CN114558142B - Glutathione-responsive polydopamine-based nano-drug as well as preparation method and application thereof - Google Patents

Glutathione-responsive polydopamine-based nano-drug as well as preparation method and application thereof Download PDF

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CN114558142B
CN114558142B CN202210080061.8A CN202210080061A CN114558142B CN 114558142 B CN114558142 B CN 114558142B CN 202210080061 A CN202210080061 A CN 202210080061A CN 114558142 B CN114558142 B CN 114558142B
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drug
polydopamine
based nano
glutathione
preparation
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CN114558142A (en
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李永生
王清华
曹渊渊
郝继娜
管梦佳
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East China University of Science and Technology
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • 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
    • A61K31/11—Aldehydes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The invention relates to a preparation method of a glutathione-responsive polydopamine-based nano-drug, which comprises the steps of co-dissolving a drug molecule solution, copper chloride dihydrate and dopamine hydrochloride in water to interact to obtain a mixed solution, wherein the molar ratio of drug molecules, copper ions and dopamine hydrochloride is 2:1:4-4:1:4; adding tris (hydroxymethyl) amino ethane into the mixed solution for reaction to obtain a reaction solution; and centrifuging and washing the reaction liquid to obtain the polydopamine-based nano-drug. The invention also provides a polydopamine-based nano-drug, wherein the polydopamine-based nano-drug comprises a copper-polydopamine carrier loaded with drug molecules. The invention also provides application of the polydopamine-based nano-drug in pharmacy, wherein the polydopamine-based nano-drug responds to glutathione. The polydopamine-based nano-drug has higher toxicity in cancer cells than normal cells and has the capability of selectively killing the cancer cells.

