CN115944649A - Immune-enhanced targeted hollow manganese dioxide radiosensitizer as well as preparation method and application thereof - Google Patents
Immune-enhanced targeted hollow manganese dioxide radiosensitizer as well as preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses an immune enhanced targeted hollow manganese dioxide radiotherapy sensitizer and a preparation method and application thereof, belonging to the technical field of tumor treatment. Aiming at the problems of short circulation time and poor targeting of the radiotherapy sensitizer, the invention adopts an engineered extracellular vesicle modification method to improve the circulation time so as to enable the radiotherapy sensitizer to have tumor targeting; aiming at the problem of poor improvement effect of hypoxic microenvironment in the prior art, the invention prepares the hollow MnO by the template self-etching method 2 Improves the catalytic efficiency of over-expression hydrogen peroxide in tumor cells,the cell respiration inhibitory drug metformin is used cooperatively, so that the oxygen consumption of cells is reduced, the hypoxic microenvironment is improved from two aspects, and the radiotherapy sensitization effect is improved; meanwhile, manganese ions generated by reduction of the sensitizer effectively regulate and control the immunosuppressive microenvironment of the tumor, and the natural immune cell activity is enhanced, the immune factors are released, and the metastasis and recurrence of the tumor after radiotherapy are inhibited by activating the cGAS-STING pathway.
Description
Technical Field
The invention belongs to the technical field of tumor treatment, and particularly relates to an immune enhanced targeted hollow manganese dioxide radiation sensitizer as well as a preparation method and application thereof.
Background
Cancer has become the first killer of human health in the 21 st century, and most malignant tumor patients in clinic at present adopt four modes of operation treatment, chemotherapy, radiotherapy and immunotherapy. The radiotherapy has the advantages of wide application range, quick response, no wound and the like, so that more than 50 percent of malignant tumor patients need to receive single or combined radiotherapy clinically. However, since malignant tumor grows rapidly and the oxygen supply to the blood in the tumor tissue is relatively insufficient, the hypoxic microenvironment of the tumor is caused, so that the tumor patient is easy to generate the phenomenon of radiotherapy resistance after a plurality of radiotherapy cycles, and on the other hand, the characteristics of the immunosuppressive microenvironment of the tumor tissue cause the residual tumor cells to be easy to transfer and relapse after radiotherapy. According to survey, more than 90% of cancer patients die from metastasis and recurrence after treatment, so how to improve tumor hypoxia microenvironment and immunosuppression microenvironment becomes a key for improving the effect of radiotherapy.
The appearance of the radiotherapy sensitizer brings about eosin for improving tumor hypoxia microenvironment and solving the problem of radiotherapy resistance, and the radiotherapy sensitizer can be divided into three categories according to the structure: small molecule radiotherapy sensitizer, macromolecular radiotherapy sensitizer and nano material radiotherapy sensitizer. The nano material sensitizer has the advantages of high sensitization efficiency, easy functional modification, stable structure, controllability and capability of being combined with other cancer therapies for cooperative treatment, so that the nano material sensitizer has huge potential in tumor radiotherapy sensitization.
In recent years, manganese dioxide (MnO) 2 ) Has attracted wide attention as a tumor microenvironment response type radiotherapy sensitizer. Research shows that MnO is 2 Can catalyze excessive hydrogen peroxide in tumor cells to generate oxygen, thereby improving tumor hypoxia microenvironment and improving radiotherapy effect; in addition, mnO 2 And the Mn ions can be reduced by GSH over-expressed by tumor cells to generate Mn ions, so that the immunosuppression microenvironment of the tumor is effectively regulated and controlled, the host autoimmune system is activated, and the metastasis and recurrence of the tumor after radiotherapy are inhibited.
At present, there are reports in the literature based on MnO 2 The nanocomposites of (a) are used in the treatment of cancer, but have several disadvantages: (1) MnO 2 The catalytic efficiency is low and the oxygen generated by unilateral catalysis is easily consumed by the respiration of tumor cells. (2) MnO 2 Short circulation time and poor targeting property. (3) MnO not investigated 2 Potential anti-metastatic relapse capacity. The preparation of a radiosensitizer which has long circulation time, can target tumor cells, can simultaneously increase the generation of oxygen in the tumor cells and reduce the consumption of the oxygen, thereby realizing the radiosensitization of the cancer and resisting the metastasis and the relapse of the tumor has not been reported.
