LU503418B1 - Metal organic framework-wrapped trimanganese tetroxide modified by folic acid, preparation method therefor and application thereof - Google Patents

Metal organic framework-wrapped trimanganese tetroxide modified by folic acid, preparation method therefor and application thereof Download PDF

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LU503418B1
LU503418B1 LU503418A LU503418A LU503418B1 LU 503418 B1 LU503418 B1 LU 503418B1 LU 503418 A LU503418 A LU 503418A LU 503418 A LU503418 A LU 503418A LU 503418 B1 LU503418 B1 LU 503418B1
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folic acid
zif
solution
modified
wrapped
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Shuya Pan
Tianfeng Chen
Xueqiong Zhu
Guanning Huang
Yizuo Song
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The 2Nd Affiliated Hospital And Yuying Childrens Hospital Of Wmuy
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    • A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
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    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
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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
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Abstract

The present invention discloses a metal organic framework-wrapped trimanganese tetroxide modified by folic acid, a preparation method therefor, and an application thereof. In the present invention, a metal organic framework-wrapped trimanganese tetroxide modified by folic acid is obtained by the following steps: modifying Mn3O4 with a surfactant; then further reacting to obtain an Mn3O4@ZIF-8; finally reacting with a folic acid-polyethylene glycol solution. This substance has good cervical cancer targeting, can effectively accumulate to a tumor site, and can automatically degrade in acidic microenvironment of tumor under the action of radiotherapy. It releases locally Mn3O4 in tumor, and oxidizes excessive oxygen ions of hydrogen peroxide to oxygen gas in tumor, improving the hypoxic environment of the tumor, and achieving ideal radiotherapy synergy and sensitization effect.

Description

! LU503418
METAL ORGANIC FRAMEWORK-WRAPPED TRIMANGANESE TETROXIDE
MODIFIED BY FOLIC ACID, PREPARATION METHOD THEREFOR AND
APPLICATION THEREOF
Technical Field
The present invention belongs to the field of a medical material, specifically relates to trimanganese tetroxide wrapped in a metal organic framework modified by folic acid, a preparation method therefor, and an application thereof.
Background
Cervical cancer is one of the most common malignant tumors for women worldwide. There were about 600,000 new cases and 340,000 dead cases all over the world in 2020. Radiotherapy is an important means of treatment for cervical cancer. The ionizing radiation generated by radiotherapy can directly destroy DNA molecules, or indirectly cause irreparable DNA damage such as
DNA double-strand breakage in tumor cells by inducing the increase of a content of free radicals, especially active oxygen in a tumor tissue, thereby causing death of tumor cells. Meanwhile, the active oxygen can also lead to apoptosis of tumor cells by destroying related biomolecules and activating related signaling pathways. The effectiveness of radiotherapy is related to the oxygen effect. Hypoxic tumors tend to tolerate rays better than well-oxygenated tumors, and require larger doses of radiation for treatment.
In case of better oxygenation, Cells are 3 times more sensitive to X-ray than in hypoxic condition. Hypoxia is one of the important features of solid tumors, and the efficacy of radiotherapy is limited by the hypoxic microenvironment of the tumor tissue.
In recent years, there are gradually many studies of developing a nano
2 LU503418 system to promote the efficacy of radiotherapy. Most of the prior-art radiosensitive nano-materials are based on metal materials with high atomic numbers. However, the prerequisite for these materials to function is that there needs to be sufficient oxygen gas in the environment. Consequently, the radiosensitivity effect of the metal nano-materials tends to be hindered by the lack of oxygen for the microenvironment of the tumor. Therefore, a strategy of overcoming the hypoxia of tumor in sensitizing radiotherapy is particularly important.
Summary
A primary objective of the present invention is to overcome the shortcomings and deficiencies of the prior art, and provide a preparation method for a metal organic framework-wrapped trimanganese tetroxide modified by folic acid.
Another objective of the present invention is to provide the metal organic framework-wrapped trimanganese tetroxide modified by folic acid prepared by the method described above. The metal organic framework-wrapped trimanganese tetroxide modified by folic acid has efficient radiosensitivity effect responding to X-ray.
Still another objective of the present invention is to provide an application of the above-described metal organic framework-wrapped trimanganese tetroxide modified by folic acid.
