisms at the same site, so that the integration of tumor diagnosis and treatment can be realized.

The double-layer hollow mesoporous HMn prepared by the invention₂O₃The nanoparticles have large pore volume inside, and the hollow and pore channel structures of the nanoparticles can be loaded with drugs, so that the nanoparticles have large specific surface area and high drug loading capacity. In the experiment, HMn is found in the neutral environment of human body₂O₃Can maintain structural integrity, and in a microenvironment with acidity and strong reducibility at the tumor site, HMn₂O₃The structure will gradually erode to generate Mn²⁺On one hand, the loaded medicine is released into tumor cells, and the Mn at the target position of the tumor is realized²⁺The aim of synchronous fixed-point release is fulfilled, and the toxic and side effects of the medicine are reduced; mn on the other hand²⁺The generation of (A) leads to an increase in the osmotic pressure of the tumor cell lysosomes, leading to the phenomenon of lysosome escape, and in addition, Mn²⁺The incubation with ART can destroy the peroxide bridge of ART to generate free radical, and the destruction of free radical on the lysosome membrane of tumor cell can accelerate lysosome escape and cell nucleus targeting, thus obviously enhancing the toxicity of ART on tumor cell. Thus preparing Mn²⁺And the ART co-transport system are important for enhancing the anti-tumor effect of ART. Has the function of releasing the drug in response to the tumor while enhancing the anti-tumor effect.

Due to the protection effect of the hollow spherical shell layer, the drug can be prevented from interacting with plasma protein or other biomolecules in the conveying process, so that the drug can be protected from enzymolysis. In addition, the carrier provides high concentrations of Mn at the tumor site²⁺Can obviously enhance the magnetic resonance imaging and realize the diagnosis and treatment integration of the tumor.

Mn of the invention²⁺Co-transport drug carrier system with donor and ART, composed of Mn²⁺Donor (HMn)₂O₃Vector) and ART; ART loaded HMn₂O₃Enters tumor cells through endocytosis, is further distributed in acid organelles such as endosome, lysosome and the like, and HMn₂O₃Decomposing in acidic and reducing environment to generate and release Mn²⁺，Mn²⁺The synergistic effect is generated by non-enzymatic reaction and ART, thereby effectively killing cancer cells and obviously enhancing the anti-tumor effect of ART.

The invention is beneficialWith HMn₂O₃Structural destruction to Mn in the tumor environment²⁺Replacing the prior Fe²⁺Reacting with the peroxybridge of ART, the drug delivery system is found in two mechanisms in the therapeutic regime (Mn: Mn, on the one hand)²⁺The generation of the lysosome is accompanied with the increase of osmotic pressure in the lysosome, so that the lysosome is broken and escapes, thereby entering a cell nucleus; on the other hand: mn²⁺Reaction with ART produces free radicals, which alter the stability of the lysosomal membrane, leading to drug egress from the lysosome into the nucleus. ) Realizes lysosome escape and cell nucleus targeting, enhances the damage of ART to DNA and obviously improves the anti-tumor effect. At the same time, Mn accumulated in tumor sites²⁺Can obviously enhance the nuclear magnetic imaging function and realize the diagnosis and treatment integration of the tumor.

The invention adopts Mn²⁺Co-transport with ART to generate lysosome escape and nucleus targeting phenomena, and exert synergistic anti-tumor effect and Mn²⁺The nuclear magnetic imaging function of the system realizes the diagnosis and treatment integration of the tumor.

Hollow mesoporous gated Mn²⁺The synergic co-transport of the donor and ART can obviously enhance the anti-tumor effect

The Mn²⁺The donor and ART are cooperated to co-transport the medicine carrying system, and can be used for injection, oral administration or implantation administration. Wherein the injection is preferably injection or lyophilized powder for injection, the oral administration is preferably selected from tablet, capsule, pill, syrup, and granule, and the implantation is preferably selected from gel and solution.

The mesoporous gating Mn²⁺The donor and ART co-transport drug carrying system can be used for a tumor drug delivery system, and can realize targeted drug delivery, in-vivo long circulation and the like through proper modification.

The invention obtains consistent results through repeated experiments, and the related experimental data are as follows

Experiment 1: hollow mesoporous manganese sesquioxide (Hollow Mn)₂O₃，HMn₂O₃) Mn of nano-particle under acid environment²⁺Generating assays

HMn formulated at 100. mu.g/ml₂O₃Aqueous solution, solventPhosphate PBS buffer (simulated normal body fluid) with different pH =7.4, pH =4.0, GSH 5mM/L (simulated tumor cell lysosome), shaking at 37 deg.C at 100r/min, taking out part at regular intervals, and adopting Mn²⁺Reagent kit for measuring Mn²⁺And (4) concentration. The results show that HMn₂O₃Is easier to decompose to generate Mn under acidic environment²⁺This indicates HMn₂O₃Environmentally sensitive release of Mn in acidic and strongly reducing tumor sites²⁺And has synergistic effect with Artemisinin (ART).

