CN113975291A - Iron death inducer and preparation method and application thereof - Google Patents

Iron death inducer and preparation method and application thereof Download PDF

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CN113975291A
CN113975291A CN202111254923.6A CN202111254923A CN113975291A CN 113975291 A CN113975291 A CN 113975291A CN 202111254923 A CN202111254923 A CN 202111254923A CN 113975291 A CN113975291 A CN 113975291A
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张鹏飞
于兴华
蔡林涛
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Shenzhen Institute of Advanced Technology of CAS
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Abstract

The invention provides an iron death inducer and a preparation method and application thereof. The iron death inducer provided by the invention comprises vermiculite nanosheets, wherein the thickness of the vermiculite nanosheets is 1.0-1.3nm, the length is 305-335nm, and the width is 305-335 nm. The iron death inducer provided by the invention has good biocompatibility and strong cancer cell killing effect, can be used for synthesizing tumor treatment medicines, and has good application prospect.

Description

Iron death inducer and preparation method and application thereof
Technical Field
The invention belongs to the technical field of preparation of antitumor drugs, and particularly relates to an iron death inducer as well as a preparation method and application thereof.
Background
With the increasing morbidity and mortality, cancer has become a significant global public health problem. At present, the main treatment modes of cancer comprise surgery, chemotherapy, radiotherapy, immunotherapy and the like, but the common treatment modes also have some defects, such as easy recurrence of the surgery, unsatisfactory radiotherapy effect caused by the problem of radiation resistance of the radiotherapy, and serious side effect caused by poor drug selectivity of the chemotherapy. Therefore, new cancer treatment modalities such as biotherapy are also emerging to solve the problems of the prior art.
Iron death is a novel programmed cell death mode that leads to cell death by the accumulation of iron-dependent lipid peroxides, first proposed in 2012 by the teaching of Brent r. Recent studies have shown that induction of iron death can be useful in cancer therapy, particularly in eradication of aggressive malignancies that are resistant to traditional therapies. With the development of nano biotechnology, iron death-based anticancer nano-drugs have also made important progress, and are mainly divided into two major categories, namely iron-based nano-materials and non-iron-based nano-materials.
The iron-based nano material can enrich iron ions in cells and accelerate Fenton (Fenton) reaction, so that the level of Reactive Oxygen Species (ROS) in the cells is improved, and iron death is induced. The cisplatin-loaded iron oxide nano prodrug (FePt NP2) constructed by Ma and the like can release cisplatin and Fe at specific parts of tumors2+/Fe3+And Fenton reaction is generated in situ, so that the ROS level in the cells is obviously improved, the death of tumor cells by iron is induced, and the anticancer activity is enhanced. Pu et al reported iron-chelating semiconductor multi-composite nanoparticles (spfens) combined photothermal therapy with iron-death therapy to enhance cancer treatment. However, iron-based nanomaterials such as cisplatin-loaded iron oxide nanoprecursors and iron-chelating semiconductor multi-composite nanoparticles enhance the anti-tumor effect by inducing the iron death effect, but often need to use a higher iron dose or be used in combination with other treatment modes, so that the iron-based nanomaterials have complex nanostructures and multi-metal components, and are low in biological safety.
The non-iron-based nano material can inhibit glutathione peroxidase (GPX4) or induce iron death by exogenously regulating and increasing the degree of lipid peroxidation of tumor cells. Gao et al use amphiphilic polymer micelles to deliver GPX4 inhibitor RSL3, and synergistically induce iron death to reverse multidrug resistance through GPX4 inhibition, Glutathione (GSH) attenuation and lipid peroxidation. The arginine-rich manganese-silicon nanobubble prepared by Wang and the like can be used as an iron death inducer to realize tumor targeted diagnosis and treatment through intracellular GSH depletion. However, the polymer micelle encapsulating the small-molecule iron death inducer and the amorphous calcium carbonate composite nano-drug disclosed in the prior art can effectively reverse drug resistance by inducing iron death or further kill tumor cells by combined chemotherapy, but have the risks of drug leakage and toxic and side effects. The manganese-silicon nanobubbles with GSH consumption capability can realize diagnosis and treatment of tumors at the same time, but only can be used for tumor cells with arginine succinate synthetase deficiency, and have no universality for the tumor cells. In addition, the residual nano-materials in the body may have a risk of long-term toxicity, etc.