Objectives of the present invention are realized by the following technical solutions. A preparation method for a metal organic framework-wrapped trimanganese tetroxide modified by folic acid comprises the following steps: (1) modification for Mn304
D dispersing Mn:04 with an organic solvent to obtain an Mn;Oy
3 LU503418 solution; (2) dispersing or dissolving evenly a surfactant with an organic solvent, then adding the Mn:O4 solution obtained in step ©), stirring and reacting; and subjecting a resulting mixture to a solid-liquid separation, and dispersing the obtained solid evenly with the organic solvent, to obtain a surfactant-modified
Mn;0Oy solution; and (2) synthesis for FA-Mn304@ZIF-8
D synthesis for a folic acid-polyethylene glycol solution (FA-PEG): dissolving folic acid and NaHCO; into water to obtain a folic acid solution; dissolving NHS, EDC and PEG into water to obtain a mixed solution A; mixing the folic acid solution with the mixed solution A to obtain a mixed solution B, stirring and reacting; and dialyzing after stopping the reaction to obtain a FA-PEG solution; © synthesis for Mn:04@ZIF-8: dissolving 2-methylimidazole into the organic solvent to obtain a 2-methylimidazole solution; mixing the 2-methylimidazole solution with the surfactant-modified Mn304 solution obtained in step (1), to obtain a mixed solution C; dissolving zinc nitrate into the organic solvent, to obtain a zinc nitrate solution; and mixing the mixed solution C with the zinc nitrate solution, to obtain a mixed solution D, standing still and reacting, subjecting to a solid-liquid separation, and washing the obtained solid, to obtain a solid Mn304@ZIF-8; and © synthesis for FA-Mn:04@ZIF-8: dispersing Mn:04@ZIF-8 evenly with the FA-PEG solution, then stirring and reacting overnight, to obtain a mixed solution E; subjecting the mixed solution E to a solid-liquid separation, and washing the obtained solid, to obtain the metal organic framework-wrapped trimanganese tetroxide modified by folic acid.
In step (1) ©, the Mn3;O-4 is preferably to be obtained by calcining of a
4 LU503418 manganese source; and more preferably, it is to be prepared by the following steps: dispersing or dissolving the manganese source into a solvent A, calcining, cooling down and washing to obtain Mn304.
The manganese source is preferably inorganic manganese, more preferably at least one of manganese acetate, potassium permanganate and manganese (II) chloride.
The solvent A is preferably at least one of absolute ethanol, water and methanol.
The conditions for the calcining are preferably reacting for 20 to 30 h in a muffle furnace at a condition of heating at 100 to 140 °C; and more preferably reacting for 24 h in the muffle furnace at 120 °C.
The degree of cooling is preferably cooling down to room temperature.
The room temperature is 10 to 40 °C, more preferably 20 to 30 °C, and most preferably 24 to 27 °C.
The washing 1s washing with absolute ethanol and ultrapure water respectively.
The number of times for the washing is preferably at least one time, more preferably three times.
In step (1) Q), the organic solvent is preferably at least one of methanol and absolute ethanol.
In step (1) ©, an amount of the used organic solvent is preferably calculated in terms of a ratio of Mn304 to the organic solvent of 0.8 to 1 g :4 mL.
In step (1) @), the organic solvent is preferably at least one of methanol and absolute ethanol.
In step (1) @, an amount of the used organic solvent is preferably calculated in terms of a ratio of the surfactant to the organic solvent of 10 to 11 mg :1 mL.
> LU503418
In step (1) ©, the surfactant is preferably polyvinyl pyrrolidone, more preferably PVP10, PVP15, PVP25 and PVP30 etc.
In step (1) @), the amount of the used surfactant is preferably calculated in terms of a weight ratio of MnsO4 to the surfactant of 1 to 1.01:1.
In step (1) @, the time for the stirring and reacting is preferably 10 to 16 h, more preferably 12 h.
In step (1) @, the solid-liquid separation is performed preferably by means of centrifuging.
The speed of the centrifuging is preferably at 10000 to 12000 rpm for 10 to 15 min.
In step (2) ©, a weight ratio of the folic acid to NaHCO; is preferably 5:3.5 to 4, more preferably 5:3.8.
In step (2) ©, the water is preferably ultrapure water.
In step (2) ©, a weight ratio of NHS to EDC to PEG in the mixed solution A is preferably 1:1:1.4 to 1.8, more preferably 1:1:1.6.
In step (2) D), the PEG is preferably at least one of PEG2000 and
PEG5000.
In step (2) ©, a weight ratio of folic acid to PEG in the mixed solution
B is preferably 1:3 to 5, more preferably 1:4.
In step (2) ©, the time for the stirring and reacting is preferably 10 to 16 h, more preferably 12 h.
In step (2) ©, the dialyzing is to remove the unreacted reagents.
In step (2) ©, the time for the dialyzing is preferably 12 to 36 h, more preferably 24 h.
In step (2) Q), the concentration of the FA-PEG solution is preferably 5 mg/mL.
6 LU503418
In step (2) @, the organic solvent is preferably methanol.
In step (2) @), the concentration of the 2-methylimidazole solution is preferably 2 to 2.1 mg/mL.
In step (2) @, a weight ratio of 2-methylimidazole to zinc nitrate to
Mn304 in the mixed solution D is preferably 1 to 1.01:3.5 to 4:1, more preferably 1 to 1.01:3.6 to 3.7:1.
In step (2) @, the time for the standing still and reacting is preferably 40 to 80 min, more preferably 60 min.
In step (2) @), the solid-liquid separation is preferably performed by means of centrifuging.
The speed of the centrifuging is preferably at 10000 to 12000 rpm for 10 to 15 min.
In step (2) @), the washing is washing with methanol.
In step (2) @, the number of times for the washing is preferably at least one time, more preferably three times.
In step (2) ©, a weight ratio of FA-PEG to Mn:04@ZIF-8 in the mixed solution E is preferably 1 to 5:1, more preferably 1:1.
In step (2) ©), the dispersing is preferably performed by ultrasonic dispersing.
The conditions for the ultrasonic dispersing are preferably 120 W, 20 kHz, and 10 min.