Experiment 2: HMn₂O₃Preparation of Supported ART

10mg of HMn are weighed out₂O₃Adding 10ml of ultrapure water, and carrying out 400W ultrasonic treatment for 20min to uniformly disperse the ultrapure water in the water for later use. Then weighing 30mg ART to be dissolved in 3ml ethanol to obtain ART mother liquor, and slowly dripping the ART mother liquor into HMn under the action of 400W ultrasound and ice water bath₂O₃In the solution, after the dropwise addition is finished, continuing to perform ultrasonic treatment for 0.5h to ensure that ART is fully diffused into HMn under the violent movement₂O₃Then the solution probe is subjected to ultrasonic treatment (300W, 10 times, 6s each time), centrifuged (4000 r/min, 5 min), put into a dialysis bag (molecular weight cutoff MW =3500Da) for dialysis for 2 days to remove organic solvent and free drug, and freeze-dried for 48h to obtain HMn loaded with ART₂O₃（HMn₂O₃/ART) at 4 ℃ until use.

Experiment 3: HMn₂O₃Controlled drug release in acidic environments

Mixing HMn₂O₃the/ART was placed in dialysis bags (MW =3500Da cut-off) and immersed in phosphate PBS buffer solutions of different pH values (7.4: mock normal body fluid, 6.5: mock tumor tissue and pH =4.0, C)_GSH=5 mM/L: simulated lysosome), shaking at 37 ℃ at 100r/min, taking out parts at regular intervals, measuring ART by using an ultraviolet spectrometer, measuring the concentration of the ART and calculating the release speed. The result shows that the preparation has obvious acidity sensitivity when releasing the medicine, and the medicine releasing speed is as follows: pH4.0>pH6.5>pH7.4。

Experiment 4: HMn₂O₃Intracellular behavior of/ART drug-loaded systems

Cytological Experimental design ① FITC ② HMn₂O₃；③HMn₂O₃The results show that ① FITC only has lysosome red fluorescence and cell nucleus blue fluorescence, ② HMn₂O₃The lysosome escape and the cell nucleus targeting of the group have time dependence, partial lysosome escape from the lysosome into the cell nucleus is carried out at the beginning of 4h, and the number of the cells entering the cell nucleus and subjected to the lysosome escape and the cell nucleus targeting is remarkably improved no matter the number of the cells entering the cell nucleus or the number of the cells subjected to the lysosome escape and the cell nucleus targeting is 6h, ③ HMn₂O₃The lysosome escape phenomenon of the/FITC group is more obvious, and almost all carriers in the cells escape from the lysosome and are distributed in the cell nucleus after 6 h. The damage of ART to the cell nucleus is greatly enhanced through the mechanism, so that the cell nucleus generates holes, and the anti-tumor effect is also obviously improved.

Experiment 5: HMn₂O₃Determination of antitumor Activity of/ART drug-loaded System

In vitro antitumor activity (with mouse breast cancer cell strain MCF-7 as the research object): time effect: with HMn₂O₃The cells were treated once with ART and their inhibitory effect on the growth of tumor cells was examined at different time points (SRB method); dose effect: with different doses of HMn₂O₃The cells were treated with/ART and examined for their inhibitory effect on tumor cell growth by the SRB method.

Different experimental groups are set for the above experiments: HMn₂O₃、ART、HMn₂O₃and/ART. The results show that HMn₂O₃The cell inhibitory effect of ART is significantly time-dependent and concentration-dependent, and ART and HMn₂O₃Has obvious synergistic tumor inhibition effect;

in vivo antitumor activity: MCF-7 cells were inoculated subcutaneously into the flank of nude mice and the swelling was monitored every other dayGrowth of the tumors and general conditions of the nude mice were recorded. When the tumor volume reaches 100-300 mm³At this time, animals were randomly assigned and treatment (i.v.) was started ① ART (Amersham pharmacia Biotech) ② HMn₂O₃；③HMn₂O₃and/ART. A normal saline control group and a positive control group are simultaneously arranged. Tumor volume was continuously monitored until the animals were sacrificed. By week seven, all mice were sacrificed and tumors were removed and weighed. The effect was evaluated in terms of relative tumor proliferation rate T/C.

