CN111939174A - Metal polyphenol nano-composite as well as preparation method and application thereof - Google Patents
Metal polyphenol nano-composite as well as preparation method and application thereof Download PDFInfo
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- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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Abstract
The invention provides a metal polyphenol nano-composite as well as a preparation method and application thereof, belonging to the technical field of chemokinetic therapy and medicine preparation. The metal polyphenol nano-composite consists of polyphenol compounds of gallic acid and Cu2+Self-assembly, simple and efficient preparation method, can realize effective tumor chemokinetic treatment and can also realize effective tumor chemokinetic treatmentCan be used as a good drug delivery system. The invention prepares the metal polyphenol nano-composite under the ultra-simple and convenient condition, develops a comprehensive nano-platform to realize sustainable ROS generation and further realize effective cancer chemokinetic treatment, thereby having good practical popularization and application values.
Description
Technical Field
The invention belongs to the technical field of chemokinetic therapy and medicine preparation, and particularly relates to a metal polyphenol nano-composite as well as a preparation method and application thereof.
Background
The information in this background section is only for enhancement of understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art that is already known to a person of ordinary skill in the art.
Chemokinetic therapy (CDT) is an emerging therapeutic strategy, defined as the use of the Fenton (Fenton) or Fenton-like response to convert hydrogen peroxide (H) within tumor cells2O2) Conversion to Reactive Oxygen Species (ROS) can trigger apoptosis and inhibit tumor growth. Due to the Fenton reaction, there is not enough H in weak alkaline conditions or in normal tissues2O2Is substantially inhibited, and thus CDT is considered to be a new promising approach for cancer-specific therapy.
Currently, some fenton catalysts are activated by the endogenous hydrogen peroxide (H) of cancer cells2O2) Conversion to OH, thereby effecting cancer CDT. However, endogenous H of the tumor cells themselves2O2Are not sufficient to achieve satisfactory chemokinetic efficacy. Thus, the development has increased intracellular H2O2Functional chemokinetic catalysts are of great interest.
To increase intracellular H2O2The methods of (1) are mainly divided into two types: endogenous H2O2Amplification of production and exogenous H2O2Or delivery. Endogenous H produced by mitochondria2O2Is easy to be subjected to intracellular H before being close to Fenton catalyst2O2Enzymes and peroxidases, etc., are eliminated with limited availability. Therefore, in order to sufficiently improve the chemical kinetic effect, it is necessary to prepare a catalyst capable of forming or releasing exogenous H around the Fenton catalyst2O2The CDT catalyst of (1). The metal peroxide is composed of peroxy groups and metal ions, and is useful for supplying H2O2The material of (1). While in the prior art such as Fe is reported2+、Mn2+、Co2+Some of these metal ions have a certain fenton catalytic activity, however, the inventors believe that considering the limited catalytic activity and stability of those previously developed catalysts in biological environments, there is an urgent need to develop innovative formulations with effective catalytic activity to convert H2O2To OH to achieve efficient cancer CDT.
Disclosure of Invention
In view of the problems in the prior art, the present invention aims to provide a metal polyphenol nanocomposite, and a preparation method and an application thereof. Proved by tests, the metal polyphenol nano-composite is prepared from polyphenol compounds of gallic acid and Cu2+The self-assembly is obtained, the preparation method is simple and efficient, effective tumor chemokinetic treatment can be realized, and the drug delivery system can be used as a good drug delivery system, so that the drug delivery system has good practical application value.
In order to achieve the technical purpose, the technical scheme of the invention is as follows:
in a first aspect of the present invention, there is provided a metal polyphenol nanocomposite, which is composed of Gallic Acid (GA) and Cu2+And (4) self-assembly.
In a second aspect of the present invention, there is provided a method for preparing the above metal polyphenol nanocomposite, comprising uniformly mixing Gallic Acid (GA) and a compound containing divalent copper in a solution, and centrifuging the mixture to obtain a precipitate.
In a third aspect of the present invention, there is provided a use of the above metal polyphenol nanocomposite in any one or more of the following:
(1) preparing a chemokinetic therapeutic agent;
(2) preparing a drug delivery system.
(3) Preparing the antitumor drug.
In a fourth aspect of the present invention, an antitumor drug is provided, wherein the antitumor drug comprises the above metal polyphenol nanocomposite;
the anti-tumor drug also comprises other anti-tumor active components, such as small molecule compounds or gene drugs, wherein the gene drugs comprise but are not limited to small interfering RNA and mRNA.