In step (2) ©), the solid-liquid separation is preferably performed by means of centrifuging.
The speed of the centrifuging is preferably at 10000 to 12000 rpm for 10 to 15 min.
In step (2) ©), the washing is preferably washing by using ultrapure water.
7 LU503418
The number of times for the washing is preferably at least one time; and more preferably three times.
A metal organic framework-wrapped trimanganese tetroxide modified by folic acid is obtained by the method described above.
The metal organic framework-wrapped trimanganese tetroxide modified by folic acid is applied in radiotherapy for cancer.
The cancer is preferably cervical cancer.
The metal organic framework ZIF-8-wrapped trimanganese tetroxide modified by folic acid has good cervical cancer targeting, can effectively accumulate in a tumor site, and can automatically degrade in acidic microenvironment of tumor under the action of radiotherapy. It releases locally Mn304 in tumor, which oxidizes excessive oxygen ions of hydrogen peroxide to oxygen in tumor, improving the hypoxic environment of tumor and achieving ideal radiotherapy synergy and sensitization effects.
Relative to the prior art, the present invention has the following advantages and effects: (1) The present invention overcomes the disadvantage that the effect of radiotherapy alone is limited by the hypoxic microenvironment of the tumor.
Based on trimanganese tetroxide having a good responsiveness to H,O, and being able to generate oxygen gas to alleviate the hypoxic microenvironment of the tumor, it 1s selected as a radiotherapy sensitizer. In particular, it has stronger responsiveness to H20; after combining with ZIF-8, especially as one of the comprehensive means of cervical cancer treatment. (2) We found, by transmission electron microscopy, that the metal organic framework ZIF-8-wrapped trimanganese tetroxide modified by folic acid as described in the present invention responds better to radiation than
ZIF-8 and trimanganese tetroxide alone.
8 LU503418 (3) We found, by portable dissolved oxygen analyzer, that the metal organic framework ZIF-8-wrapped trimanganese tetroxide modified by folic acid in the present invention has good biological responsiveness to the acidic microenvironment of tumor. Meanwhile, it can reverse the enrichment of
HO, in tumor, and releases oxygen gas to alleviate hypoxia of tumor for enhancing the effect of radiotherapy. Concurrently, the metal organic framework ZIF-8-wrapped trimanganese tetroxide modified by folic acid in the present invention has a faster and stronger ability to release oxygen gas than ZIF-8 and manganese tetroxide alone. (4) We found, through cell experiments and subcutaneous tumorigenesis experiments in nude mice, that the metal organic framework ZIF-8-wrapped trimanganese tetroxide modified by folic acid in the present invention can effectively enhance the inhibitory effect of radiotherapy for cervical cancer.
Description of Drawings
Fig. 1 shows a transmission electron microscopy image of a metal organic framework ZIF-8-wrapped trimanganese tetroxide modified by folic acid.
Fig. 2 shows images for a morphological change in different pH environments of a metal organic framework ZIF-8-wrapped trimanganese tetroxide modified by folic acid; wherein, A is image for the environment of pH=5.3; B is image for the environment of pH=6.8; and C is image for the environment of pH=7 4.
Fig. 3 shows images for morphological changes of a nano-system and its different components under different doses of radiation.
Fig. 4 shows an oxygen production curve graph (A) of a nano-system and its different components in 0.5% H,O», solution and an image (B) for situations of producing bubbles 20 min after reaction of nano-particles and
? LU503418 different components thereof with 0.5% H,O, solution.
Fig. 5 shows graphs for results of effects on survival rates of SiHa cells (A) and C33a cells (B) of FA-Mn;04@ZIF-8 (10 mg/L) in combination with radiotherapy (4 Gy) for 72 h; wherein, * represents P < 0.05.
Fig. 6 shows images for results of effects of different nano systems in combination with radiotherapy on clonal formation of SiHa cells.
Fig. 7 shows a graph for results of an apoptosis rate of different groups of SiHa cells stained with Annexin V-FITC/PI double staining kit and detected by flow cytometer after radiotherapy in combination with different nano-systems for 72 h; wherein, Annexin V-FITC+/PI- of the right lower quadrant and Annexin V-FITC+/PI+ of the right upper quadrant in the figure show that the cell populations are apoptotic cells.
Fig. 8 shows a graph for results of in vivo antitumor activity of
FA-Mn:04@ZIF-8 in combination with radiotherapy, wherein, A) is a graph for weights and images of tumors; B) is a graph for growth curves for volumes of tumors; and C) is a graph for weight curves of tumor-bearing nude mice.
Fig. 9 shows images for distribution situation = of
FA-ICG@Mn304@ZIF-8 in nude mice (panel A) and images for distribution situation of nano-systems in various organs 72 h after tail vein injection of
FA-ICG@Mn:04@ZIF-8 and ICG@ Mn:04@ZIF-8 (panel B).
Detailed Description of Embodiments
The present invention will be further described below in detail in combination with Examples and the drawings, but embodiments of the present invention are not limited thereto.