Description

Glutathione-responsive polydopamine-based nano-drug as well as preparation method and application thereof
Technical Field
The invention relates to a nano biological medicine, in particular to a glutathione-responsive polydopamine-based nano medicine, a preparation method and application thereof.
Background
In recent years, polydopamine-based nanomaterials have attracted considerable attention from researchers as a drug delivery vehicle with good biocompatibility and ease of functionalization (J.controlled Release,2018,290,56-74; angew.chem., int. Ed.,2021,133 (16): 9020-9029;ACS nano,2020,14 (3): 3546-3562). Typically the preparation of such materials comprises at least two steps: 1) Synthesizing polydopamine nano particles; 2) Drug molecule loading. If the drug loaded is a hydrophobic molecule, surface modifications to the resulting materials are also required to improve their biocompatibility and dispersibility.
The nano material prepared by the preparation method has poor selectivity, and can release medicines in normal cells and cancer cells at the same time, so that the normal tissues can be damaged. In addition, the drug loading step is cumbersome, and additional modification components may be introduced to affect the function of the material. Therefore, it is necessary to develop a novel polydopamine-based carrier which has both the characteristics of simple synthesis and characteristic response of cancer cells, thereby reducing the introduction of uncontrollable components and improving anticancer effects.
Disclosure of Invention
In order to solve the problems of complicated preparation steps and poor selectivity of the polydopamine-based nanomaterial in the prior art, the invention provides a polydopamine-based nanomaterial with glutathione response, and a preparation method and application thereof.
The invention provides a preparation method of a glutathione-responsive polydopamine-based nano-drug, which comprises the following steps: s1, dissolving a drug molecule in alcohol to obtain a drug molecule solution; s2, co-dissolving a medicine molecule solution, copper chloride dihydrate and dopamine hydrochloride in water to perform interaction to obtain a mixed solution, wherein the mol ratio of medicine molecules, copper ions and dopamine hydrochloride in the mixed solution is 2:1:4-4:1:4; s3, adding trimethylolethane into the mixed solution for reaction to obtain a reaction solution; s4, centrifuging and washing the reaction liquid to obtain the polydopamine-based nano-drug.
Preferably, the drug molecule in the step S1 is cinnamaldehyde.
Preferably, the alcohol in the step S1 is ethanol.
Preferably, the water in the step S2 is deionized water.
Preferably, the interaction in step S2 is performed at normal temperature. Preferably, the interaction is performed by stirring so that the drug, copper ions, and dopamine hydrochloride interact well. More preferably, the stirring is magnetic stirring. In a preferred embodiment, the stirring is carried out for 1 hour.
Preferably, the concentration of the tris (hydroxymethyl) aminoethane in the reaction solution in the step S3 is 2.5 to 5mg/mL. In a preferred embodiment, the concentration of trimethylolethane is 2.5mg/mL.
Preferably, the reaction in the step S3 is performed at normal temperature. Preferably, the reaction is carried out by stirring. More preferably, the stirring is magnetic stirring. In a preferred embodiment, the stirring is carried out for 3 hours.
Preferably, the centrifugal speed in the step S4 is 11000 to 13000rpm. In a preferred embodiment, the centrifugation speed is 13000rpm.
Preferably, the centrifugation time in the step S4 is 15 to 20 minutes. In a preferred embodiment, the centrifugation time is 15min.
Preferably, the centrifugation and the washing in step S4 are performed twice, respectively.
The invention also provides a polydopamine-based nano-drug, wherein the polydopamine-based nano-drug is obtained according to the preparation method, and the polydopamine-based nano-drug comprises a copper-polydopamine carrier loaded with drug molecules.
Preferably, the particle size distribution of the polydopamine-based nano-drug is 100-200 nm. More preferably, the average particle size of the polydopamine-based nano-drug is 167-184 nm.
The invention also provides application of the polydopamine-based nano-drug in pharmacy, wherein the polydopamine-based nano-drug responds to glutathione.
Preferably, after the doped copper ions in the polydopamine-based nano-drug are extracted by glutathione, the structure is broken and the contained drug molecules are released. Therefore, the polydopamine-based nano-drug is extracted by the ligand in the cell by utilizing the binding capacity of the doped copper ion, so that the polydopamine-based nano-drug becomes unstable and breaks, and the response breaking of the polydopamine-based carrier and the release of the load are realized.
Preferably, the concentration of glutathione is 10mM or more. It should be appreciated that the higher the concentration of glutathione in the cancer cells, the better the corresponding ability of the polydopamine-based nanomedicine. In a preferred embodiment, the cancer cell is a human liver cancer cell SMMC-7721.
According to the preparation method of the glutathione-responsive polydopamine-based nano-drug, the polymer co-doping method is utilized to dope drug molecules and copper ions into the polydopamine structure in one step, the flow is simple and quick, the operation is simple, the material cost is low, the reaction condition is mild, the repeatability is good, and the mass production is convenient. The polydopamine-based nano-drug prepared by the invention is solid spherical, uniform in particle size and good in dispersibility, and can be broken under the response of glutathione to release copper ions and drugs loaded in the structure. The polydopamine-based nano-drug has glutathione-responsive drug and copper ion release functions, ensures the response release of the polydopamine-based nano-drug in a high glutathione concentration environment of tumor tissues, has good anticancer effect, and has less damage to normal cells, namely the toxicity in cancer cells is higher than that of the normal cells, and the capacity of selectively killing the cancer cells is realized.
Drawings
FIG. 1 is a flow chart of a method for preparing a polydopamine-based nano-drug according to the present invention;
FIG. 2a is a polydopamine-based nano-drug (CA) obtained in example 1 according to the present invention 2 -Cu-PDA) dynamic light scattering particle size distribution statistics;
FIG. 2b is a polydopamine-based nano-drug (CA) obtained according to example 2 of the present invention 3 -Cu-PDA) dynamic light scattering particle size distribution statistics;
FIG. 2c is a polydopamine-based nano-drug (CA) obtained in example 3 according to the present invention 4 -Cu-PDA) dynamic light scattering particle size distribution statistics;
FIG. 3 is a polydopamine-based nano-drug (CA) obtained in example 2 according to the present invention 3 -Cu-PDA);
FIG. 4 is a polydopamine-based nano-drug (CA) obtained in example 2 according to the present invention 3 -Cu-PDA);
FIG. 5 is a polydopamine-based nano-drug (CA) obtained in example 2 according to the present invention 3 -Cu-PDA) post-glutathione triggered structural rupture;
FIG. 6 shows a polydopamine-based nano-drug (CA) obtained by the preparation method according to the present invention 3 -Cu-PDA) different glutathioneCopper ion release profile at the concentration of glycopeptide;
FIG. 7 shows a polydopamine-based nano-drug (CA) obtained by the preparation method according to the present invention 3 -Cu-PDA) drug release profile at different glutathione concentrations;
FIG. 8 shows a polydopamine-based nano-drug (CA) obtained by the preparation method according to the present invention 3 -Cu-PDA) toxicity statistics for cancer cells (human hepatoma cell SMMC-7721);
FIG. 9 shows a polydopamine-based nano-drug (CA) obtained by the preparation method according to the present invention 3 -Cu-PDA) toxicity statistics for normal cells (human normal hepatocytes LO-2).
Detailed Description
Preferred embodiments of the present invention will be described in detail with reference to the accompanying drawings.
Example 1
Referring to FIG. 1, 78.4mg of cinnamaldehyde was dissolved in 1mL of ethanol to obtain a cinnamaldehyde stock solution. 200. Mu.L of the cinnamaldehyde stock solution, 20.25mg of cupric chloride dihydrate and 45mg of dopamine hydrochloride are dissolved in 80mL of deionized water together to obtain a mixed solution. Stirring the mixed solution for 1h at normal temperature to ensure that the medicine, the copper ions and the dopamine hydrochloride fully interact, adding 200mg of trimethylolethane, and continuing to magnetically stir and react for three hours to obtain a reaction solution containing the raw materials and the polydopamine-based nano medicine. Washing the reaction solution with water twice at 13000rpm for 15min to obtain polydopamine nanometer medicine (CA) with average particle diameter of 167nm 2 -Cu-PDA), the product was dispersed in deionized water and stored at 4 ℃.
Example 2
The implementation method and the basic formulation are the same as those of example 1, and the addition amount of CA is only changed to 300 mu L, so that the nano-drug (CA) with the average particle size of 176nm is finally obtained 3 -Cu-PDA)。
Example 3
The implementation method and the basic formulation are the same as those of example 1, and the nano-drug (CA) with the average particle diameter of 184nm is finally obtained by only changing the adding amount of CA to 400 mu L 4 -Cu-PDA)。
FIG. 2a is the particle size distribution of the sample in example 1.
FIG. 2b is the particle size distribution of the sample in example 2.
FIG. 2c is the particle size distribution of the sample in example 3.
Fig. 3-4 are scanning electron microscope and transmission electron microscope images of the sample in example 2. The image shows that the obtained polydopamine-based nano-drug is solid sphere, has the particle size distribution of 100-200nm and has uniform size.
FIGS. 5 to 7 are graphs showing the material structure, copper ion release and drug release of samples of example 2 after different concentrations of glutathione. The data demonstrate that polydopamine-based nanomedicines can produce significant structural disruption upon stimulation with 10mM glutathione. Furthermore, more than 75% of the copper ions can be released over 4 hours under stimulation with 10mM glutathione, whereas less than 5% can be released without glutathione. Similarly, polydopamine nanomedicines can release more than 30% of the drug over 8 hours with 10mM glutathione stimulation, whereas release is only 16% without glutathione. Both the drug and the release of copper ions showed a pronounced glutathione responsiveness.
FIGS. 8-9 are graphs showing cytotoxicity statistics of the samples of example 2 against human liver cancer cell SMMC-7721 and human normal liver cell LO-2. Obviously, the obtained polydopamine-based nano-drug has no obvious toxicity (cell survival rate is more than 90%) to normal cells at a higher concentration (200 mu g/mL), and can kill about 50% of cells when the material concentration reaches 100 mu g/mL for tumor cells with high GSH expression, and the inhibition rate for cancer cells at a higher concentration (200 mu g/mL) is more than 90%. The above results further demonstrate that polydopamine-based nanomedicines have the ability to respond to glutathione, can release more drugs in cancer cells and exhibit better killing effects.
In summary, according to the preparation method of the invention, after the drug, copper ions and dopamine hydrochloride are blended, trimethylolethane is added to initiate polymerization to obtain the polydopamine-based nano-drug. The method can simplify the drug loading step, and the prepared anticancer agent has glutathione response drug and copper ion release capability.
The foregoing description is only a preferred embodiment of the present invention, and is not intended to limit the scope of the present invention, and various modifications can be made to the above-described embodiment of the present invention. All simple, equivalent changes and modifications made in accordance with the claims and the specification of this application fall within the scope of the patent claims. The present invention is not described in detail in the conventional art.