Disclosure of Invention
One of the purposes of the invention is to provide a preparation method of an immune enhanced targeted hollow manganese dioxide radiosensitizer, which comprises the following steps:
step 1A) reacting Zn (NO) 3 ) 2 ·6(H 2 O) methanol solution (293.4 mgZn (NO) 3 ) 2 ·6(H 2 O) into 20mL of methanol solution) into 2-methylimidazole in methanol solution (649 mg of 2-methylimidazole into 20mL of methanol solution), stirred for 1 hour, then centrifuged at 10000 × rpm for 5 minutes at room temperature, washed 3 times with methanol (10000 × rpm for 5 minutes), to obtain ZIF-8 nanoparticles.
Step 1B) the ZIF-8 nanoparticles obtained in step 1A) were dispersed in 15mL of methanol, and 20mL of Tris-HCl (10 mmol mL) was added -1 And pH = 8.5), then adding dopamine under stirring, stirring for 8 hours, centrifuging at room temperature, and washing with methanol to obtain ZIF-8@ PDA nanoparticles;
step 1C) the ZIF-8@ PDA obtained in step 1B) was dispersed in 15mL of water, and 8.25mL of KMnO was added dropwise with stirring 4 Performing oxidation-reduction reaction on the aqueous solution, stirring for 5 min, centrifuging at room temperature, washing with water, and suspending in ultrapure water under illumination for 24 hrTo obtain hollow MnO 2 I.e. HollowMnO 2 (HMn) nanoparticles, the resulting HMn solution was centrifuged at room temperature and washed with water, dried under vacuum to obtain HMn powder, which was then resuspended in ultrapure water to prepare 2mgmL -1 The stock solution of (1).
Step 2A) keeping mouse macrophages at 37 ℃,5% 2 In a cell incubator, cells were cultured in DMEM medium containing 10% FBS and 1% penicillin-streptomycin, and when the cell density reached about 60-80%, the cells were washed with PBS and incubated with the medium without FBS for 12 hours;
step 2B) collecting the cell culture fluid, centrifuging the collected cell culture fluid to remove sediment and cells, centrifuging the collected supernatant at 1000 Xg for 10 minutes to remove apoptotic bodies and debris, centrifuging the supernatant again at 10000 Xg for 30 minutes to remove larger microvesicles, passing the supernatant through a 0.22 μm filter to further remove residual microvesicles, collecting the supernatant, centrifuging the supernatant at 100000 Xg for 2 hours to obtain Extracellular Vesicles (EVs), quantifying the extracellular vesicles using a Nanoparticle Tracking Analyzer (NTA), and preparing the extracellular vesicles at a concentration of 1X 10 13 Each mL -1 The engineered extracellular vesicles (EVs-RGD) are in the range of 1X 10 13 One mL -1 EVs and 40-60 μ gmL -1 Distearoylphosphatidylethanolamine-polyethylene glycol-arginyl-glycyl-aspartic acid (DSPE-PEG-RGD) was synthesized at a molar ratio of 2:1 for 24 hours after co-incubation;
step 3A) 2mgmL obtained in step 1C -1 5mL of the HMn nanoparticle aqueous solution was added to 5mL of the metformin aqueous solution (10 mgmL) -1 ) After being mixed uniformly, the mixture is stirred for 24 hours at room temperature under the dark condition and is washed by water for three times to obtain the HollowMnO 2 @ Met (HMn @ Met) aqueous solution; then, the aqueous solution of HMn @ Met was dried under vacuum to obtain HMn @ Met powder, which was then resuspended in ultrapure water to prepare 1mgmL -1 The stock solution of (1);
step 3B) mixing the EVs-RGD PBS solution obtained in step 2B) with prepared 1mgmL -1 Hmn @ met aqueous solution as per 1:1, co-incubating for 24 hours, and extruding through a 0.22 mu m membrane to obtain Hollow MnO 2 @ Met @ EVs-RGD (HMnER @ Met) solution.