Example 1:
Preparation for FA-Mn304@ZIF-8 nano-system
10 LU503418 (1) modifying and synthesizing Mn304
The following steps are performed: weighing 816.8 mg (3.33mmol) MnC4H6O4 * 4H,0 and adding it into 40 mL absolute ethanol, stirring until completely dissolving, reacting in a muffle furnace at 120 °C for 24 h, cooling down to room temperature, then washing with absolute ethanol for three times and with ultrapure water for three times, performing centrifugation at 12000 rpm for 10 min for each washing, and finally resuspending with 4 mL methanol, to obtain an Mn304-methanol solution; and weighing 400 mg polyvinyl pyrrolidone (PVP10) and dissolving it into 38 mL methanol, adding 2 mL of the Mn3;Os-methanol solution, stirring overnight at room temperature, centrifuging an obtained mixture at 12000 rpm for 10 min to remove excessive unreacted reagents, and resuspending with 2 mL methanol, to obtain an Mn304 * PVP solution. (2) synthesis for FA-Mn304@ZIF-8 synthesis for FA-PEG: weighing 50 mg folic acid and 38 mg NaHCOs, mixing them in 10 mL ultrapure water, and stirring until completely dissolving to obtain a folic acid solution; weighing 25 mg N-hydroxy succinimide (NHS), 25 mg 1-ethyl-(3-dimethylaminopropyl) carbonyldiimide (EDC) and 40 mg PEG (with a molecular weight of 2000), completely dissolving them in 8 mL ultrapure water, then adding 2 mL the freshly prepared folic acid solution, stirring overnight at room temperature, and then dialyzing by a dialysis bag with a molecular weight of 3000 for 24 h to remove unreacted reagents, to obtain an FA-PEG solution with a concentration of about 5 mg/mL.
Synthesis for Mn:04@ZIF-8: weighing 375.6 mg zinc nitrate and dissolving it into 50 mL methanol to obtain a zinc nitrate-methanol solution; weighing 104.7 mg 2-methylimidazole and dissolving it into 50 mL methanol,
Il LU503418 and adding 0.5 mL of the Mn3;O4 * PVP solution (5 mg/mL) into the 2-methylimidazole methanol solution, and performing ultrasonic mixing evenly to obtain a mixed solution 1; mixing the zinc nitrate-methanol solution and the mixed solution, standing still for 1 h, then centrifuging the mixture at a rotation speed of 12000 rpm to remove excessive unreacted reagents, and washing with methanol for three times, at a rotation speed of 12000 rpm each time, to obtain an Mn304@ZIF-8.
Synthesis for FA-Mn304@ZIF-8: resuspending the Mn:04@ZIF-8 precipitate with 5 mL of the FA-PEG solution, ultrasonic (120 W, 20 kHz) mixing them for 10 min, then stirring overnight at room temperature; subsequently centrifuging the mixture at a rotation speed of 12000 rpm to remove excessive unreacted reagents, and washing with ultrapure water for three times, at a rotation speed of 12000 rpm each time, to obtain an
FA-Mn304@ZIF-8.
A transmission electron microscopy image of the FA-Mn304@ZIF-8 successfully prepared by the in-situ synthesis method is shown in Figure 1.
Example 2:
Experiment for multiple responsiveness of FA-Mn304@ZIF-8 nano-system (1) verifying a responsiveness of FA-Mn:04(@ZIF-8 nano-system to acid
The following steps are performed: formulating a PBS buffer solution (0.01 M, pH=7.4), and adjusting the
PBS buffer solution to three different pH of 5.3, 6.8 and 7.4 by using HCI and
NaHCOs; adding 100 uL of the FA-Mn;O4@ZIF-8 (with an effective Mn concentration of 45 mg/mL, and an effective Zn concentration of 100 mg/mL, as measured by ICP-MS measuring method) into 2 mL of the PBS buffer solutions with different pH values, co-incubating for 4 h, and then observing
12 LU503418 different pH groups for morphological change of nano-particles by transmission electron microscopy.
The results are shown in Fig. 2. In the environment of pH=5.3 and 6.8,
FA-Mn:04@ZIF-8 loses its original regular shape, and ZIF-8 cracks, exposing Mn304 therein; and in the environment of pH=7.4 (Fig. 2C), the shape of FA-Mn:04@ZIF-8 has not changed significantly. Therefore,
FA-Mn:04@ZIF-8 has good responsiveness to acidic environment. (2) verifying a responsiveness of FA-Mn;O4@ZIF-8 nano-system to
X-ray
The following steps are performed: taking 2 mL of the FA-Mn;O4@ZIF-8, Mn:04 and ZIF-8 (with an effective Mn concentration of 20 mg/mL, and an effective Zn concentration of 45 mg/mL) and placing on a panel of biological X-ray irradiator, accepting a radiation with X-rays of 4 Gy, 16 Gy and 32 Gy at the same time, and observing different groups for morphological change of nano-particles after irradiating by TEM.
