CN114042059A - Preparation and application of metal chelate nanoparticle of caffeic acid or derivative thereof - Google Patents
Preparation and application of metal chelate nanoparticle of caffeic acid or derivative thereof Download PDFInfo
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- CN114042059A CN114042059A CN202111067832.1A CN202111067832A CN114042059A CN 114042059 A CN114042059 A CN 114042059A CN 202111067832 A CN202111067832 A CN 202111067832A CN 114042059 A CN114042059 A CN 114042059A
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- caffeic acid
- chloride
- metal
- metal chelate
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- QAIPRVGONGVQAS-DUXPYHPUSA-N trans-caffeic acid Chemical compound OC(=O)\C=C\C1=CC=C(O)C(O)=C1 QAIPRVGONGVQAS-DUXPYHPUSA-N 0.000 title claims abstract description 121
- ACEAELOMUCBPJP-UHFFFAOYSA-N (E)-3,4,5-trihydroxycinnamic acid Natural products OC(=O)C=CC1=CC(O)=C(O)C(O)=C1 ACEAELOMUCBPJP-UHFFFAOYSA-N 0.000 title claims abstract description 43
- 229940074360 caffeic acid Drugs 0.000 title claims abstract description 43
- 235000004883 caffeic acid Nutrition 0.000 title claims abstract description 43
- QAIPRVGONGVQAS-UHFFFAOYSA-N cis-caffeic acid Natural products OC(=O)C=CC1=CC=C(O)C(O)=C1 QAIPRVGONGVQAS-UHFFFAOYSA-N 0.000 title claims abstract description 43
- 239000002105 nanoparticle Substances 0.000 title claims abstract description 42
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- 239000002184 metal Substances 0.000 title claims abstract description 16
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 41
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- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 6
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 6
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 4
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 3
- 229910021578 Iron(III) chloride Inorganic materials 0.000 claims description 3
- GVPFVAHMJGGAJG-UHFFFAOYSA-L cobalt dichloride Chemical compound [Cl-].[Cl-].[Co+2] GVPFVAHMJGGAJG-UHFFFAOYSA-L 0.000 claims description 3
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- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 3
- 239000011592 zinc chloride Substances 0.000 claims description 3
- 235000005074 zinc chloride Nutrition 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 2
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- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 abstract description 7
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- DHRRIBDTHFBPNG-UHFFFAOYSA-L magnesium dichloride hexahydrate Chemical compound O.O.O.O.O.O.[Mg+2].[Cl-].[Cl-] DHRRIBDTHFBPNG-UHFFFAOYSA-L 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- -1 DPPH free radical Chemical class 0.000 description 3
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- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
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- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 2
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
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- 239000010941 cobalt Substances 0.000 description 2
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 2
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- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 2
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- WDKYDMULARNCIS-GQCTYLIASA-N Caffeic acid ethyl ester Chemical compound CCOC(=O)\C=C\C1=CC=C(O)C(O)=C1 WDKYDMULARNCIS-GQCTYLIASA-N 0.000 description 1
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- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
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- WDKYDMULARNCIS-UHFFFAOYSA-N ethyl caffeoate Natural products CCOC(=O)C=CC1=CC=C(O)C(O)=C1 WDKYDMULARNCIS-UHFFFAOYSA-N 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- 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
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
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- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/26—Iron; Compounds thereof
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- A61K33/30—Zinc; Compounds thereof
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- A61K33/34—Copper; Compounds thereof
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/5115—Inorganic compounds
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
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- A61P39/06—Free radical scavengers or antioxidants
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Abstract
S1 dissolving caffeic acid or its derivative and metal chloride in water phase solution, stirring to dissolve completely, and adjusting pH value of the solution to neutral or alkaline; s2, reacting the solution obtained in the step S1 for a period of time, washing, and freeze-drying the obtained reaction product to obtain dark brown powder, namely the caffeic acid metal chelate nano-particles. The invention chelates caffeic acid or derivatives thereof with metal ions to obtain metal chelate nanoparticles of caffeic acid or derivatives thereof, and the nanoparticles have the functions of scavenging free and intracellular active oxygen and can reverse apoptosis induced by oxidative stress. The preparation method of the invention has simple process and easy operation.
Description
Technical Field
The invention relates to the field of medicines, in particular to preparation and application of metal chelate nanoparticles of caffeic acid or derivatives thereof.