Therefore, the research and development of the ultrathin vermiculite nanosheet which has universality for tumor cells and no cytotoxicity risk for inducing iron death has a good application prospect and wide applicability.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention provides an iron death inducer and a preparation method and application thereof. The iron death inducers provided by the invention, once taken up by hypoxic tumor cells, redox couple (Fe)2+/Fe3+) Formation of OH and O by disproportionation of hydrogen peroxide and Fenton reaction2And oxygen can be supplemented automatically. In addition, the iron death inducer of the present invention can regulate Tumor Microenvironment (TME) by consuming glutathione, which can induce iron droop of tumor cells, thus being suitable for preparing iron death-based anticancer nano-drugs.
The method is realized by the following technical scheme:
an iron death inducer comprising vermiculite nanoplates.
Further, the thickness of the vermiculite nanosheet is 1.0-1.3 nm.
Further, the length of the vermiculite nanosheet is 305-335 nm.
Further, the width of the vermiculite nanosheet is 305-335 nm.
The invention also provides a preparation method of the iron death inducer, which comprises the steps of obtaining vermiculite nanosheets; the vermiculite nanosheets are obtained by adding vermiculite into an alkali metal ion salt solution for intercalation treatment and stripping; wherein 0.1-10 mol/L alkali metal salt modifier is added per mg vermiculite. If the concentration of the alkali metal salt modifier added is less than 0.1 mol per liter per mg of vermiculite, the thickness of the vermiculite sheet obtained becomes thicker; if the concentration of alkali metal modifier is higher than 10 moles per liter, a longer washing time is required to wash the alkali metal modifier away.
The specific preparation method of the vermiculite nanosheet comprises the following steps:
s1: adding vermiculite into an alkali metal salt solution modifier to expand the vermiculite;
s2: separating after expansion, and collecting upper layer colloidal slurry;
s3: and carrying out ultrasonic treatment on the upper layer colloidal slurry, and stripping to obtain the vermiculite nanosheet.
Preferably, the alkali metal salt solution modifier is one or more of a lithium salt solution, a potassium salt solution or a sodium salt solution.
More preferably, the alkali metal salt solution modifier is one or more of a lithium chloride solution, a lithium ethylenediaminetetraacetate solution or a lithium citrate solution. Compared with the vermiculite obtained by a thermal expansion or hydrogen peroxide expansion physical method, the chemically-expanded vermiculite obtained by treatment with the lithium salt modifier can be completely peeled off and has a thinner thickness. The modifier of lithium ethylene diamine tetraacetate and lithium citrate has the best effect on the expansion of vermiculite, so that the order degree of vermiculite-phlogopite mixed layer minerals, phlogopite and other crystals in the vermiculite can be reduced, and the vermiculite can be stripped more completely.
Further, the step S1 is performed under the condition of reflux heating at the temperature of 80-90 ℃ for 24-36 h.
Further, in step S3, the duration of the ultrasonic treatment is 0.3-0.6 h.
The invention also provides application of the iron death inducer as an anti-tumor medicament in regulating tumor microenvironment.
The beneficial effects of the invention include:
the iron death inducer provided by the invention has good biocompatibility and strong cancer cell killing effect, can be used for synthesizing tumor treatment medicines, and has good application prospect.