The results are shown in Fig. 3. With an increase of the irradiation dose, there is no obvious change of morphology for Mn;04 alone; for ZIF-8, the irradiation doses of 4 Gy and 16 Gy have no significant effects on the morphology, and under the irradiation dose of 32 Gy, its edges and corners disappear, while its shape becomes rounded, and its surface is notched; whereas for the FA-Mn304@ZIF-8, under the irradiation dose of 4 Gy, the surface of a single particle breaks, under the irradiation doses of 16 Gy and 32
Gy, the structure of ZIF-8 collapses, exposing Mn304 therein. In conclusion, compared with Mn304 or ZIF-8 alone, FA-Mn3;O4@ZIF-8 has better responsiveness to radiation, and can still disintegrate and expose Mn;04 after smaller doses of irradiation. (3) verifying a responsiveness to H,O, and an ability of producing
13 LU503418 oxygen of Mn:04@ZIF-8 nano-system
The following steps are performed: formulating Mn:04@ZIF-8, Mn;O4 and ZIF-8 into water dispersion systems with the same Mn and Zn concentrations (Mn: 45 mg/mL, and Zn: 100 mg/mL), taking 4 mL 0.5% v/v HO, solution, inserting a probe of a portable dissolved oxygen analyzer below the liquid level, after appearing a stable reading, adding 0.5 mL of a nano solution to be tested, monitoring in real time by the portable dissolved oxygen analyzer for a concentration change of the dissolved oxygen in the solution, photographing and recording to evaluate the responsiveness to H,O, and the ability of producing oxygen of the nano-drugs.
The results are shown in Fig. 4. As shown in Fig. 4A and table 1, within 20 min of reaction with 0.5% H,O, solution, the dissolved oxygen for the
ZIF-8 group has no significant change; the dissolved oxygen for the Mn304 group has a slight increase with a slower increasing rate; and the dissolved oxygen for the Mn:04@ZIF-8 group has a rapid increase, reaching a peak value at 15 min, with its uptrend tending to flatten after 15 min, and after 20 min, the dissolved oxygen for the Mn:04(@ZIF-8 group reaches 35.57 mg/L.
It can be intuitively visualized from Fig. 4B that, after 20 min, there are produced lots of large bubbles in the Mn3;O4@ZIF-8 group, while there are only produced a small number of small bubbles or no bubbles in other groups.
The results above show that Mn304@ZIF-8 has better responsiveness to HO», and can release oxygen gas to improve the hypoxic microenvironment of tumor. Meanwhile, compared with Mn304 and ZIF-8 alone, Mn;O4@ZIF-8 has faster and stronger responsiveness to H,O, and the ability of releasing oxygen gas, which is one of the foundations of radiotherapy’s sensitization ability.
14 LU503418
Table 1 Amount of the dissolved oxygen for different time and in different groups (mg/L) ____ MmO@ZIF-84H202 | MmsO,"H202 | ZIF-8+H:0 | 10:
Example 3:
Exploring radiotherapy’s sensitization ability of FA-Mn;O4«@ZIF-8 nano-system on cervical cancer cells (1) an effect of FA-Mn304@ZIF-8 nano-system in combination with radiotherapy on viability of cervical cancer cells
The present invention explores the influence of FA-Mn:04@ZIF-8 nano-system in combination with radiotherapy on viability of cervical cancer cells by MTT experiments: taking cells in the logarithmic growth phase and inoculating at a density of 3x10* cells/mL in a 96-well plate with 100 uL per well, culturing for 24 h and waiting for cells to adhere to the wall, and culturing with DMEM medium. FA-Mn;O4@ZIF-8 (10 mg/L, with a solvent of DMEM medium, 100 uL/per well) and cells are co-incubated for 6 h, then cells are irradiated with X-ray irradiator at 4 Gy. After continuing to be incubated for 72 h, 25 pL of a freshly formulated MTT solution (5 mg/mL) is added in each well, incubating for 4 h. After extracting the upper layer of liquid, 150 uL DMSO is added into each well, and is shaken for 15 min to be fully dissolved. The absorbance of each well at 570 nm (OD570) 1s measured by using a fully automated microplate reader. The cell survival rate is calculated according to the following formula, cell survival rate (%)=(ODs70 for experimental group/OD570 for blank control group)x100%. All is divided
15 LU503418 into four groups, i.e. a group for blank control, a group for radiotherapy alone, a group for FA-Mn:04@ZIF-8 therapy alone and a group for radiotherapy in combination with FA-Mn304@ZIF-8 therapy. At least 3 parallels are set per group.
The results are shown in Fig. 5. From the analysis of the cell survival rate, the groups for radiotherapy alone (86.24+7.03%), FA-Mn304@ZIF-8 alone (65.20+3.64%) and combination therapy (44.53+1.85%) can all significantly inhibit the cell viability of SiHa cells (National Collection of
Authenticated Cell Cultures). At the same time, the cell viability for the combination therapy is significantly lower than those of the groups for therapy alone. The differences are statistically significant (P<0.05). The groups for radiotherapy alone (65.95+18.49%), FA-Mn3;O4@ZIF-8 (55.53+2.60%) alone and combination therapy (41.19 +2.12%) can all significantly inhibit cell viability of C33a cells (American type culture collection, ATCC). At the same time, the cell viability for the combination therapy 1s significantly lower than those of the groups for therapy alone. The differences are statistically significant(P<0.05).