Preferably, the amount of dopamine added in step 1B) is 100mg.
More preferably, the method is characterized in that KMnO in the step 1C) 4 The concentration of the aqueous solution is 5mgmL -1 。
More preferably, the concentration of DSPE-PEG-RGD in the step 2B) is 50 μ gmL -1 。
More preferably, the HollowMnO in the step 1C) 2 (HMn) has a particle size of 40-60nm.
The second purpose of the invention is to provide the immune enhanced targeted hollow manganese dioxide radiation sensitizer prepared by the preparation method.
The invention also aims to provide the application of the immune enhanced targeted hollow manganese dioxide radiosensitizer in the preparation of radiosensitizing drugs.
Compared with the prior art, the invention has the following beneficial effects:
(1) The HMn of the invention loads the medicine metformin for treating diabetes, the metformin can obviously inhibit the mitochondrial respiration process and reduce the intracellular oxygen consumption rate, and the HMn catalyzes H 2 O 2 Production of O 2 The functions of the two parts are coordinated, and the tumor hypoxia microenvironment is greatly improved in an open source throttling mode; in addition, the metformin can block the tumor cell cycle in the G2-M stage, and also has a remarkable improvement effect on radiotherapy sensitization.
(2) In the invention, the HMn @ Met coats the engineered macrophage-derived EVs outside, and the targeting and long-circulating capabilities are endowed.
(3) In the invention, mn ions generated by reducing HMn by GSH can effectively regulate and control the immunosuppressive microenvironment of tumors, activate a cGAS-STING pathway, enhance the activity of natural immunocytes, release immune factors and inhibit the metastasis and recurrence of tumors after radiotherapy.
Drawings
Fig. 1 is a technical route diagram of the present invention.
FIG. 2 is a TEM representation of the particle size at various stages of HMnER in test example 1.
FIG. 3 is a graph representing the average hydrated particle size at each stage of HMnER in Experimental example 1.
FIG. 4 is a Zeta potential characterization chart for each stage of HMnER in Experimental example 1.
FIG. 5 shows the results of stability analysis of HMnER in test example 1.
FIG. 6 is a graph showing the results of the sensitization therapy of HMnER @ Met to tumors in Experimental example 2, wherein 6 (A) is a therapeutic schedule, 6 (B) is a graph showing tumors after 8 groups of treatments, 6 (C) is a mouse weight change curve, and 6 (D) is a mouse tumor volume change curve.
FIG. 7 is the results of evaluating the efficacy of HMnER @ Met in the treatment of recurrence resistance and pulmonary metastasis in vivo in test example 3, wherein 7 (A) is a graph of a recurrence-metastasis resistant protocol, 7 (B) is a graph of two groups of induced tumors, 7 (C) is a graph of a comparison of tumor weights in two groups, 7 (D) is a graph of lungs in two groups, and 7 (E) is a graph of a comparison of lung weights in two groups of mice.
Detailed Description
Example 1
The embodiment provides a preparation method of an immune enhanced targeted cooperative radiotherapy sensitizer, which comprises the following steps:
step 1A) reacting Zn (NO) 3 ) 2 ·6(H 2 O) methanol solution (293.4 mgZn (NO) 3 ) 2 ·6(H 2 O) into 20mL of methanol solution) into 2-methylimidazole in methanol solution (649 mg of 2-methylimidazole into 20mL of methanol solution), stirred for 1 hour, then centrifuged at 10000 × rpm for 5 minutes at room temperature, washed 3 times with methanol (10000 × rpm for 5 minutes), to obtain ZIF-8 nanoparticles;
step 1B) the ZIF-8 nanoparticles obtained in step 1A) were dispersed in 15mL of methanol, and 20mL of Tris-HCl (10 mmol mL) was added -1 pH = 8.5), then adding 100mg of dopamine under stirring, stirring for 8 hours, centrifuging at room temperature, and washing with methanol to obtain ZIF-8@ PDA nanoparticles;
step 1C) the ZIF-8@ PDA obtained in step 1B) was dispersed in 15mL of water, and 8.25mL of KMnO was added dropwise with stirring 4 (5mgmL -1 ) Performing oxidation-reduction reaction on the aqueous solution, stirring for 5 minutes, centrifuging at room temperature, washing with water, suspending in ultrapure water under the condition of illumination for 24 hours to obtain hollow MnO 2 I.e. HollowMnO 2 (HMn) nanoparticles, the resulting HMn solution was centrifuged at room temperature and washed with water, dried under vacuum to obtain HMn powder, which was then resuspended in ultrapure water to prepare 1mgmL -1 The stock solution of (1).