Claims (9)

1. The preparation method of the glutathione-responsive polydopamine-based nano-drug is characterized by comprising the following steps:
s1, dissolving a drug molecule in alcohol to obtain a drug molecule solution, wherein the drug molecule is cinnamaldehyde;
s2, co-dissolving a medicine molecule solution, copper chloride dihydrate and dopamine hydrochloride in water to perform interaction to obtain a mixed solution, wherein the mol ratio of medicine molecules, copper ions and dopamine hydrochloride in the mixed solution is 2:1:4-4:1:4;
s3, adding trimethylolethane into the mixed solution for reaction to obtain a reaction solution;
s4, centrifuging and washing the reaction liquid to obtain the polydopamine-based nano-drug.
2. The method according to claim 1, wherein the concentration of trimethylolethane in the reaction solution in step S3 is 2.5 to 5mg/mL.
3. The method according to claim 1, wherein the centrifugal rotational speed in the step S4 is 11000 to 13000rpm.
4. The method according to claim 1, wherein the centrifugation time in step S4 is 15 to 20min.
5. A polydopamine-based nano-drug, characterized in that the polydopamine-based nano-drug is obtained according to the preparation method of any one of claims 1-4, wherein the polydopamine-based nano-drug comprises a copper-polydopamine carrier loaded with drug molecules.
6. The polydopamine-based nano-drug according to claim 5, wherein the average particle size of the polydopamine-based nano-drug is 167-184 nm.
7. Use of the polydopamine-based nano-drug according to claim 5 or 6 in the manufacture of a medicament, wherein the polydopamine-based nano-drug is responsive to glutathione.
8. The use according to claim 7, wherein the doped copper ions in the polydopamine-based nano-drug, when extracted by glutathione, lead to structural rupture and release of the incorporated drug molecules.
9. The use according to claim 7, wherein the concentration of glutathione is 10mM or more.
CN202210080061.8A 2022-01-24 2022-01-24 Glutathione-responsive polydopamine-based nano-drug as well as preparation method and application thereof Active CN114558142B (en)

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