In conclusion, FA-Mn3;O4@ZIF-8 can significantly enhance the inhibitory effect of radiotherapy on the viability of various cervical cancer cells (including SiHa cells and C33a cells). (2) an effect of FA-Mn:04@ZIF-8 nano-system in combination with radiotherapy on an ability for proliferating of cervical cancer cells
The present invention explores the effect of FA-Mn;O4@ZIF-8 nano-system in combination with radiotherapy on the ability for proliferating of cervical cancer cells by clone formation experiments: taking SiHa cells in the logarithmic growth phase and inoculating at a density of 1x10? cells/mL in a 6-well plate, with 2 mL per well, culturing with DMEM medium for 24 h and waiting for cells to adhere to the wall. FA-Mn304@ZIF-8, Mn304@ZIF-8,
16 LU503418
Mn304 and ZIF-8 formulated into drugs with DMEM medium are respectively co-incubated with cells for 6 h according to a set concentration (with an Mn304 concentration of 5 mg/L and a Zn concentration of 11 mg/L), the cells are then irradiated with X-ray irradiator respectively according to the set doses, and the cells are continued to be cultured for 10 to 14 days.
Subsequently, the following steps are performed: sucking the supernatant, rinsing with a phosphate buffer solution having pH of 7.4 and a concentration of 0.01 M for three times, then fixing adherent cells with 4% polyformaldehyde at normal temperature for 15 min, and rinsing with PBS for three times, staining the cells with 0.5% crystal violet solution for 20 min, rinsing with PBS for three times, drying the 6-well plate by air at normal temperature, and then observing and photographing.
The results are shown in Fig. 6. Effects of radiotherapy alone and
FA-Mn:04@ZIF-8 alone on cells can both effectively inhibit a formation of cell clonal colonies. However, a synergistic effect of FA-Mn:04@ZIF-8 and radiotherapy can achieve an effect of better inhibition of cell clone formation.
The above results further prove that FA-Mn304@ZIF-8 in combination with radiotherapy can effectively inhibit the ability for proliferating of cervical cancer cells. (3) an effect of FA-Mn304@ZIF-8 nano-system in combination with radiotherapy on apoptosis of cervical cancer cells
In this study, Annexin V-FITC/PI double staining experiment is adopted to analyze the apoptosis of SiHa cells for cervical cancer, and the following steps are performed: taking SiHa cells in the logarithmic growth phase and inoculating at a density of 3x10* cells/mL in a 6-well plate, with 2 mL per well, culturing for 24 h and waiting for cells to adhere to the wall; co-incubating FA-Mn304(@ZIF-8, Mn304@ZIF-8, Mn304 and ZIF-8 with the cells for 6 hours at the set concentrations (with an Mn304 concentration of 15
17 LU503418 mg/L and a Zn concentration of 33 mg/L), irradiating the cells by the X-ray irradiator respectively according to the set dose (4Gy); continuing to culture for 48 h, then collecting the supernatant, digesting and collecting the cells with free-EDTA trypsin, and washing with pre-chilled PBS at 4 °C for three times. According to the steps of the Annexin V-FITC/PI double staining kit, each sample is resuspended with 500 pL of Binding buffer, then under a dark condition, it 1s stained with Annexin V-FITC and PI at normal temperature for 30 min, and finally, the cell apoptosis rate is analyzed by a flow cytometer.
The results are shown in Fig. 7: the cell apoptosis rate for the group for radiotherapy alone is 11.94%. After combination with FA-Mn304@ZIF-8, the apoptosis rate increases to 85.45%, which 1s higher than those of the group for radiotherapy alone and the group for FA-Mn;O4@ZIF-8 alone. Thus,
FA-Mn:04@ZIF-8 can effectively induce the apoptosis of cervical cancer cells and thereby promote the antitumous effect of radiotherapy.
Example 4:
Exploring radiotherapy’s sensitization ability of FA-Mn304@ZIF-8 nano-system in subcutaneous transplantation tumor model in nude mice
Establishing unilateral subcutaneous tumor-bearing model of female
Balb/c nude mice (purchased from GuangDong YaoKang biotechnology
Company Limited): digesting and collecting human cervical cancer cells SiHa in the logarithmic growth phase with trypsin/EDTA, resuspending the cells to 2x107 cells/mL with DMEM, taking 100 pL of the cell suspension and inoculating it in a right back of nude mice.
Study on radiotherapy sensitization effect in vivo of FA-Mn304@ZIF-8: when the size of the subcutaneous tumor grows to 100 to 150 mm°, randomly dividing the tumor-bearing nude mice into 4 groups with 6 mice per group.
The following steps are performed respectively: for the first group (control
18 LU503418 group), injecting 100 pl. physiological saline by tail vein twice a week; for the second group (radiotherapy group), injecting 100 uL physiological saline by tail vein twice a week, and performing local radiotherapy to the tumor site after 6 h (irradiation dose: 2 Gy); for the third group (FA-Mn;O4@ZIF-8 therapy group), injecting 100 pL. FA-Mn;O4@ZIF-8 (Mn: 5 mg/kg, and Zn: 11 mg/kg) by tail vein twice a week; and for the forth group (FA-Mn:04(@ZIF-8 in combination with radiotherapy group), injecting 100 uL FA-Mn:04(@ZIF-8 (Mn: 5 mg/kg, and Zn: 11 mg/kg) by tail vein twice a week, and performing local radiotherapy to the tumor site after 6 h (irradiation dose: 2 Gy). The treatment period 1s 24 days. Length and width of the tumors are measured with a vernier caliper and the tumor-bearing nude mice are weighed every other day after starting treatment. A calculation formula for a volume of tumor: volume=1/2xlengthxwidth?. After 24 days, the nude mice are euthanized. The tumor of every nude mouse is collected and weighed.