Step 2A) maintenance of mouse macrophages at 37 ℃,5% CO 2 In a cell incubator, cells were cultured in DMEM medium containing 10% FBS and 1% penicillin-streptomycin, and when the cell density reached about 70%, the cells were washed with PBS and incubated with the medium without FBS for 12 hours;
step 2B) collecting the cell culture fluid to remove the pellet and the cells by centrifugation at 300 Xg for 10 minutes, centrifuging the collected supernatant at 1000 Xg for 10 minutes to remove apoptotic bodies and debris, and centrifuging the supernatant again at 10000 Xg for 30 minutes to remove larger microvesicles, passing the supernatant through a 0.22 μm filter to further remove residual microvesicles, then collecting the supernatant, centrifuging at 100000 Xg for 2 hours to obtain Extracellular Vesicles (EVs), and configuring to have a concentration of 1X 10 after quantification using a Nanoparticle Tracking Analyzer (NTA) 13 Each mL -1 The EVs solution of (4), the engineered extracellular vesicles (EVs-RGD) is at 1X 10 13 Each mL - 1 EVs and 50. Mu.gmL -1 Distearoylphosphatidylethanolamine-polyethylene glycol-arginyl-glycyl-aspartic acid (DSPE-PEG-RGD) was synthesized at a molar ratio of 2:1, the molecular weight of PEG in DSPE-PEG-RGD is 2000;
step 3A) the EVs-RGD PBS solution obtained in step 2B) and the prepared HMn aqueous solution (1 mgmL) -1 ) According to the following steps of 1:1, incubating for 24 hours, and extruding through a 0.22 mu m membrane to obtain Hollow MnO 2 @ EVs-RGD, HMnER solution.
Test example 1
This experimental example performed a correlation performance test on HMnER prepared in example 1:
1) The HMnER prepared in example 1 was characterized by Transmission Electron Microscopy (TEM) and shown in FIG. 2, wherein A, B, C and D in FIG. 2 represent ZIF-8, ZIF-8@ PDA, HMn, HMnER and HMnER, respectively, and the particle size was about 100 nm.
2) The particle size of HMnER prepared in example 1 was characterized by Dynamic Light Scattering (DLS), and the results are shown in FIG. 3, in which A, B, C, and D in FIG. 3 represent ZIF-8, ZIF-8@ PDA, HMn, HMnER, and HMnER, respectively, and the average hydrated particle size was 142nm.
3) The Zeta potential of the HMnER prepared in example 1 was characterized by Dynamic Light Scattering (DLS) and was-35.3 mV as shown in FIG. 4.
4) The stability analysis of HMnER prepared in example 1 was performed at each stage, and as a result, 40. Mu.gmL of each medium was added as shown in FIG. 5 -1 The particle size of the HMnER of (1) was kept constant after 7 days at room temperature.