In a fifth aspect of the present invention, there is provided a method for preparing an antitumor drug, the method comprising:
mixing Gallic Acid (GA) and CuCl under stirring2And the aqueous solution of the siVEGF is centrifuged, and the obtained precipitate is washed by deionized water to obtain the antitumor drug.
The beneficial technical effects of one or more technical schemes are as follows:
1. the technical scheme provides the metal polyphenol nanocomposite for chemokinetic treatment, has high catalytic effect, realizes sustainable ROS generation, and successfully solves the problem of low efficiency of CDT.
2. The technical scheme provides a metal polyphenol nano-complex for chemokinetic treatment, and the metal polyphenol nano-complex can be used for drug delivery, and can be used for delivering gene drugs such as small interfering RNA and mRNA.
3. The technical scheme synthesizes the metal polyphenol nano-composite for the first time, which can be used for the chemical kinetics treatment and is based on Cu2+The ionic nano-composite, taking delivery of small interfering RNA VEGF (siVEGF) as an example, is obtained by means of self-assembly of polyphenol Gallic Acid (GA) under a very simple condition, not only can realize effective CDT treatment of tumors, but also can carry out drug delivery, and can realize strong tumor killing power of co-excitation of drugs and CDT, so that the ionic nano-composite has good value of practical application.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, 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 embodiments of the present invention, and it is obvious for those skilled in the art to obtain other drawings according to the provided drawings without creative efforts.
FIG. 1 is a graph of nanoparticle size and morphology as measured by Dynamic Light Scattering (DLS) and TEM in example 1 of the present invention;
FIG. 2 is a diagram showing the localization of major elements of a metal polyphenol nanocomposite by EPMA in example 2 of the present invention;
FIG. 3 is a graph of nanoparticle size and morphology by Dynamic Light Scattering (DLS) and TEM as determined in example 2 of the present invention;
FIG. 4 is a TEM image of nanoparticles prepared in example 2 of the present invention;
FIG. 5 is a graph showing the VEGF silencing efficiency of each preparation in colon cancer cells measured by western blot in example 3 of the present invention;
FIG. 6 is a graph showing GSH levels in CT26 cells in example 4 of the present invention;
FIG. 7 is a CLSM image of DCFH-DA stained CT26 cells, characterizing ROS production, according to example 4 of the present invention;
FIG. 8 shows the antitumor therapeutic effect of in-situ colon cancer mice in Experimental example 5 of the present invention.
Detailed Description
It is to be understood that the following detailed description is exemplary and is intended to provide further explanation of the invention as claimed. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of example embodiments according to the present application. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, and it should be understood that when the terms "comprises" and/or "comprising" are used in this specification, they specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof, unless the context clearly indicates otherwise.
As previously mentioned, given the limited catalytic activity and stability of those previously developed catalysts in biological environments, there is an urgent need to develop innovative formulations with effective catalytic activity to convert H2O2 to OH to achieve effective cancer CDT.
In view of the above, the present invention develops a metal polyphenol nanocomposite (RT) useful for chemokinetic therapy, specifically a Cu-based nanocomposite2+Ionic nanocomplexes for obtaining by means of polyphenol Gallic Acid (GA) self-assembly under very simple conditions. Thanks to a hypoxic Tumor Microenvironment (TME), it can prevent Cu during Fenton-like reactions+Quilt O2Oxidized and consumed the antioxidant Glutathione (GSH), and it is estimated that Cu+Compared with the previously reported Fe2+The catalytic effect is 160 times higher. High GSH consumption efficiency actually breaks the subtle redox balance of cancer cells and promotes the production of more ROS, which is crucial to solving the problem of low efficiency of CDT. Meanwhile, the metal polyphenol nano-composite obtained by self-assembly can also be used for delivering drugs, and can realize co-treatment of tumors by the drugs in cooperation with CDT, so that the anti-tumor immunity is further enhanced.
Specifically, in one embodiment of the present invention, a metal polyphenol nanocomposite is provided, wherein the metal polyphenol nanocomposite is prepared from Gallic Acid (GA) and Cu2+And (4) self-assembly. The average particle size of the metal polyphenol nanocomposite is not more than 100nm, and further the average particle size is 90-100 nm, such as 90nm, 95nm and 100 nm.
Wherein the gallic acid is mixed with Cu2+In a molar ratio of 1 to 5:1, such as 1:1, 3:1 and 5: 1; the ratio is preferably 3:1, and the metal polyphenol nanocomposite obtained by self-assembly has stable property, and main elements are uniformly distributed in the metal polyphenol nanocomposite.