The results are shown in Fig. 8. After treating for 24 days, the volume of tumor FA-Mn;O4@ZIF-8 in combination with radiotherapy group is much less than those for the control group, the FA-Mn304@ZIF-8 group and the radiotherapy group (P<0.05). Meanwhile, the weight of tumor for
FA-Mn:04@ZIF-8 in combination with radiotherapy group is less than those for the control group, the radiotherapy group and the FA-Mn3;O4@ZIF-8 group (P<0.05). The above results suggest that FA-Mn:04@ZIF-8 in combination with radiotherapy has better antitumous ability in vivo. At the same time, the weight of nude mice is detected. Within 24 days of treatment, there are no significant differences in weight between different groups of nude mice, suggesting that the radiotherapy and the FA-Mn:04@ZIF-8 therapy have no significant damage to normal organs of nude mice. It indicates that
FA-Mn:04@ZIF-8 has better biological safety.
19 LU503418
Example 5:
Exploring targeting of FA-MnsO4,@ZIF-8 nano-system in subcutaneous transplantation tumor model in nude mice
Firstly, = nano-systems of FA-ICG@ Mn;O4@ZIF-8 and
ICG@Mn:04@ZIF-8 labeled by Indocyanine green (ICG) are synthesized, and the detailed steps are as follows: weighing 375.6 mg zinc nitrate and dissolving it into 50 mL methanol, weighing 104.7 mg 2-methylimidazole and dissolving it into 50 mL methanol, and adding 0.5 mL Mn304-PVP solution (5 g/l.) and 0.5 mL Indocyanine green solution (5 mg/ml) into the 2-methylimidazole solution, ultrasonic mixing evenly, mixing the above-described two solutions, after standing still for 1 h, centrifuging the mixture at a rotation speed of 12000 rpm to remove excessive unreacted reagents, and washing with methanol for three times at a rotation speed of 12000 rpm each time, to obtain an ICG@Mn304(@ZIF-8; resuspending the
ICG@Mn:04@ZIF-8 precipitate with 5 mL FA-PEG solution, after ultrasonic mixing for 10 min, stirring overnight at room temperature in the dark; subsequently centrifuging the mixture at a rotation speed of 12000 rpm to remove excessive unreacted reagents, and washing with ultrapure water for three times at a rotation speed of 12000 rpm each time, to obtain an
FA-ICG(@Mn304@ZIF-8.
According to the operation in Example 4, when the size of the subcutaneous tumor in nude mice grows to 150 mm?, 6 tumor-bearing nude mice are randomly divided into 2 groups, with 3 mice per group. For one group, FA-ICG@Mn304@ZIF-8 is injected by tail vein; and for another group,
ICG(@Mn:04@ZIF-8 is injected by tail vein (with an Mn concentration of 5 mg/kg and a Zn concentration of 11 mg/kg for both two group). At 0, 2, 4, 8, 12, 24, 48 and 72 hours, nude mice are anesthetized with 4% chloral hydrate
20 LU503418 (400 mg/kg), and a distribution of the drugs in nude mice is observed by a small animal living imaging apparatus.
The results are shown in Fig. 9. As shown in A of Fig. 9, after injecting
FA-ICG@Mn:04@ZIF-8 by tail vein, the nano-material is first distributed throughout the whole body and the liver, and the nano-material begins to accumulate in tumor at 4 hours. At 12 h, it accumulates more at the tumor site.
At 72 h, most of the nano-material 1s metabolized, with a small portion still distributed and accumulating in tumor. As shown in B of Fig. 9, at 72 h, after removing the organs from the body, the liver and the spleen are the organs where the two nano-materials accumulate most. At the same time, some
FA-ICG@Mn304@ZIF-8 still accumulates in tumor, and
ICG@Mn:04@ZIF-8 without modification by folic acid do not accumulates in tumor. The above results suggest that the nano-system modified by folic acid has a better tumor targeting effect in vivo.
The above-described Examples are preferred embodiments of the present invention, but embodiments of the present invention are not limited to the above-described Examples, and any other changes, modifications, substitutions, combinations, and simplifications made without departing from the spirit and the principle of the present invention should all be equivalent replacement modes, and all be contained in the protection scope of the present invention.

