CN115350175A - Self-assembled nano-drug, preparation method and application thereof - Google Patents

Self-assembled nano-drug, preparation method and application thereof Download PDF

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CN115350175A
CN115350175A CN202210998085.1A CN202210998085A CN115350175A CN 115350175 A CN115350175 A CN 115350175A CN 202210998085 A CN202210998085 A CN 202210998085A CN 115350175 A CN115350175 A CN 115350175A
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hydroxycinnamic acid
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林君
孟琪
马平安
丁彬彬
逄茂林
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Changchun Institute of Applied Chemistry of CAS
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Abstract

The invention provides a self-assembled nano-drug, a preparation method and application thereof. The self-assembly nano-drug is formed by the reaction of ferric iron and alpha-cyano-4-hydroxycinnamic acid. The preparation method of the self-assembly nano-drug is simple, the preparation is carried out in aqueous solution at room temperature, the conditions are mild, the environment is friendly, the repeatability is strong, the batch preparation can be realized, the raw material cost is low, the stability and the drug encapsulation rate are excellent, the encapsulation rate of the alpha-cyano-4-hydroxycinnamic acid is not less than 85%, the tumor cell selectivity is good, the self-assembly nano-drug can be used for preparing tumor treatment drugs, and the tumor treatment effect can be improved.