Background
It is currently believed that aging is the result of a combination of intrinsic and extrinsic factors that cause cell damage and death. With the development of free radical biomedical research, research on aging caused by free radicals is gradually expanded to more fields, for example, various diseases accompanied by aging, such as senile dementia, arteriosclerosis and diabetes, are closely related to free radical damage. Later studies have progressed to the cellular level, demonstrating that apoptosis and necrosis associated with many diseases are the result of free radical damage.
According to the aging free radical theory, the decline of tissue and organ functions is closely related to oxidative stress induced by Reactive Oxygen Species (ROS). For example: the development and progression of disc degeneration, ROS, in the network of signaling pathways for nucleus pulposus cells, serves as an important mediator that regulates extracellular matrix metabolism, pro-inflammatory factor phenotype, apoptosis, autophagy, aging, and the like. On the other hand, the oxidation resistant protein in the degenerated intervertebral disc tissue is obviously reduced, and the oxidation resistance of the intervertebral disc tissue is obviously reduced. These changes result in an imbalance in the redox of the disc cells, which are susceptible to oxidative damage.
Caffeic acid, chemical name is 3- (3, 4-dihydroxyphenyl) -acrylic acid, molecular formula is C9H8O4No. CAS 331-39-5, is present in various plants, and has the functions of contracting, reinforcing blood capillary and promoting blood coagulation factor. The caffeic acid tablet is a common clinical medicine and is used for treating leucopenia and thrombocytopenia. In addition, the caffeic acid has a structure of dihydric phenol, can effectively remove various oxygen free radicals, and has strong antioxidant, anti-inflammatory and immunoregulatory effects. The research of applying caffeic acid in treating cardiovascular and cerebrovascular diseases, resisting bacteria, inflammation and tumor has been reported in literature. In the invention, caffeic acid and compounds thereof have protective effect on intervertebral disc injury. However, caffeic acid belongs to active small molecule drugs, has short half-life period in vivo, is easy to metabolize, and is difficult to concentrate on pathological change parts of intervertebral discs to play a role, so the invention aims to improve the drug effect of the caffeic acid and reduce the toxicity of a system by a nano technology.
The nano-drug is a nano-complex which is obtained by compounding bioactive molecules such as antitumor drugs and the like with a carrier material by using a nano-biotechnology and further changing the properties of the drugs in aspects of pharmacokinetics, pharmacodynamics, pharmacology and the like by using a nano effect and has obvious clinical advantages. For early degeneration of intervertebral disc, the current artificial intervention is to promote intervertebral disc cells to secrete extracellular matrix and slow down apoptosis, the common mode is injection through a fiber ring, but caffeic acid or other small molecules are rapidly metabolized after in vivo injection, and the effect of long-term treatment cannot be achieved.
Disclosure of Invention
In order to solve the problems, the invention prepares the metal chelate nanoparticle of caffeic acid or derivatives thereof, which can be retained in a spondylopathy part and play an anti-oxidation role for a long time. The nano-particles have obvious effect of removing DPPH free radicals. Has obvious ROS eliminating and apoptosis reversing effects on nucleus pulposus cell oxidative damage caused by hydrogen peroxide.
The invention adopts the following technical scheme to realize the purpose of the invention:
a method for preparing metal chelate nanoparticles of caffeic acid or a derivative thereof, comprising the following steps:
s1, dissolving caffeic acid or derivatives thereof and metal chloride in the water phase solution, stirring until the caffeic acid or derivatives thereof and the metal chloride are completely dissolved, and adjusting the pH value of the solution to be neutral or alkaline;
s2, reacting the solution obtained in the step S1 for a period of time, washing, and freeze-drying the obtained reaction product to obtain dark brown powder, namely the caffeic acid metal chelate nano-particles.
The metal chelate nanoparticle of the caffeic acid or the derivative thereof is obtained by chelating the caffeic acid or the derivative thereof with metal ions, and the nanoparticle has the functions of removing free active oxygen and intracellular active oxygen, can reverse apoptosis induced by oxidative stress, can be retained at a pathological change part of a vertebra and plays an antioxidant role for a long time.
Preferably, the molar ratio of caffeic acid or a derivative thereof to metal chloride is: 0.01 to 100.