Test example 2
The experimental example evaluates the tumor inhibition effect of the radiotherapy sensitizer in vivo, and the method comprises the following steps: tumors were inoculated into the right thigh groin of BALB/cA-nu nude mice, each mouse was inoculated with MCF-7 cells until the tumor volume reached 100mm 3 The treatment is started. MCF-7 tumor-bearing mice were randomly divided into 8 groups (each group n = 3) Control, met, HMnER @ Met, RT (radiotherapy), met + RT, HMnER @ Met + RT. The composite material is injected into vein four times, each time 200 mu L1 mg mL -1 Once every other day. Radiotherapy-associated groups received radiotherapy (5 Gy) on day 2 post-injection, and tumor volume and mouse body weight were measured every 2 days. Tumor volume was calculated as volume = (tumor length) × (tumor width) 2/2. FIG. 6 (A) is a therapeutic schedule, FIG. 6 (B) is a graph of tumors after 8 groups of treatment, FIG. 6 (C) is a graph of mouse body weight change, and FIG. 6 (D) is a graph of mouse tumor volume change. The tumor growth of the mice treated by the radiotherapy sensitizer of the invention combined with radiotherapy is obviously inhibited, and the obvious difference with that of a single radiotherapy group shows that the composite nano-particles have good radiotherapy sensitization effect.
Test example 3
This test example evaluates the therapeutic effects of the radiosensitizers prepared in example 1 on in vivo recurrence resistance and pulmonary metastasis by the following methods: firstly, two groups are set, a control group and a treatment group are respectively injected with tumor cells, after induced to be tumorous, the control group adopts a PBS + RT mode for treatment, and the treatment group adopts an HMnER @ Met + RT mode for treatmentBy the fifth day after the tumors of both groups were completely eliminated, the anti-recurrence and metastasis effects were evaluated by examining MCF-7 tumor cells (5X 10) 6 Individual cells) were suspended in 0.1mL of PBS and injected subcutaneously into the right hind limb of each mouse on day 5 after completion of treatment in the control and treatment groups, to induce recurrent tumors. The size of the recurrent tumor was observed on day 21, and the volume of the recurrent tumor in the treatment group was significantly smaller than that in the control group.
For the anti-metastatic model, MCF-7 tumor cells (1X 10) were treated on day 5 after completion of the treatment in the control and treatment groups 6 Individual cells) were injected into mice of the control group and the treatment group via tail vein. On day 21 after intravenous injection, lungs of the mice were removed and body weights of the lungs were recorded. The lungs of the control group showed a large number of metastatic cancer plaques, no significant lung metastasis was observed in the treated group and lung significance was significantly lower than that of the control group. FIG. 7 (A) is a graph of the anti-recurrent metastasis regimen, FIG. 7 (B) is a graph of two groups of induced tumors, FIG. 7 (C) is a graph of tumor weight comparison of two groups, FIG. 7 (D) is a graph of lung weight comparison of two groups, and FIG. 7 (E) is a graph of lung weight comparison of two groups of mice. The radiotherapy sensitizer can enhance the immune response in vivo, and can obviously inhibit the recurrence and metastasis of tumors compared with a control group.
The above-described embodiments are merely illustrative of the preferred embodiments of the present invention, and do not limit the scope of the present invention, and various modifications and improvements of the technical solutions of the present invention can be made by those skilled in the art without departing from the spirit of the present invention, and the technical solutions of the present invention are within the scope of the present invention defined by the claims.