Description

Self-assembled nano-drug, preparation method and application thereof
Technical Field
The invention relates to the technical field of biomedical nano materials, in particular to a self-assembled nano medicine, a preparation method and application thereof.
Background
In 1923, the phenotypic characteristics of cancer cells were first observed by Otto Warburg, showing that high glucose uptake and excess lactate formation occurred even in the presence of sufficient oxygen, which was later referred to as the Warburg effect. Lactic acid generated by cancer cells is further secreted to extracellular space for accumulation, and the lactic acid accumulated in a tumor microenvironment can inhibit the immune response of an organism through various ways, thereby seriously affecting the tumor immunotherapy effect. Thus, targeting lactate metabolism may become an emerging, effective adjuvant cancer treatment strategy.
alpha-Cyano-4-Hydroxycinnamic Acid (alpha-Cyano-4-Hydroxycinnamic Acid, CHCA) is a monocarboxylic Acid transporter 1 (MCT 1) inhibitor, can effectively destroy the lactic Acid transmission chain of tumor cells, induce the accumulation of lactic Acid in the tumor cells, reduce the content of lactic Acid outside the tumor cells, and realize the immunotherapy of lactic Acid metabolism regulation and enhancement. However, CHCA has poor water solubility and biocompatibility, greatly limiting its further use.
At present, mesoporous materials or nanomaterials are generally adopted to coat the materials and deliver the mesoporous materials or nanomaterials into tumor cells, so that the bioavailability of the mesoporous materials or nanomaterials is improved to a certain extent, but the loading rate of the materials obtained in the mode on CHCA is low, generally below 10%, and the materials cannot effectively encapsulate drugs.
Disclosure of Invention
In view of this, the present invention provides a self-assembled nano-drug, a preparation method and applications thereof. The self-assembled nano-drug can greatly improve the loading rate (not less than 85%) of CHCA, and has good tumor selectivity.
In a first aspect, the present invention provides a self-assembled nano-drug formed by the reaction of ferric iron and alpha-cyano-4-hydroxycinnamic acid.
Preferably, the encapsulation rate of the alpha-cyano-4-hydroxycinnamic acid in the self-assembled nano-medicament is not less than 85%.
Preferably, the particle size of the self-assembled nano-drug is 40-60 nm.
In a second aspect, the present invention provides a method for preparing the self-assembled nano-drug, comprising the following steps:
and mixing the ferric iron compound solution and the alpha-cyanogen-4-hydroxycinnamic acid solution, and reacting to obtain the self-assembled nano-medicament.
Preferably, the alpha-cyano-4-hydroxycinnamic acid solution is obtained by mixing alpha-cyano-4-hydroxycinnamic acid with an organic solvent.
Preferably, the organic solvent comprises any one or more of dimethylsulfoxide, N-dimethylformamide, or anhydrous methanol.
Preferably, the ferric compound comprises any one or more of ferric chloride, ferric nitrate or ferric sulphate.
Preferably, the mass ratio of the ferric iron compound to the alpha-cyano-4-hydroxycinnamic acid is 1 (0.8-1.25).
Preferably, the mass concentration of the ferric iron compound in the ferric iron compound solution is 0.2-0.8 mg/mL.
Preferably, the mass concentration of the alpha-cyano-4-hydroxycinnamic acid in the alpha-cyano-4-hydroxycinnamic acid solution is 3-8 mg/mL.
In a third aspect, the invention provides a tumor treatment drug, which comprises the self-assembled nano-drug or the self-assembled nano-drug prepared by the preparation method.
Compared with the prior art, the invention has the beneficial effects that:
(1) The self-assembled nano-drug provided by the invention has excellent stability and drug encapsulation rate, the encapsulation rate of alpha-cyano-4-hydroxycinnamic acid is not less than 85%, and the self-assembled nano-drug has good tumor cell selectivity, can be used for preparing tumor treatment drugs, and can improve the treatment effect on tumors;
(2) The preparation method of the self-assembly nano-drug provided by the invention is simple, is carried out in aqueous solution at room temperature, has mild conditions, is environment-friendly, has strong repeatability, can realize batch preparation, has low raw material cost and has great application prospect.
Drawings
FIG. 1 is an SEM image of the self-assembled nano-drug obtained in example 1;
FIG. 2 is an SEM image of the self-assembled nano-drug obtained in example 8;
FIG. 3 is an SEM image of the self-assembled nano-drug obtained in example 9;
FIG. 4 is a TEM image of the self-assembled nano-drug obtained in example 9;
FIG. 5 is a graph showing the inhibition results of the self-assembled nano-drug obtained in example 9 on mouse colon cancer cells (CT 26);
wherein Iactate-RMPI represents 1640 medium supplemented with lactic acid, and RMPI represents pure 1640 medium
FIG. 6 is a graph showing the results of inhibition of normal mouse cells (L929) by the self-assembled nano drug Fe (III) -CHCA obtained in example 9.
Detailed Description
The technical solutions of the present invention will be described clearly and completely below with reference to embodiments of the present invention, and it should be apparent 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.
All the raw materials involved in the present invention are not particularly limited in their sources, and may be purchased from the market or prepared according to a conventional method well known to those skilled in the art.
The invention provides a self-assembly nano-drug which is formed by the reaction of ferric iron and alpha-cyanogen-4-hydroxycinnamic acid.
In the invention, the self-assembled nano-drug is preferably formed by the coordination reaction of ferric iron and active groups such as hydroxyl or carboxyl on the surface of alpha-cyano-4-hydroxycinnamic acid. The alpha-cyano-4-hydroxycinnamic acid is a monocarboxylic acid transporter 1 (MCT 1) inhibitor, can effectively destroy the lactic acid transmission chain of tumor cells, induce the accumulation of lactic acid in the tumor cells, and reduce the content of lactic acid outside the tumor cells, thereby realizing the immunotherapy of lactic acid metabolism regulation and enhancement. The source of the alpha-cyano-4-hydroxycinnamic acid is not particularly limited in the present invention, and may be any commercially available product. In the invention, the encapsulation rate of the alpha-cyano-4-hydroxycinnamic acid in the self-assembled nano-medicament is preferably not less than 85 percent, even not less than 86 percent. The particle size of the self-assembly nano-medicament is preferably 40-60 nm, and more preferably 45-55 nm.