Preferably, the metal chlorides include: one of magnesium chloride, calcium chloride, ferric chloride, cupric chloride, zinc chloride or cobalt chloride.
Preferably, the aqueous phase solution is a mixed solution of ethanol and water, and the volume ratio of the ethanol to the water is as follows: 1:1.
Preferably, the pH value of the adjusting solution is 5-12.
Preferably, the specific steps of washing are: washing with deionized water, and then washing with alcohol.
The invention also provides a metal chelate nanoparticle of caffeic acid or a derivative thereof, which is prepared by the preparation method.
The invention also provides the application of the nano-particles as an antioxidant.
Preferably, the antioxidant is used to reduce intracellular reactive oxygen species levels. The nano-particles of the invention can obviously remove ROS which are oxidized and damaged by nucleus pulposus cells.
The invention also provides application of the nano-particles in preparation of resisting apoptosis. The nano-particles of the invention have significant reversal effect on nucleus pulposus apoptosis.
The invention has the beneficial effects that: the invention chelates caffeic acid or derivatives thereof with metal ions to obtain metal chelate nanoparticles of the caffeic acid or the derivatives thereof, and different metal ions combine with the caffeic acid to obtain metal chelate nanoparticles with different functions, such as Mg-containing metal chelate nanoparticles2+The nano-particles not only can promote the formation of bones and reduce the calcification of cells, but also can remove free active oxygen and active oxygen in the cells, and can reverse the apoptosis induced by oxidative stress and prolong the half-life period in vivo; containing Cu2+The nano-particles can promote endothelial cell repair, promote wound healing and resist bacteria; containing Mn2+The nanoparticles of (a) may activate the immune system. It can be seen that the nanoparticles of the present invention not only maintain the antioxidant activity of caffeic acid, but also generate other biological activities by the addition of metal ions. In addition, the preparation method of the invention has simple process and easy operation.
Drawings
FIG. 1 is a transmission electron microscope photograph of magnesium caffeate;
FIG. 2 is a graph showing the removal rate of DPPH free radicals by magnesium caffeate;
FIG. 3 is a graph showing the results of a stability test for oxidation resistance of magnesium caffeate;
FIG. 4 is a graph showing that magnesium caffeate inhibits oxidative stress-induced apoptosis of nucleus pulposus cells.
Detailed Description
In order to show technical solutions, purposes and advantages of the present invention more concisely and clearly, the technical solutions of the present invention are described in detail below with reference to specific embodiments. Unless otherwise specified, the reagents involved in the examples of the present invention are all commercially available products, and all of them are commercially available.
Example 1
The embodiment provides a preparation scheme for preparing magnesium caffeate, which comprises the following specific steps:
a 90mg caffeic acid was dissolved in 50ml of a mixed solution of ethanol and water (volume ratio 1:1) and stirred until completely dissolved, and labeled as solution A.
B dissolving 105mg of magnesium chloride hexahydrate in the solution A, stirring until the magnesium chloride hexahydrate is completely dissolved, and marking as a solution B.
C the pH of solution B was adjusted to 10.1 and labeled as solution C.
And d, reacting the solution C in a water bath at the temperature of 4 ℃ for 20 minutes, washing the solution C with deionized water for 2 times, washing the solution C with alcohol for 2 times, and freeze-drying the solution C with a freeze dryer to obtain a dark brown product, namely the magnesium caffeate nano-particles.
Example 2
The embodiment provides a preparation scheme for preparing calcium caffeate, which comprises the following specific steps:
a 90mg caffeic acid was dissolved in 50ml of a mixed solution of ethanol and water (volume ratio 1:1) and stirred until completely dissolved, and labeled as solution A.
B dissolve 165mg of anhydrous calcium chloride in solution A and stir until completely dissolved, labeled as solution B.
C the pH of solution B was adjusted to 10.1 and labeled as solution C.
And d, reacting the solution C in a water bath at the temperature of 4 ℃ for 20 minutes, washing the solution C with deionized water for 2 times, washing the solution C with alcohol for 2 times, and freeze-drying the solution C with a freeze dryer to obtain a dark brown product, namely the calcium caffeate nano-particles.
Example 3
This example provides a preparation scheme for preparing iron caffeate, which includes the following specific steps:
a 90mg caffeic acid was dissolved in 50ml of a mixed solution of ethanol and water (volume ratio 1:1) and stirred until completely dissolved, and labeled as solution A.