Claims (7)
1. The preparation method of the immune enhanced targeted hollow manganese dioxide radiosensitizer is characterized by comprising the following steps:
step 1A) reacting Zn (NO) 3 ) 2 ·6(H 2 O) into a methanol solution of 2-methylimidazole, stirring for 1 hour, then centrifuging for 5 minutes at room temperature at 10000 × rpm, and washing with methanol for 3 times to obtain ZIF-8 nanoparticles; said Zn (NO) 3 ) 2 ·6(H 2 O) in methanol was 293.4mgZn (N)O 3 ) 2 ·6(H 2 O) is poured into 20mL of methanol solution; the methanol solution of the 2-methylimidazole is prepared by pouring 649mg of 2-methylimidazole into 20mL of methanol solution;
step 1B) dispersing the ZIF-8 nanoparticles obtained in step 1A) in 15mL of methanol, and adding 20mL of 10mmol mL -1 Adding dopamine under the stirring condition, stirring for 8 hours, centrifuging at room temperature, and washing with methanol to obtain ZIF-8@ PDA nanoparticles, wherein the pH is =8.5 Tris-HCl;
step 1C) the ZIF-8@ PDA obtained in step 1B) was dispersed in 15mL of water, and 8.25mL of KMnO was added dropwise with stirring 4 Performing oxidation-reduction reaction on the aqueous solution, stirring for 5 minutes, centrifuging at room temperature, washing with water, suspending in ultrapure water under the condition of illumination for 24 hours to obtain hollow MnO 2 I.e. HollowMnO 2 (HMn) nanoparticles, the resulting HMn solution was centrifuged at room temperature and washed with water, dried under vacuum to obtain HMn powder, which was then resuspended in ultrapure water to prepare 2mgmL -1 The stock solution of (1);
step 2A) keeping mouse macrophages at 37 ℃,5% 2 In a cell incubator, cells were cultured in DMEM medium containing 10% FBS and 1% penicillin-streptomycin, and when the cell density reached about 60-80%, the cells were washed with PBS and incubated with the FBS-free medium for 12 hours;
step 2B) collecting the cell culture fluid, centrifuging to remove the sediment and the cells, centrifuging the collected supernatant at 1000 Xg for 10 minutes to remove apoptotic bodies and debris, centrifuging the supernatant again at 10000 Xg for 30 minutes to remove large microvesicles, passing the supernatant through a 0.22 μm filter to further remove residual microvesicles, collecting the supernatant, centrifuging at 100000 Xg for 2 hours to obtain extracellular vesicle EVs at a concentration of 1X 10 13 One mL -1 The EVs solution of (1) is that the EVs-RGD of the engineered extracellular vesicles is 1X 10 13 One mL -1 EVs and 40-60. Mu.g mL -1 Distearoyl phosphatidylethanolamine-polyethylene glycol-arginyl-glycyl-aspartic acid DSPE-PEG-RGD was reacted with a mixture of 2:1 for 24 hours after co-incubation;
step 3A) obtained by step 1C2mg mL of -1 5mL of HMn nanoparticle aqueous solution was added to 5mL, 10mg mL -1 Uniformly mixing the mixture in the metformin aqueous solution, stirring the mixture for 24 hours at room temperature under the dark condition, and washing the mixture for three times by using water to obtain Hollow MnO 2 @ Met, i.e., an aqueous solution of HMn @ Met; then, the aqueous solution of HMn @ Met was dried under vacuum to obtain HMn @ Met powder, which was then resuspended in ultrapure water to prepare 1mgmL -1 The stock solution of (1);
step 3B) mixing the EVs-RGD PBS solution obtained in step 2B) with prepared 1mg mL -1 Hmn @ met aqueous solution as per 1:1, co-incubating for 24 hours, and extruding through a 0.22 mu m membrane to obtain Hollow MnO 2 @ Met @ EVs-RGD, i.e., HMnER @ Met solution.
2. The method for preparing the immune-enhanced targeted hollow manganese dioxide radiosensitizer according to claim 1, wherein the amount of dopamine added in step 1B) is 100mg.
3. The preparation method of the immune-enhanced targeted hollow manganese dioxide radiosensitizer according to claim 2, wherein KMnO is used in the step 1C) 4 The concentration of the aqueous solution was 5mg mL -1 。
4. The method for preparing the immune-enhanced targeted hollow manganese dioxide radiosensitizer according to claim 3, wherein the concentration of DSPE-PEG-RGD in the step 2B) is 50 μ g mL -1 。
5. The preparation method of the immune-enhanced targeted hollow manganese dioxide radiosensitizer according to claim 4, wherein the particle size of HMn in the step 1C) is 40-60nm.
6. The immune enhanced targeted hollow manganese dioxide radiosensitizer prepared by the preparation method of any one of claims 1 to 5.
7. The use of the immune-enhanced targeted hollow manganese dioxide radiosensitizer of claim 6 in the preparation of a radiosensitizing drug.
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| CN117138055B (en) * | 2023-06-02 | 2024-04-16 | 中山大学附属第一医院 | Double-carrier doxorubicin drug-loaded nano material and preparation method thereof |
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