Wherein the compound containing divalent copper is soluble copper salt, preferably CuCl2。
In still another embodiment of the present invention, there is provided the method for preparing the metal polyphenol nanocomposite, comprising the steps of uniformly mixing Gallic Acid (GA) and a compound containing divalent copper in a solution, and centrifuging the mixture to obtain a precipitate.
In another embodiment of the present invention, the preparation method comprises:
mixing Gallic Acid (GA) and CuCl under stirring2Centrifuging the aqueous solution of (1), and precipitating the obtained precipitateThe product is washed by deionized water to obtain the product.
In another embodiment of the present invention, gallic acid is mixed with Cu2+In a molar ratio of 1 to 5:1, such as 1:1, 3:1 and 5: 1; preferably 3: 1.
The stirring time is controlled to be 5-20 min, preferably 10 min.
The centrifugal speed is controlled to be 5000-8000 rpm, and the centrifugal time is controlled to be 5-10 min.
The obtained precipitate is washed with deionized water for 2-5 times.
The metal polyphenol nano-composite prepared by the preparation method has stable structure and uniform size, and the average particle size is not more than 100 nm. The prepared metal polyphenol nano-composite is suitable for being stored at low temperature (such as 4 ℃).
In another embodiment of the present invention, there is provided a use of the above metal polyphenol nanocomposite in any one or more of the following:
(1) preparing a chemokinetic therapeutic agent;
(2) preparing a drug delivery system.
(3) Preparing the antitumor drug.
In another embodiment of the present invention, an antitumor drug is provided, wherein the antitumor drug comprises the above metal polyphenol nanocomposite;
the anti-tumor medicine also comprises other anti-tumor active components, such as small molecule compounds or gene medicines, wherein the gene medicines comprise but are not limited to small interfering RNA and mRNA;
in yet another embodiment of the invention, the small interfering RNA is vascular endothelial growth factor small interfering RNA (siVEGF).
In another embodiment of the present invention, the anti-tumor drug is a drug for treating colorectal cancer.
It should be noted that, in the above antitumor drugs, the metal polyphenol nanocomposite not only serves as a chemokinetic therapeutic drug to exert an antitumor effect, but also serves as a drug delivery system for other antitumor active ingredients, so that the synergistic stimulation of other antitumor drugs with CDT to generate a strong tumor killing power is realized, and the antitumor effect is improved.
In another embodiment of the present invention, there is provided a method for preparing an antitumor drug, the method comprising:
mixing Gallic Acid (GA) and CuCl under stirring2And the aqueous solution of the siVEGF is centrifuged, and the obtained precipitate is washed by deionized water to obtain the antitumor drug.
In still another embodiment of the present invention, GA and Cu2+The mixing molar ratio of the siVEGF and the siVEGF is 50-70: 10-30: 1-3; preferably 60:20: 1.
In another embodiment of the present invention, the stirring time is controlled to be 5 to 20min, preferably 10 min.
In another embodiment of the present invention, the rotation speed of the centrifugation is 5000rpm to 8000rpm, and the time of the centrifugation is 5 to 10 min.
In another embodiment of the present invention, the obtained precipitate is washed with deionized water 2 to 5 times.
In order to make the technical solutions of the present disclosure more clearly understood by those skilled in the art, the technical solutions of the present disclosure will be described in detail below with reference to specific embodiments.
Example 1
Synthesis of metal polyphenol nanocomposite:
25 μ L of gallic acid (60mmol/L) was added dropwise to 25 μ L of CuCl2(20mmol/L) and stirred for 10 minutes. Then, the obtained metal polyphenol nanocomposite was collected by centrifugation (5000rpm × 5min), followed by washing with water. The prepared metal polyphenol nanocomposite was stored at 4 ℃. The size (particle size: 92.71nm) and morphology of the metal polyphenol nanocomposite were examined by Dynamic Light Scattering (DLS) and TEM (FIG. 1).