Drawings
In order to more clearly illustrate the technical solutions in the embodiments of the present application, the drawings needed to be used in the description of the embodiments are briefly introduced below, and it is obvious that the drawings in the following description are only some embodiments of the present application, and it is obvious for those skilled in the art to obtain other drawings based on these drawings without creative efforts.
FIG. 1 shows a difference H2O2Absorption spectrum of TMB at concentration;
FIG. 2 shows a difference H2O2Absorbance change at 650nm at concentration;
FIG. 3 is a graph of the absorption spectrum of DTNB at different GSH concentrations;
FIG. 4 is a graph of the change in absorbance at 412nm for different GSH concentrations;
FIG. 5 shows the results of the intracellular iron content measurement of MC38 in example 4;
FIG. 6 shows the results of intracellular GPX4 activity assay of MC38 of example 5;
FIG. 7 shows the results of tumor tissue analysis in example 6.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
An iron death inducer comprising vermiculite nanoplates. The vermiculite nanosheet is obtained by adding vermiculite into an alkali metal ion salt solution for intercalation treatment and stripping, wherein 0.1-10 mol/L of alkali metal salt modifier is added into each milligram of vermiculite. The thickness of the vermiculite nano sheet is 1.0nm, the length is 310nm, and the width is 315 nm.
The preparation method comprises the following steps:
s1: adding 50mg of commercial vermiculite powder into 5 mol/L lithium chloride solution, heating under reflux at 80 deg.C for 24 hr, and performing intercalation treatment to make it expand;
s2: after the swelling is finished, centrifuging at the rotating speed of 3000rpm for 20 minutes, and collecting the upper layer colloidal slurry;
s3: and (4) carrying out ultrasonic treatment on the upper layer colloidal slurry for multiple times, wherein the ultrasonic treatment time is 0.5h, and stripping to obtain the vermiculite nanosheet.
The iron death inducer provided by the embodiment can be used as an anti-tumor drug for regulating the tumor microenvironment and realizing the anti-tumor effect.
Example 2
An iron death inducer comprising vermiculite nanoplates. The vermiculite nanosheet is obtained by adding vermiculite into an alkali metal ion salt solution for intercalation treatment, wherein 0.1-10 mol/L of alkali metal salt modifier is added into each mg of vermiculite. The thickness of the vermiculite nano-sheet is 1.2nm, the length is 305nm, and the width is 335 nm.
The preparation method comprises the following steps:
s1: adding 50mg of commercial vermiculite powder into 100 mol/L of lithium ethylenediamine tetraacetate solution, refluxing and heating at 85 ℃ for 24h, and performing intercalation treatment on the vermiculite powder to expand the vermiculite powder;
s2: after the expansion is finished, centrifuging at 3500rpm for 30 minutes, and collecting the upper layer colloidal slurry;
s3: and (4) carrying out ultrasonic treatment on the upper layer colloidal slurry for multiple times, wherein the ultrasonic treatment time is 0.3h, and stripping to obtain the vermiculite nanosheet.
The iron death inducer provided by the embodiment can be used as an anti-tumor drug for regulating the tumor microenvironment and realizing the anti-tumor effect.
Example 3
The iron death inducer comprises vermiculite nanosheets, wherein the vermiculite nanosheets are obtained by adding vermiculite into an alkali metal ion salt solution for intercalation treatment and stripping, wherein XX mol of alkali metal salt modifier is added into each mg of vermiculite. The thickness of the vermiculite nano-sheet is 1.3nm, the length is 335nm, and the width is 305 nm.
The preparation method comprises the following steps:
s1: adding 50mg of commercial vermiculite powder into 500 mol/L lithium citrate solution, heating under reflux at 90 deg.C for 32h, and performing intercalation treatment to the vermiculite powder to make it expand;
s2: after the swelling is finished, centrifuging at the rotating speed of 3000rpm for 25 minutes, and collecting the upper layer colloidal slurry;
s3: and (4) carrying out ultrasonic treatment on the upper layer colloidal slurry for multiple times, wherein the ultrasonic treatment time is 0.6h, and stripping to obtain the vermiculite nanosheet.