B dissolve 165mg of anhydrous ferric chloride in solution A, stir until completely dissolved, and label as solution B.
C the pH of solution B was adjusted to 10.1 and labeled as solution C.
And d, reacting the solution C in a water bath at the temperature of 4 ℃ for 20 minutes, washing the solution C with deionized water for 2 times, washing the solution C with alcohol for 2 times, and freeze-drying the solution C by a freeze dryer to obtain a dark brown product, namely the ferric caffeate nano-particles.
Example 4
The embodiment provides a preparation scheme for preparing copper caffeate, which comprises the following specific steps:
a 90mg caffeic acid was dissolved in 50ml of a mixed solution of ethanol and water (volume ratio 1:1) and stirred until completely dissolved, and labeled as solution A.
B165 mg of anhydrous cupric chloride was dissolved in the solution A and stirred until completely dissolved, and the solution was labeled as solution B.
C the pH of solution B was adjusted to 10.1 and labeled as solution C.
And d, reacting the solution C in a water bath at the temperature of 4 ℃ for 20 minutes, washing the solution C with deionized water for 2 times, washing the solution C with alcohol for 2 times, and freeze-drying the solution C with a freeze dryer to obtain a dark brown product, namely the copper caffeate nano-particles.
Example 5
The embodiment provides a preparation scheme for preparing zinc caffeate, which comprises the following specific steps:
a 90mg caffeic acid was dissolved in 50ml of a mixed solution of ethanol and water (volume ratio 1:1) and stirred until completely dissolved, and labeled as solution A.
B165 mg of anhydrous zinc chloride was dissolved in the solution A and stirred until completely dissolved, and the solution was marked as solution B.
C the pH of solution B was adjusted to 10.1 and labeled as solution C.
And (d) reacting the solution C in a water bath at the temperature of 4 ℃ for 20 minutes, washing the solution C with deionized water for 2 times, washing the solution C with alcohol for 2 times, and freeze-drying the solution C by a freeze dryer to obtain a dark brown product, namely the zinc caffeate nano-particles.
Example 6
The embodiment provides a preparation scheme for preparing cobalt caffeate, which comprises the following specific steps:
a 90mg caffeic acid was dissolved in 50ml of a mixed solution of ethanol and water (volume ratio 1:1) and stirred until completely dissolved, and labeled as solution A.
B165 mg of anhydrous cobalt chloride was dissolved in the solution A and stirred until completely dissolved, and the solution was marked as solution B.
C the pH of solution B was adjusted to 10.1 and labeled as solution C.
And d, reacting the solution C in a water bath at the temperature of 4 ℃ for 20 minutes, washing the solution C with deionized water for 2 times, washing the solution C with alcohol for 2 times, and freeze-drying the solution C with a freeze dryer to obtain a dark brown product, namely the cobalt caffeate nano-particles.
Example 7
The embodiment provides a preparation scheme for preparing caffeic acid derivative magnesium, which comprises the following specific steps:
a 90mg of caffeic acid ethyl ester was dissolved in aqueous solution at pH11 and stirred until completely dissolved, labeled as solution a.
B dissolving 105mg of magnesium chloride hexahydrate in the solution A, stirring until the magnesium chloride hexahydrate is completely dissolved, and marking as a solution B.
C the pH of solution B was adjusted to 10.1 and labeled as solution C.
And (d) reacting the solution C in a water bath at the temperature of 4 ℃ for 20 minutes, then washing with deionized water for 2 times, washing with alcohol for 2 times, and freeze-drying by a freeze dryer to obtain a dark brown product, namely the caffeic acid derivative magnesium nanoparticles.
Effect verification
Test one: experiment for removing DPPH free radical by using magnesium caffeate
2, 2-biphenyl-1-picrylhydrazino (2, 2-Diphenyl-1-piperidinylhydrazyl, abbreviated as DPPH) is dissolved in absolute ethyl alcohol and is completely dissolved to prepare 0.1 mg/LDPPH-ethanol solution. Adding magnesium caffeate solutions with different concentrations into 0.1 mg/LDPPH-ethanol solution, reacting for 10 minutes, and detecting the absorption value of the mixed solution at 517nm by using a UV-VIS absorption spectrometer. The removal rate of DPPH & of magnesium caffeate at different concentrations is calculated.