Example 2
Synthesis of metal polyphenol nano antitumor drugs:
15 μ L of gallic acid (60mmol/L) was added dropwise to 600 μ L of siVEGF (25 μmol/L) solution, and then 15 μ L of CuCl was added dropwise2(20mmol/L) of the solution, and stirred for 10 minutes. Then, the obtained metal polyphenol nano antitumor agent was collected by centrifugation (5000rpm × 5min), followed by washing with water. The prepared metal polyphenol nano anti-tumor medicine is stored at 4 ℃. The metal polyphenol nanocomposite prepared in this example was plotted using an Electron Probe Microanalyzer (EPMA), and the EPMA spectrum results are shown in fig. 2, which demonstrated that the main elements were uniformly distributed in the metal polyphenol nanocomposite. The size and morphology of the metal polyphenol nanocomposite were examined by Dynamic Light Scattering (DLS) and TEM, and DLS analysis showed that the average diameter of the metal polyphenol nanocomposite was 95.29nm (fig. 3 and 4). The siVEGF in this example was purchased from Biotech, Inc., of the Qingke family.
Example 3
This example illustrates colorectal cancer that highly expresses VEGF, and demonstrates the feasibility of metal polyphenol nanocomplex drug loading based on whether metal polyphenol nanocomplexes can deliver siVEGF-silenced VEGF genes of colorectal cancer.
Western blotting: CT26 cells were seeded in 6-well plates at 5% CO2And cultured overnight at 37 ℃. After 48 hours of treatment with siVEGF, Lipo3000, metal polyphenol nanocomposite at a siVEGF dose of 50nM, cells were washed 3 times with pre-chilled PBS and lysed in RIPA buffer plus PMSF. Protein samples were separated by electrophoresis on 15% SDS-PAGE gels, transferred to PVDF membrane, then blocked in TBST containing 5% skim milk, and incubated with the indicated and secondary antibodies. The western blot results in fig. 5 show the effective silencing of the metal polyphenol nanocomposite on the gene, demonstrating the feasibility of drug loading of the metal polyphenol nanocomposite.
Example 4
Measurement of intracellular GSH: colon cancer CT26 cells were plated at 1X105Density per well seeded on 6-well cell plates at 5% CO2Incubated overnight at 37 ℃. Then treated with PBS, RT, under hypoxic conditions for 6 hours (Cu ═ 1.0 mM). Thereafter, cells were harvested and washed 3 times with cold PBS and lysed with Triton-X-100 lysate. After centrifugation, the DTNB solution was added to the lysis flask for 30 minutes of incubation and the flask was openedThe content of cellular GSH was determined by UV-vis absorbance at 412 nm.
According to OH formation and Cu2+Mediated intracellular GSH depletion the Fenton-like catalytic activity of BRTs prepared in this disclosure was studied. As shown in figure 6, the intracellular GSH in CT26 cells decreased dramatically when incubated with other groups, when incubated with RT-mediated nanopreparations, indicating that Cu2+Effectively reacts with intracellular GSH, resulting in an imbalance of redox states in tumor cells and promoting cell death.
In vitro DCFH-DA assay: ROS production was measured by CLSM using the sensitive probe 2', 7' -dichlorofluororesin diacetate (DCFH-DA). 5X 10 in Petri dish4CT26 cells at 5% CO2Incubated overnight at 37 ℃ and then treated with different samples under hypoxic conditions for 24 hours. Subsequently, CT26 cells were stained with DCFH-DA (10 μ M) and incubated for 30 minutes, and finally washed with PBS to observe CLSM. Intracellular oxidative stress of cancer cells after each treatment was imaged by CLSM using 2', 7' -dichlorodihydrofluorescein diacetate (DCFH-DA) as an intracellular ROS probe. The imaging results showed that the RT treated cells showed significantly stronger intracellular green fluorescence intensity than the PBS treated cells (fig. 7).
The above results indicate that the metal polyphenol nanocomposite prepared by the present disclosure, which can be used for chemokinetic treatment, has high catalytic effect, and realizes sustainable ROS generation, successfully solving the problem of low efficiency of CDT.
Example 5
Antitumor effect of metal polyphenol nanocomposite synergistic gene medicine on in-situ colorectal tumor model
This example illustrates colorectal cancer with high expression of VEGF, and the feasibility of metal polyphenol nanocomposite to cooperate with gene drug to resist tumor was demonstrated by loading siVEGF with metal polyphenol nanocomposite.
In vivo evaluation of the antitumor activity of BRT (metal polyphenol nanocomplex loaded with siVEGF):
an in situ CRC model was established by injecting murine CT26 colon cancer cells into the cecal wall of BALB/c mice. Tumor-bearing mice were dosed 7d after in situ tumor cell inoculation with 1mg kg of PBS (control), RT, siVEGF, BRT on days 8, 11, 14, 17 and 20. Tumor burden was monitored every three days using bioluminescence imaging. As shown in fig. 8, the mice treated with RT showed significant tumor growth inhibition compared to the mice treated with PBS (control), indicating that the metal polyphenol nanocomposite prepared according to the present disclosure has good anti-colon cancer effect, but the mice treated with BRT showed stronger tumor growth inhibition than the mice treated with RT and siVEGF, indicating that the metal polyphenol nanocomposite synergizes with the gene drug to stimulate stronger anti-tumor effect.