In a second aspect, the present invention provides a method for preparing the self-assembled nano-drug, comprising the following steps:
and mixing the ferric iron compound solution and the alpha-cyanogen-4-hydroxycinnamic acid solution, and reacting to obtain the self-assembled nano-medicament.
In the present invention, it is preferable that the compound solution of ferric iron and the α -cyano-4-hydroxycinnamic acid solution are mixed and then reacted to obtain the self-assembled nano-drug. In the present invention, the ferric compound solution is preferably obtained by mixing a ferric compound and a solvent. The ferric compound preferably comprises any one or more of ferric chloride, ferric nitrate or ferric sulphate. In the present invention, the source of the ferric iron compound is not particularly limited, and a commercially available product is generally used. The solvent is preferably water, more preferably deionized water. The mass concentration of the ferric compound in the ferric compound solution is preferably 0.2 to 0.8mg/mL, and more preferably 0.2 to 0.6mg/mL. In the present invention, the α -cyano-4-hydroxycinnamic acid solution is preferably obtained by mixing α -cyano-4-hydroxycinnamic acid with an organic solvent. The organic solvent preferably comprises any one or more of dimethylsulfoxide, N-dimethylformamide or anhydrous methanol. The mass concentration of the alpha-cyano-4-hydroxycinnamic acid in the alpha-cyano-4-hydroxycinnamic acid solution is preferably 3 to 8mg/mL, and more preferably 3 to 6mg/mL.
In the present invention, the order of addition of the ferric compound solution and the α -cyano-4-hydroxycinnamic acid solution is not particularly limited, and it is preferable to add the α -cyano-4-hydroxycinnamic acid solution to the ferric compound solution for reaction, and it is more preferable to add the α -cyano-4-hydroxycinnamic acid solution to the ferric compound solution under stirring. The reaction is preferably carried out under stirring. The reaction temperature is preferably room temperature, and the reaction time is preferably 1min to 24 hours, and more preferably 1min to 12 hours. In the present invention, the mass ratio of the ferric iron compound to the α -cyano-4-hydroxycinnamic acid is preferably 1 (0.8-1.25), and may be 1. In the invention, preferably, after the ferric iron compound solution and the alpha-cyanogen-4-hydroxycinnamic acid solution are mixed and reacted, the mixed solution is centrifuged, and the precipitate is collected to obtain the self-assembled nano-drug. The invention also preferably washes the precipitate, the reagent for washing is preferably water, more preferably deionized water, and the number of washing is preferably not less than 2.
In the preparation method provided by the invention, the whole reaction process is carried out under the conditions of aqueous solution and room temperature, the conditions are mild, the environment is friendly, the operation steps are simple, the reaction time is short, ultrafast self-assembly can be realized under the room temperature condition through the coordination between ferric ions and CHCA, the repeatability is strong, the cost of raw materials is low, and batch preparation can be realized.
In a third aspect, the invention provides a tumor treatment drug, which comprises the self-assembled nano-drug or the self-assembled nano-drug prepared by the preparation method.
In the invention, the self-assembly nano-drug does not introduce any other chemical substances except CHCA drugs and ferric ions, the encapsulation rate of the CHCA drugs is not lower than 85%, and the obtained nano-drug has good tumor cell selectivity, can be used for preparing tumor treatment drugs, and can effectively improve the treatment effect on tumor cells.
In order to further illustrate the present invention, the following examples are provided for illustrative purposes. The starting materials used in the following examples of the present invention are not particularly limited in their sources, and may be purchased from the market or prepared according to conventional methods well known to those skilled in the art.
Example 1
This example provides a self-assembled nano-drug, which is prepared by the following steps:
5mg of ferric chloride was dispersed in 20mL of deionized water and 4mg of α -cyano-4-hydroxycinnamic acid was dispersed in 1mL of dimethyl sulfoxide at room temperature. And (3) placing the aqueous solution of the ferric chloride on a magnetic stirrer, dropwise adding the alpha-cyanogen-4-hydroxycinnamic acid solution under rapid stirring, and stirring and reacting for 10 hours at room temperature. And centrifuging to collect the precipitate, and washing for 2 times by using deionized water to obtain the Fe (III) -CHCA self-assembled nano-drug.
The surface morphology of the Fe (III) -CHCA self-assembled nano-drug is characterized by a scanning electron microscope, and the result is shown in figure 1, and the self-assembled nano-drug can be seen to be spherical particles with uniform size.
Example 2
4mg of ferric chloride was dispersed in 20mL of deionized water and 5mg of α -cyano-4-hydroxycinnamic acid was dispersed in 1mL of dimethyl sulfoxide at room temperature. And (3) placing the aqueous solution of the ferric chloride on a magnetic stirrer, dropwise adding the alpha-cyanogen-4-hydroxycinnamic acid solution while rapidly stirring, and stirring and reacting for 10 hours at room temperature. And centrifuging, collecting the precipitate, and washing twice with deionized water to obtain the Fe (III) -CHCA self-assembly nano-medicament.
Example 3
5mg of ferric chloride was dispersed in 20mL of deionized water and 5mg of α -cyano-4-hydroxycinnamic acid was dispersed in 1mL of dimethyl sulfoxide at room temperature. And (3) placing the aqueous solution of the ferric chloride on a magnetic stirrer, dropwise adding the alpha-cyanogen-4-hydroxycinnamic acid solution under rapid stirring, and stirring and reacting for 10 hours at room temperature. And (3) centrifuging, collecting the precipitate, and washing with deionized water for 3 times to obtain the Fe (III) -CHCA self-assembly nano-medicament.
Example 4
5mg of ferric chloride was dispersed in 20mL of deionized water and 5mg of alpha-cyano-4-hydroxycinnamic acid was dispersed in 1mL of N, N-dimethylformamide at room temperature. And (3) placing the aqueous solution of the ferric chloride on a magnetic stirrer, dropwise adding the alpha-cyanogen-4-hydroxycinnamic acid solution while rapidly stirring, and stirring and reacting for 10 hours at room temperature. And centrifuging, collecting the precipitate, and washing twice with deionized water to obtain the Fe (III) -CHCA self-assembly nano-medicament.
Example 5