As a result, as shown in FIG. 2, the magnesium caffeate of the present invention reduced DPPH in the solution and showed strong oxidation resistance.
And (2) test II: stability test of magnesium caffeate against oxidation
Caffeic acid and magnesium caffeate was dispersed in PBS solution. 2, 2-biphenyl-1-picrylhydrazino (2, 2-Diphenyl-1-piperidinylhydrazyl, abbreviated as DPPH) is dissolved in absolute ethyl alcohol and is completely dissolved to prepare 0.1 mg/LDPPH-ethanol solution. Caffeic acid and magnesium caffeate were added to the 0.1mg/LDPPH & solution, respectively, and the free radical clearance rate at 0h was marked as 100%. The DPPH-free radical scavenging rate was measured by placing caffeic acid and magnesium caffeate in PBS at 37 ℃ for various times.
As a result, as shown in fig. 3, the magnesium caffeate nanoparticles of the present invention have more stable antioxidant performance and more durable antioxidant performance.
And (3) test III: experiment for inhibiting oxidative stress induced apoptosis of nucleus pulposus cells by using magnesium caffeate nanoparticles
Firstly, constructing nucleus pulposus cell in vitro oxidation stress model
a isolation and culture of Primary cells
The primary nucleus pulposus cells are obtained from rat intervertebral discs by the specific method as follows: under aseptic condition, the annulus fibrosus of intervertebral disc is punctured with scalpel blade, the semitransparent jelly nucleus pulposus tissue is picked out and placed in PBS, centrifuged at 1200rpm for 3min, the redundant tissue is removed, at the same time, 3ml of 2% type II collagenase digestive juice is added, and placed on a constant temperature shaking bed at 37 ℃ for digestion for 30 min. The digested tissue was added to 6ml of DMEM/F12 medium containing 10% FBS to stop the digestion. The digested suspension was filtered through a 40 μm sieve and centrifuged at 1200rpm for 3 min. The supernatant was discarded, 5ml of DMEM/F12 medium containing 10% FBS was added again to the suspension, and the suspension was resuspended in a T25 cell culture flask at 37 ℃ in 5% CO2Cultured in an incubator. The 1:3 subcultures were performed when the cell density reached 80% and the P4 cells were used for subsequent experiments.
b addition of 1ml 0.25% Trypsin to cells in logarithmic growth phase at 37 ℃ 5% CO2The digestion was stopped with DMEM/F12 medium containing 10% FBS for 1min, and the cell suspension was centrifuged at 1200rpm for 3min and then resuspended in 10% FBS DMEM/F12 medium and counted. The cells were seeded at 10k per well in 96-well plates at 37 ℃ with 5% CO2The incubator of (1) was left standing overnight. After the cells are attached to the wall, 100. mu.l of the mixture containing 0. mu.M, 50. mu.M, 100. mu.M, 150. mu.M, 200. mu.M, and 250. mu. M H were added2O2DMEM/F12 medium. After 4h incubation, the medium was aspirated and discarded and washed 3 times with PBS, DMEM/F12 mixed with 10% CCK8 at 37 ℃ with 5% CO according to the instructions2After incubation for 2h in an incubator of (1)Absorbance values were measured for each group on the instrument using absorbance at 450 nm.