It should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention and not for limiting the same. Although the present invention has been described in detail with reference to the examples given, those skilled in the art can modify the technical solution of the present invention as needed or equivalent substitutions without departing from the spirit and scope of the technical solution of the present invention.
Claims (10)
1. A metal polyphenol nanocomposite, characterized in that the nanocomposite is prepared from gallic acid and Cu2+Self-assembly is carried out; the average particle size of the metal polyphenol nanocomposite is not more than 100 nm.
2. The metal polyphenol nanocomposite as claimed in claim 1, wherein the gallic acid is in combination with Cu2+The molar ratio of (A) to (B) is 1 to 5:1, preferably 3: 1.
3. The metal polyphenol nanocomposite as claimed in claim 1, wherein the divalent copper containing compound is a soluble copper salt, preferably CuCl2。
4. The method for preparing a metal polyphenol nanocomposite as claimed in any one of claims 1 to 3, which comprises: mixing gallic acid and compound containing cupric in solution, centrifuging to obtain precipitate.
5. The method of claim 4, comprising:
mixing gallic acid and CuCl under stirring2Centrifuging the aqueous solution, and washing the obtained precipitate with deionized water.
6. The method according to claim 4, wherein the gallic acid is mixed with Cu2+The molar ratio of (A) to (B) is 1-5: 1, preferably 3: 1;
the stirring time is controlled to be 5-20 min, preferably 10 min;
controlling the centrifugal rotation speed to be 5000-8000 rpm, and controlling the centrifugal time to be 5-10 min;
the obtained precipitate is washed with deionized water for 2-5 times.
7. Use of a metal polyphenol nanocomposite as claimed in any one of claims 1 to 3 in any one or more of:
(1) preparing a chemokinetic therapeutic agent;
(2) preparing a drug delivery system;
(3) preparing the antitumor drug.
8. An antitumor agent comprising the metal polyphenol nanocomposite as described in any one of claims 1 to 3;
preferably, the anti-tumor medicament also comprises other anti-tumor active ingredients;
preferably, the other antitumor active ingredients comprise small molecule compounds or gene drugs;
preferably, the gene drug comprises small interfering RNA and mRNA;
preferably, the small interfering RNA is siVEGF;
preferably, the anti-tumor drug is a drug for treating colorectal cancer.
9. A preparation method of an antitumor drug is characterized by comprising the following steps:
mixing gallic acid and CuCl under stirring2And the aqueous solution of the siVEGF is centrifuged, and the obtained precipitate is washed by deionized water to obtain the antitumor drug.
10. The method according to claim 9, wherein the gallic acid and Cu are present2+The mixing molar ratio of the siVEGF and the siVEGF is 50-70: 10-30: 1-3; preferably 60:20: 1;
preferably, the stirring time is controlled to be 5-20 min, preferably 10 min;
preferably, the rotating speed of the centrifugation is 5000-8000 rpm, and the time of the centrifugation is 5-10 min;
preferably, the obtained precipitate is washed with deionized water for 2-5 times.
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| CN114748446A (en) * | 2022-02-18 | 2022-07-15 | 广东粤港澳大湾区国家纳米科技创新研究院 | Aluminum-based self-assembly delivery system of mRNA (messenger ribonucleic acid), and preparation method and application thereof |
| CN114748446B (en) * | 2022-02-18 | 2023-11-28 | 广州瑞贝斯药业有限公司 | Aluminum-based self-assembly delivery system of mRNA (messenger ribonucleic acid) as well as preparation method and application thereof |
| CN115317461A (en) * | 2022-08-05 | 2022-11-11 | 常州大学 | Adriamycin delivery system Cu-GA-DOX NPs and preparation method thereof |
| CN116077527A (en) * | 2023-04-11 | 2023-05-09 | 山东大学 | Needle-like copper-gallic acid nano enzyme and preparation method and application thereof |
| CN116077527B (en) * | 2023-04-11 | 2023-10-03 | 山东大学 | Needle-like copper-gallic acid nano enzyme and preparation method and application thereof |
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