5mg of ferric chloride was dispersed in 20mL of deionized water and 5mg of α -cyano-4-hydroxycinnamic acid was dispersed in 1mL of anhydrous methanol at room temperature. And (3) placing the aqueous solution of the ferric chloride on a magnetic stirrer, dropwise adding the alpha-cyanogen-4-hydroxycinnamic acid solution while rapidly stirring, and stirring and reacting for 10 hours at room temperature. Centrifuging, collecting the precipitate, and washing twice with deionized water to obtain the Fe (III) -CHCA self-assembled nano-drug.
Example 6
5mg of ferric chloride was dispersed in 10mL of deionized water and 5mg of α -cyano-4-hydroxycinnamic acid was dispersed in 1mL of dimethyl sulfoxide at room temperature. And (3) placing the aqueous solution of the ferric chloride on a magnetic stirrer, dropwise adding the alpha-cyanogen-4-hydroxycinnamic acid solution under rapid stirring, and stirring and reacting for 10 hours at room temperature. Centrifuging, collecting the precipitate, and washing twice with deionized water to obtain the Fe (III) -CHCA self-assembled nano-drug.
Example 7
5mg of ferric chloride was dispersed in 5mL of deionized water and 5mg of α -cyano-4-hydroxycinnamic acid was dispersed in 1mL of dimethyl sulfoxide at room temperature. And (3) placing the aqueous solution of the ferric chloride on a magnetic stirrer, dropwise adding the alpha-cyanogen-4-hydroxycinnamic acid solution while rapidly stirring, and stirring and reacting for 10 hours at room temperature. And (3) centrifuging, collecting the precipitate, and washing with deionized water for 3 times to obtain the Fe (III) -CHCA self-assembly nano-medicament.
Example 8
5mg of ferric chloride was dispersed in 20mL of deionized water and 5mg of α -cyano-4-hydroxycinnamic acid was dispersed in 1mL of dimethyl sulfoxide at room temperature. And (3) placing the aqueous solution of the ferric chloride on a magnetic stirrer, dropwise adding the alpha-cyanogen-4-hydroxycinnamic acid solution under rapid stirring, and stirring at room temperature for reaction for 1min. And centrifuging to collect the precipitate, and washing with deionized water for 4 times to obtain the Fe (III) -CHCA self-assembled nano-drug.
The surface morphology of the Fe (III) -CHCA self-assembled nano-drug is characterized by a scanning electron microscope, and the result is shown in figure 2, which shows that the self-assembled nano-drug is spherical particles with uniform size.
Example 9
5mg of ferric chloride was dispersed in 20mL of deionized water and 5mg of α -cyano-4-hydroxycinnamic acid was dispersed in 1mL of dimethyl sulfoxide at room temperature. And (3) placing the aqueous solution of the ferric chloride on a magnetic stirrer, dropwise adding the alpha-cyanogen-4-hydroxycinnamic acid solution while rapidly stirring, and stirring and reacting for 5min at room temperature. And centrifuging, collecting the precipitate, and washing with deionized water for 3 times to obtain the ultrafast self-assembled nano-drug Fe (III) -CHCA.
The surface morphology of the Fe (III) -CHCA self-assembled nano-drug was characterized by using a scanning electron microscope and a transmission electron microscope, respectively, and the results are shown in fig. 3-4, where fig. 3 is an SEM image of the self-assembled nano-drug and fig. 4 is a TEM image of the self-assembled nano-drug, and it can be seen that the self-assembled nano-drug is spherical particles with uniform size.
Example 10
5mg of ferric chloride was dispersed in 20mL of deionized water and 5mg of α -cyano-4-hydroxycinnamic acid was dispersed in 1mL of dimethyl sulfoxide at room temperature. And (3) placing the aqueous solution of the ferric chloride on a magnetic stirrer, dropwise adding the alpha-cyanogen-4-hydroxycinnamic acid solution under rapid stirring, and stirring at room temperature for reaction for 24 hours. Centrifuging, collecting the precipitate, and washing twice with deionized water to obtain the ultrafast self-assembled nano-drug Fe (III) -CHCA.
Performance testing
The self-assembled nano-drug obtained in examples 1 to 10 was subjected to Fe using an inductively coupled plasma spectrometer 3+ And CHCA content, as shown in table 1 below:
TABLE 1
Group of Fe 3+ Content (wt%) CHCA content (wt%)
Example 1 13.87 86.13
Example 2 13.77 86.23
Example 3 12.63 87.37
Example 4 14.72 85.28
Example 5 14.47 85.53
Example 6 13.52 86.48
Example 7 11.78 88.22
Example 8 13.25 86.75
Example 9 13.30 86.70
Example 10 12.57 87.43
As can be seen from the data in the table above, the self-assembled nano-drug provided by the present application has an excellent encapsulation efficiency on CHCA, which is all above 85%. In the prior art, zwitterionic Sulfobetaine (SBMA) is selected as a polymerization monomer, N, N' -bis- (acryloyl) cysteine (BAC) is selected as a cross-linking agent, PSBMA zwitterionic nanoparticles (PNPs for short) are obtained through free radical polymerization, and then L-Cys and CHCA are loaded to construct the zwitterionic H 2 Compared with the PCA of the S-driven nanomotor, the loading of L-Cys and CHCA by the PCA nanomotor is only 10% and 8%. In addition, the nano-drug has certain inhibition effect on tumor cells and dose dependence, but the concentration is 400 mug.mL -1 When the cell viability is increased, the cell viability can be reduced to about 34.3% within 24 hours.
The self-assembled nano-drug obtained in example 1 was tested for in vitro cytotoxicity analysis by the following method:
cytotoxicity was determined by the CCK-8 method: CT26 cells were seeded at a density of 6000 cells per well in 96-well plates and cultured in RMPI medium and RMPI medium containing 10mM lactic acid (Iactate-RMPI), respectively, for 12h. L929 cells were seeded in 96-well plates at a density of 6000 cells per well and cultured in MEM medium for 12h. Adding different concentrations of Fe (III) -CHCA (concentration range is 0-400 mug. Multidot.mL) -1 ) And (5) incubating for 24h, and detecting cell proliferation by using a CCK-8 detection method.
The test results are shown in FIGS. 5-6, and FIG. 5 is a graph showing the inhibition results of the self-assembled nano-drug Fe (III) -CHCA obtained in example 9 on mouse colon cancer cells (CT 26), wherein Iactate-RMPI indicates 1640 medium supplemented with lactic acid, and RMPI indicates pure 1640 medium; FIG. 6 is a graph showing the inhibition results of the self-assembled nano drug Fe (III) -CHCA obtained in example 9 on mouse normal cells (L929). As can be seen from FIG. 5, the self-assembled nano-drug Fe (III) -CHCA can achieve a certain inhibition effect on CT26 cells through the inhibition of lactic acid, and has dose dependence. As can be seen from FIG. 6, fe (III) -CHCA did not have a significant toxic effect on L929 cells. From the comparison of fig. 5-6, it can be seen that the self-assembled nano-drug Fe (III) -CHCA has good tumor cell selectivity.
The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.