② the magnesium caffeate nano-particles for inhibiting oxidative stress induction of nucleus pulposus cells
Cells in log-extended phase were treated with 1ml of 0.25% trypsin at 37 ℃ in 5% CO2The digestion was stopped with DMEM/F12 medium containing 10% FBS for 1min, and the cell suspension was centrifuged at 1200rpm for 3min and then resuspended in 10% FBS DMEM/F12 medium and counted. The cells were seeded at 10k per well in 96-well plates at 37 ℃ with 5% CO2The incubator of (1) was left standing overnight. After the cells adhered to the wall, 100. mu.l of the corresponding culture medium was added, respectively, as shown in Table 1. After 4h incubation, the medium was aspirated and discarded and washed 3 times with PBS, DMEM/F12 mixed with 10% CCK8 at 37 ℃ with 5% CO according to the instructions2After incubation for 2h in the incubator, absorbance values of each group were measured on a microplate reader with absorbance of 450 nm. The experimental groups are shown in table 1:
table 1: test grouping
| Group of | 1 | 2 | 3 | 4 | 5 | 6 | 7 |
| 150μM H2O2 | - | + | + | + | + | + | + |
| Magnesium caffeate nanoparticles (mg/L) | - | 5 | 2.5 | 1.25 | 0.625 | 0.3125 | - |
③ magnesium caffeate nanoparticles for inhibiting nucleus pulposus oxidative stress induced apoptosis detection
Cells in log-extended phase were treated with 1ml of 0.25% trypsin at 37 ℃ in 5% CO2The digestion was stopped with DMEM/F12 medium containing 10% FBS for 1min, and the cell suspension was centrifuged at 1200rpm for 3min and then resuspended in 10% FBS DMEM/F12 medium and counted. 100k cells per well were seeded in 24-well plates and left overnight in an incubator with 5% CO2 at 37 ℃. After the cells adhered to the wall, 1000. mu.l of the corresponding culture medium was added, respectively, as shown in Table 1. After culturing for 4h, sucking and discarding the culture medium, washing with PBS for 3 times, digesting the cells with 0.25% trypsin to obtain cell suspension, adding 10% FBS DMEM/F12 culture solution to stop digestion, centrifuging at 1200rpm for 3min, adding Annexin V-FITC/PI reaction solution, incubating at room temperature for 15min, and detecting by using an image flow detection system.
Magnesium caffeate nano-particles for inhibiting oxidative stress induction of nucleus pulposus cells
For in logarithmic growth periodAdding 1ml of 0.25% trypsin at 37 ℃ and 5% CO2The digestion was stopped with DMEM/F12 medium containing 10% FBS for 1min, and the cell suspension was centrifuged at 1200rpm for 3min and then resuspended in 10% FBS DMEM/F12 medium and counted. 100k cells per well were seeded in 24-well plates at 37 ℃ with 5% CO2The incubator of (1) was left standing overnight. After the cells adhered to the wall, 1000. mu.l of the corresponding culture medium was added, respectively, as shown in Table 1. After 4h of culture, the medium was aspirated and discarded, washed 3 times with PBS, the cell suspension was obtained after digestion of the cells with 0.25% trypsin, digestion was stopped by adding 10% FBS DMEM/F12, and after centrifugation at 1200rpm for 3min 500. mu.l of a 1: 1000 diluted DCFH-DA working solution is resuspended, incubated in a cell culture box at 37 ℃ for 30min, and then taken out every 10min and lightly blown to resuspend. After incubation, the cells were washed 3 times with serum-free medium to remove sufficiently active oxygen fluorescent probe (DCFH-DA) that did not enter the cells, and resuspended in serum-free medium of appropriate volume before detection using an image flow detection system.
As a result, as shown in FIG. 4, the magnesium caffeate of the present invention was capable of reducing H2O2Damage to cells can be prevented by2O2Induced apoptosis.
Finally, 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 protection scope of the present invention, and although the present invention is described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.
Claims (9)
1. A preparation method of metal chelate nanoparticles of caffeic acid or derivatives thereof is characterized by comprising the following steps:
s1, dissolving caffeic acid or derivatives thereof and metal chloride in the water phase solution, stirring until the caffeic acid or derivatives thereof and the metal chloride are completely dissolved, and adjusting the pH value of the solution to be weakly acidic, neutral or alkaline;
s2, reacting the solution obtained in the step S1 for a period of time, washing, and freeze-drying the obtained reaction product to obtain dark brown powder, namely the caffeic acid metal chelate nano-particles.
2. The method of claim 1, wherein the molar ratio of caffeic acid or a derivative thereof to metal chloride is: 0.1-10: 1.
3. The method of claim 1, wherein the metal chloride comprises: one of magnesium chloride, calcium chloride, ferric chloride, cupric chloride, zinc chloride or cobalt chloride.
4. The method according to claim 1, wherein the aqueous solution is a mixed solution of ethanol and water, and the volume ratio of the ethanol to the water is: 1:1.
5. The method according to claim 1, wherein the pH of the solution is adjusted to 5 to 12.
6. A metal chelate nanoparticle of caffeic acid or a derivative thereof prepared by the preparation method as described in any one of claims 1 to 5.
7. Use of the nanoparticles of claim 6 as an antioxidant.
8. The use of claim 7, wherein the antioxidant is for reducing intracellular reactive oxygen species levels.
9. Use of the nanoparticle of claim 6 as an agent against apoptosis.
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