The iron death inducer provided by the embodiment can be used as an anti-tumor drug for regulating the tumor microenvironment and realizing the anti-tumor effect.
Experimental example 1 evaluation of peroxidase mimic Activity of vermiculite nanosheets
Degrading H vermiculite nano-sheets (NSs) in PBS (phosphate buffer solution) at 37 ℃ and pH 6.5 by using 3,3', 5,5' -Tetramethylbenzidine (TMB) as a dyeing indicator2O2The peroxidase mimic activity evaluation of (4).
The detection principle is as follows: the vermiculite nanosheet acts as peroxidase, catalyzes TMB to generate a soluble blue product, and simultaneously reacts H2O2Catalytic formation of H2The blue product of O, TMB can typically be measured for absorbance at 620-650 nm.
Figure BDA0003323557560000071
TMB solution (100. mu.g/mL) with H2O2(0, 1, 2.5, 5, 10 and 30mM) were mixed. NSs (200. mu.g/mL) was added and reacted at 37 ℃ for 15 minutes for steady state kinetic analysis. For this, the absorbance peak was collected and plotted as H2O2And (4) concentration graph. Moreover, using ∈ 39000M-1cm-1Linear Lineweaver-Burk on oxTMBPlotted to determine Km and Vmax.
Results referring to FIGS. 1 and 2, in FIG. 1, reference numerals 1 to 6 denote H, respectively2O2Absorbance results for test groups at concentrations of 30mM, 10mM, 5mM, 2.5mM, 1mM, 0 mM. The OH generated by the degradation of hydrogen peroxide catalyzed by vermiculite nanosheets can oxidize TMB, presents blue oxTMB, has Km and maximum reaction speed (Vmax) of 3.4mM and 7.97X 10 by plotting substrate concentration and reaction rate calculations of absorbance at 650nm and fitting to Michaelis-Menton kinetic analysis-8Ms-1The enzyme activity of the vermiculite nanosheet is proved to be comparable to peroxidase mimic enzyme in the prior art.
Experimental example 2 evaluation of glutathione oxidase mimic Activity of vermiculite nanosheets
Evaluation of activity of glutathione oxidase simulation of vermiculite nanosheets the activity of glutathione oxidase simulation of vermiculite nanosheets was evaluated using 5' -dithiobis (2-nitrobenzoic acid) (DTNB) as an indicator and Glutathione (GSH) as a substrate.
The detection mechanism is as follows: the vermiculite nano-sheets play a role of glutathione oxidase, and DTNB will appear yellow when glutathione GSH is oxidized.
Figure BDA0003323557560000072
DTNB was mixed with GSH (0,0.0625,0.125,0.25,0.5 and 1mM) in DMSO (300. mu.g/mL). NSs (200. mu.g/mL) was added and reacted at 37 ℃ for 5 minutes for steady state kinetic analysis. Absorbance was collected for 0-15 minutes and a glutathione concentration chart was drawn. In addition, epsilon using TNB is 13600M-1cm-1Linear Lineweaver-Burk mapping was performed to determine Km and Vmax.
The results are shown in FIGS. 3 and 4, and in FIG. 3, reference numerals 1 to 6 represent the results of absorbance in the test groups at GSH concentrations of 0mM, 0.0625mM, 0.125mM, 0.25mM, 0.5mM, and 1mM, respectively. Km and maximum reaction velocity (Vmax) were 1.34mM and 1.35X 10 by plotting substrate concentration versus reaction rate calculations of absorbance at 412nm and fitting to Michaelis-Menton kinetic analysis-4Ms-1Prove that the vermiculite nano-sheetThe enzyme activity of the analogue enzyme is comparable to that of glutathione oxidation analogue enzyme in the prior art
Experimental example 3 measurement of intracellular iron content
The intracellular iron content of MC38 incubated with different treatments was determined using an iron colorimetric kit (Applygen, E1042). NSs medium (100. mu.g/mL) was added to the 6-well plates and the cells were incubated for 12 h. And finally, detecting the iron content according to the using method of the kit.