The experimental results show that HMn is compared to the other groups₂O₃the/ART has remarkable tumor inhibiting effect in vivo, and the relative tumor increment rate is minimum.

Compared with the prior art, the invention has the following advantages and beneficial effects:

(1) the invention adopts HMn₂O₃① implementation of Mn as a Carrier for ART²⁺② effectively solves the solubility problem and realizes the controlled release of the effective load of the drug and the drug at the target position of the tumor;

（2）HMn₂O₃can provide Mn at the tumor site²⁺，Mn²⁺Can be used for nuclear magnetic resonance imaging, can obtain images of parts which cannot be approached or are difficult to approach by other imaging technologies, and realizes the diagnosis and treatment integration of the tumor by cooperating with loaded medicines. Has the characteristics of safe, quick and accurate clinical diagnosis and the like;

（3）HMn₂O₃under the conditions of tumor acidity and strong reducibility, Mn is released by structural destruction²⁺So as to realize the increase of osmotic pressure and the escape of lysosomes; mn²⁺Reaction with ART destroys the peroxide bridge, releases free radicals, damages the organelle membrane and enhances lysosome escape. After the medicine realizes lysosome escape in vivo, the medicine shows the characteristic of nucleus targeting, and can obviously enhance the anti-tumor effect of ART.

Claims

1. Hollow mesoporous gated Mn²⁺Donor co-arteannuinThe preparation method of the transport system is characterized by comprising the following steps:

（1）HMn₂O₃the synthesis of (2): adding 10-45g of sucrose into 15-180mL of deionized water, reacting for 3-7h at 145-295 ℃, centrifuging for 9-11min at 12500-14000rpm, discarding the supernatant, sequentially washing the precipitate with deionized water and absolute ethyl alcohol for 2-3 times respectively, and drying at 55-59 ℃ to obtain black carbon powder; weighing 0.5-4.5g of carbon powder, ultrasonically dispersing in 10-45mL of deionized water, and dropwise adding 15-45mL of Mn (NO) with mass concentration of 50%₃)₂Ultrasonic dispersing the solution for 13-16min, soaking for 30-70h, stirring, centrifuging at 12500-₂O₃；

2. The hollow mesoporous gated Mn of claim 1²⁺The preparation method of the donor and artemisinin cotransport system is characterized by comprising the following steps:

（1）HMn₂O₃the synthesis of (2): adding 10g of sucrose into 15mL of deionized water, reacting for 7h at 145 ℃, centrifuging for 11min at 12500rpm, discarding the supernatant, sequentially washing the precipitate with deionized water and absolute ethyl alcohol for 2 times respectively, and drying at 55 ℃ to obtain black carbon powder; 0.5g of carbon powder is weighed, ultrasonically dispersed in 10mL of deionized water, and 15mL of Mn (NO) with the mass concentration of 50 percent is dropwise added₃)₂Ultrasonic dispersing for 13min, soaking for 70h, stirring, centrifuging at 12500rpm for 33min, discarding supernatant, washing precipitate with deionized water and anhydrous ethanol for 2 times respectively,drying at 55 deg.C, and calcining at 350 deg.C for 9 hr to obtain HMn₂O₃；

3. The hollow mesoporous gated Mn of claim 1²⁺The preparation method of the donor and artemisinin cotransport system is characterized by comprising the following steps:

（2）HMn₂O₃Preparation of load artemisinin: weighing 10mg of HMn prepared in step (1)₂O₃Adding into 20ml deionized water, and ultrasonic dissolving with probe to obtain HMn₂O₃Dissolving 25mg of artemisinin in 3ml of ethanol, and mixing with HMn₂O₃Mixing the solutions, carrying out ultrasonic treatment for 0.5h in an ice bath, stirring at room temperature, then putting into a dialysis bag with the molecular weight cutoff MW =3500Da for dialysis for 2 days, and carrying out freeze drying to obtain a hollow mesoporous gated Mn2+ donor and artemisinin co-transport system.

4. The hollow mesoporous gated Mn of claim 1²⁺The preparation method of the donor and artemisinin cotransport system is characterized by comprising the following steps:

5. The hollow mesoporous gated Mn of any of claims 1 or 2-4²⁺The preparation method of the donor and artemisinin cotransport system is characterized in that the hollow mesoporous gated Mn²⁺The particle size of the donor and artemisinin cotransport system is 50-300nm

6. Hollow mesoporous gated Mn prepared by the method of any of claims 1 or 2-4²⁺Application of donor and artemisinin co-transport system in preparing antitumor drugs is provided.