Claims (9)

  1. 21 LU503418 CLAIMS
    I. A preparation method for a metal organic framework-wrapped trimanganese tetroxide modified by folic acid, characterized in that, it comprises the following steps: (1) modification for Mn304 D dispersing Mn:O4 with an organic solvent to obtain an Mn;O4 solution; and (2) dispersing or dissolving a surfactant evenly with an organic solvent, adding the Mn;O4 solution obtained in step (D), stirring and reacting; subjecting the obtained mixture to a solid-liquid separation, dispersing the obtained solid evenly with the organic solvent, to obtain a surfactant-modified Mn;0Oy solution; and (2) synthesis for FA-Mn304@ZIF-8 D synthesis for FA-PEG: dissolving folic acid and NaHCOs into water to obtain a folic acid solution; dissolving NHS, EDC and PEG into water to obtain a mixed solution A; mixing the folic acid solution and the mixed solution A to obtain a mixed solution B, stirring and reacting; dialyzing after stopping the reaction to obtain a FA-PEG solution; © synthesis for Mn;O4@ZIF-8: dissolving 2-methylimidazole into an organic solvent to obtain a 2-methylimidazole solution; mixing the 2-methylimidazole solution and the surfactant-modified Mn304 solution obtained in step (1), to obtain a mixed solution C; dissolving zinc nitrate into the organic solvent, to obtain a zinc nitrate solution; mixing the mixed solution C and the zinc nitrate solution to obtain a mixed solution D, standing still and reacting, subjecting to a solid-liquid separation, and washing the obtained solid, to obtain a solid Mn304(@ZIF-8; and
    22 LU503418 © synthesis for FA-Mn;O4@ZIF-8: dispersing the Mn:04@ZIF-8 evenly with the FA-PEG solution, then stirring and reacting overnight to obtain a mixed solution E; subjecting the mixed solution E to a solid-liquid separation, and washing the obtained solid, to obtain a metal organic framework-wrapped trimanganese tetroxide modified by folic acid.
  2. 2. The preparation method for the metal organic framework-wrapped trimanganese tetroxide modified by folic acid according to claim 1, characterized in that: in step (1) ©, the Mn:O4is prepared by the following steps: dispersing or dissolving a manganese source into a solvent A, calcining, cooling down and washing, to obtain Mn3Ou.
  3. 3. The preparation method for the metal organic framework-wrapped trimanganese tetroxide modified by folic acid according to claim 2, characterized in that: the manganese source is organic manganese; the solvent A is at least one of absolute ethanol, water and methanol; the condition for the calcining is reacting in a muffle furnace at 100 to 140 °C for 20 to 30 h; and the washing is washing with absolute ethanol and ultrapure water respectively.
  4. 4. The preparation method for the metal organic framework-wrapped trimanganese tetroxide modified by folic acid according to claim 1, characterized in that: in step (1) OD, the organic solvent is at least one of methanol and absolute ethanol;
    23 LU503418 in step (1) @), the organic solvent is at least one of methanol and absolute ethanol; in step (1) @), the surfactant is polyvinyl pyrrolidone; in step (2) ©, the PEG is at least one of PEG2000 and PEG5000; and in step (2) @), the organic solvent is methanol.
  5. 5. The preparation method for the metal organic framework-wrapped trimanganese tetroxide modified by folic acid according to claim 1, characterized in that: in step (1) (D, an amount of the used organic solvent is calculated in terms of a ratio of Mn:04 to the organic solvent of 0.8 to 1 g :4 mL; in step (1) @, an amount of the used organic solvent is calculated in terms of a ratio of the surfactant to the organic solvent of 10 to 11 mg :1 mL; in step (1) @), an amount of the used surfactant is calculated in terms of a weight ratio of Mn304 to the surfactant of 1 to 1.01:1; in step (2) D), a weight ratio of the folic acid to NaHCO; is 5:3.5 to 4; in step (2) D, a weight ratio of NHS to EDC to PEG in the mixed solution Ais 1:1:1.4 to 1.8; in step (2) D, a weight ratio of the folic acid to PEG in the mixed solution B is 1:3 to 5; in step (2) @), the concentration of the 2-methylimidazole solution is 2 to 2.1 mg/mL; in step (2) ©, a weight ratio of 2-methylimidazole to zinc nitrate to Mn304 in the mixed solution Dis 1 to 1.01:3.5 to 4:1; and in step (2) ©, a weight ratio of FA-PEG to Mn:04@ZIF-8 in the mixed solution E is 1:1.
    24 LU503418
  6. 6. The preparation method for the metal organic framework-wrapped trimanganese tetroxide modified by folic acid according to claim 1, characterized in that: in step (1) @), the time for the stirring and reacting is 10 to 16 h; in step (1) @), the solid-liquid separation is performed by means of centrifuging; in step (2) ©, the time for the stirring and reacting is 10 to 16 h; in step (2) ©, the time for the dialyzing is 12 to 36 h; in step (2) @), the time for the standing still and reacting is 40 to 80 min; in step (2) @), the solid-liquid separation is performed by means of centrifuging; in step (2) ©, the washing is washing with methanol; in step (2) ©, the dispersing is performed by ultrasonic dispersing; and in step (2) ©), the solid-liquid separation is performed by means of centrifuging.
  7. 7. A metal organic framework-wrapped trimanganese tetroxide modified by folic acid, characterized in that: it is prepared by the method according to any one of claims 1 to 6.
  8. 8. An application of the metal organic framework-wrapped trimanganese tetroxide modified by folic acid according to claim 7 in radiotherapy for cancer.
  9. 9. The application according to claim 8, characterized in that: the cancer 1s cervical cancer.
LU503418A 2022-09-21 2023-02-01 Metal organic framework-wrapped trimanganese tetroxide modified by folic acid, preparation method therefor and application thereof LU503418B1 (en)

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