The results are shown in fig. 5, and the NSs-related group detected more iron ions than either PBS (control group) or DCPy group, indicating that NSs induced intracellular iron overload, inducing iron death.
EXAMPLE 4 intracellular GPX4 Activity assay
The intracellular GPX4 activity of MC38 incubated with different treatments was detected using a cell peroxidase detection kit (Beyotime, S0056). Vermiculite nanoplatelet media (100 μ g/mL) was added to 6-well plates and incubated for 0-12 h. Finally, GPX4 activity was detected according to the kit method of use.
As a result, as shown in fig. 6, glutathione peroxidase 4(GPX4) has an important role in a lipid repair system as a central regulator of iron droop, and glutathione consumption inactivates GPX4, thereby inducing iron death. NSs are a glutathione oxidase mimic enzyme, leading to glutathione depletion. In addition, NSs can also cause intracellular iron overload, inducing iron death. Cellular GPX4 activity was detected using a cellular glutathione peroxidase assay kit. The activity of GPX4 in the NSs-related group was significantly reduced compared to the control group (control group) and DCPy group. These results indicate that NSs significantly induced iron death by inhibiting GPX4 activity.
Experimental example 5 tumor tissue analysis
Set up 4 sets of experiments, PBS + light, NSs and NSs + light, respectively, and GPX4 antibody stained the differently treated tumor sections. The nuclei were subsequently stained with DAPI. These tumor sections were taken by an Olympus microscope (SLIDEVIEW VS 200).
The results are shown in fig. 7, and immunohistochemical staining of tumor tissue sections showed significant down-regulation of GPX4 in the NSs group (significant reduction of brown fraction in the NSs group compared to the PBS group), indicating that the therapeutic effect was significantly attributed to iron death.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.

Claims (10)

1. An iron death inducer comprising vermiculite nanoplates.
2. An iron death inducing agent according to claim 1 wherein said vermiculite nanoplatelets have a thickness of 1.0-1.3 nm.
3. An iron death inducing agent according to claim 1, characterized in that said vermiculite nanoplatelets are 305-335nm in length.
4. An iron death inducing agent according to claim 1, characterized in that said vermiculite nanoplatelets are 305-335nm wide.
5. A method of preparing an iron death inducer according to any one of claims 1-4 comprising obtaining vermiculite nanoplates; the vermiculite nanosheets are obtained by adding vermiculite into an alkali metal ion salt solution for intercalation treatment and stripping; wherein 0.1-10 mol/L alkali metal salt modifier is added per mg vermiculite.
6. The method for producing an iron-death inducing agent according to claim 5,
the specific preparation method of the vermiculite nanosheet comprises the following steps:
s1: adding vermiculite into an alkali metal salt solution modifier to expand the vermiculite;
s2: separating after expansion, and collecting upper layer colloidal slurry;
s3: and carrying out ultrasonic treatment on the upper layer colloidal slurry, and stripping to obtain the vermiculite nanosheet.
7. The method of claim 5 or 6, wherein the alkali metal salt solution modifier is one or more of a lithium salt solution, a potassium salt solution, or a sodium salt solution.
8. The method of claim 5 or 6, wherein the alkali metal salt solution modifier is one or more of a lithium chloride solution, a lithium ethylenediaminetetraacetate solution, or a lithium citrate solution.
9. The method for preparing an iron death inducing agent according to claim 6, wherein in step S3, the duration of the ultrasonic treatment is 0.3 to 0.6 h.
10. Use of an iron death inducer according to any one of claims 1-4 or prepared according to any one of claims 4 or 5-9 as an anti-tumour agent in the modulation of the tumour microenvironment.
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