Claims (10)

1. A self-assembled nano-medicine is prepared from the reaction between trivalent iron and alpha-cyano-4-hydroxycinnamic acid.
2. The self-assembled nano-drug according to claim 1, wherein the encapsulation efficiency of α -cyano-4-hydroxycinnamic acid in the self-assembled nano-drug is not less than 85%.
3. The self-assembled nano-drug according to claim 1, wherein the particle size is 40 to 60nm.
4. The method for preparing a self-assembled nano-drug according to any one of claims 1 to 3, comprising the steps of:
and mixing the ferric iron compound solution and the alpha-cyanogen-4-hydroxycinnamic acid solution, and reacting to obtain the self-assembled nano-medicament.
5. The method according to claim 4, wherein the α -cyano-4-hydroxycinnamic acid solution is obtained by mixing α -cyano-4-hydroxycinnamic acid with an organic solvent.
6. The method according to claim 5, wherein the organic solvent comprises any one or more of dimethylsulfoxide, N-dimethylformamide, or anhydrous methanol.
7. A method according to claim 4, wherein said ferric compound comprises any one or more of ferric chloride, ferric nitrate or ferric sulphate.
8. The preparation method according to claim 7, wherein the mass ratio of the ferric iron compound to the alpha-cyano-4-hydroxycinnamic acid is 1 (0.8-1.25).
9. The preparation method according to claim 4, wherein the mass concentration of the ferric compound in the ferric compound solution is 0.2 to 0.8mg/mL;
the mass concentration of the alpha-cyano-4-hydroxycinnamic acid in the alpha-cyano-4-hydroxycinnamic acid solution is 3-8 mg/mL.
10. A tumor treatment drug comprising the self-assembled nano-drug according to any one of claims 1 to 3 or the self-assembled nano-drug prepared by the preparation method according to any one of claims 4 to 9.
CN202210998085.1A 2022-08-19 2022-08-19 Self-assembled nano-drug, preparation method and application thereof Pending CN115350175A (en)

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CN116115751A (en) * 2023-04-07 2023-05-16 四川省医学科学院·四川省人民医院 Co-assembled photothermal starvation treatment nano regulator and preparation method thereof

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