CN113121642A - Self-assembly polypeptide, redox response polypeptide hydrogel and preparation method and application thereof - Google Patents

Self-assembly polypeptide, redox response polypeptide hydrogel and preparation method and application thereof Download PDF

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CN113121642A
CN113121642A CN202011001560.0A CN202011001560A CN113121642A CN 113121642 A CN113121642 A CN 113121642A CN 202011001560 A CN202011001560 A CN 202011001560A CN 113121642 A CN113121642 A CN 113121642A
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葛亮
李宜平
朱颖
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/02—Linear peptides containing at least one abnormal peptide link
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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    • 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
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Abstract

The invention relates to a redox response polypeptide hydrogel and a preparation method and application thereof, belonging to the technical field of biomedical materials. The invention provides a polypeptide capable of self-assembling to form hydrogel, which dissolves in water and then is put in H2O2To form a redox responsive hydrogel upon crosslinking. The hydrogel has a compact fiber network structure, strong mechanical properties and good biocompatibility. The hydrogel has higher sensitivity to glutathione GSH, and the GSH response release of the drug can be realized by loading doxorubicin hydrochloride into the hydrogel. Tong (Chinese character of 'tong')The drug-loaded hydrogel is implanted into the tumor part in an injection mode, so that the anti-tumor effect of the drug can be improved, and the toxic and side effects of the drug on normal tissues can be effectively reduced.

Description

Self-assembly polypeptide, redox response polypeptide hydrogel and preparation method and application thereof
Technical Field
The invention belongs to the technology of biomedical materials, and particularly relates to a redox response polypeptide hydrogel, a preparation method thereof and application thereof as a drug loading material.
Background
Cancer is a serious threat to human life and health, and chemotherapy is still one of the most effective treatments at present. Common anticancer drugs such as anthracyclines, platinum metal complexes, taxanes and camptothecin anticancer drugs can effectively inhibit the growth of cancer cells, but can also cause damage to normal cells, so the clinical application of the anticancer drugs is greatly limited. In order to improve the curative effect of anticancer drugs and reduce the toxic and side effects thereof, various tumor-targeting nano drug delivery carriers have been developed, such as liposomes, micelles, dendrimers, etc. Although these drug delivery systems can improve drug distribution in tumor tissue by active or passive targeting, there are still many drawbacks such as unstable blood circulation and insufficient tissue distribution.
In order to improve the distribution of anticancer drugs in tumor tissues and reduce the toxic and side effects of the anticancer drugs on normal tissues, it becomes important to construct a highly targeted anticancer drug delivery system. It has been found that polypeptide hydrogels can meet the above requirements to a large extent. The polypeptide hydrogel is a water-swelling three-dimensional fiber network and has the characteristics of high water content, tissue-like elasticity, good biocompatibility, biodegradability and the like. The drug-loaded hydrogel is injected in situ at a tumor part, so that the drug can be directly concentrated in tumor tissues, the curative effect of the drug is improved, and the toxic and side effects are reduced. The drug-loaded hydrogel is administered in an in-situ injection mode, thereby avoiding surgical implantation and relieving the pain of patients.
In recent years, the design of polypeptide hydrogels has evolved from static systems to smart response systems. Smart-responsive polypeptide hydrogels can respond sensitively to environmental factors, including pH, metal ions and enzymes, and change their own properties (e.g., gel-to-sol transition) to achieve an irritating release of the drug. Currently, the most studied smart response polypeptide hydrogel is pH response type and metal ion response type, so that designing a more abundant smart response polypeptide hydrogel such as redox response type according to the characteristics of the tumor microenvironment (e.g. higher glutathione concentration) is a significant search.
Disclosure of Invention
The invention aims to provide a self-assembly polypeptide, which has a shorter amino acid sequence.
Another object of the present invention is to provide a redox-responsive polypeptide hydrogel formed from the self-assembled polypeptide described above.
Another objective of the invention is to provide a preparation method of the redox response polypeptide hydrogel, which is convenient to operate and low in cost.
The invention also aims to provide application of the redox response polypeptide hydrogel in preparing the anticancer drug-loaded hydrogel.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
a self-assembling polypeptide having the amino acid sequence: Ac-Leu-Ile-Val-Ala-Gly-Orn-Cys.
Figure BDA0002694509140000021
A redox-responsive polypeptide hydrogel is prepared by dissolving the polypeptide in H2O2A solution is formed.
A preparation method of redox response polypeptide hydrogel comprises the following specific steps: dissolving the self-assembled polypeptide in H2O2And (3) swirling the solution until the solution is dissolved to form a polypeptide solution, and standing the polypeptide solution at room temperature to form gel.
Wherein the concentration of the formed polypeptide solution is 10-30mg/ml, preferably 15-25 mg/ml.
Said H2O2The concentration of the solution is 0% to 0.3%, preferably 0.03% to 0.1%.
The application of the obtained redox response polypeptide hydrogel in preparing anticancer drug-loaded hydrogel is also within the protection scope of the invention.
Wherein, the anticancer drug is preferably adriamycin hydrochloride.
Has the advantages that: the invention has the advantages that: (1) the self-assembled polypeptide provided by the invention has lower immunogenicity and good biodegradability. (2) The invention is through H2O2The sulfhydryl of cysteine in the polypeptide is oxidized to form a disulfide bond, thereby effectively shortening the gelling time and improving the crosslinking degree of the hydrogel. And H2O2Is a mild oxidant, and is a mixture of a mild oxidant,has little harm to human body at low concentration. (3) The hydrogel provided by the invention has a simple preparation method, and only the polypeptide needs to be in H2O2The solution is dissolved in a vortex mode, and the redox response polypeptide hydrogel with uniformity, transparency and stable performance can be prepared by standing at room temperature. (4) The redox response hydrogel has higher sensitivity to reducing substances such as glutathione and the like. Glutathione reduces disulfide bonds in the hydrogel into sulfhydryl groups, reduces the crosslinking degree of the hydrogel, and therefore the release of the drug wrapped in the hydrogel is increased. The hydrogel is used as a delivery carrier of an anticancer drug, can form a drug reservoir at a tumor site, and can continuously release the drug under the stimulation of glutathione in a tumor microenvironment.
In conclusion, the invention uses the redox response hydrogel to load the anticancer drug, the delivery system forms a drug reservoir at the tumor part through in-situ injection, and has higher responsiveness to glutathione in tumor tissues, thereby realizing the redox response release of the anticancer drug, and effectively reducing the toxic and side effects of the anticancer drug while improving the curative effect of the anticancer drug.
Drawings
FIG. 1 is a graph of in vitro drug release of a drug-loaded hydrogel of example 10 of the present invention;
FIG. 2 is a graph showing the in vitro anti-tumor effect of the drug-loaded hydrogel in example 11 of the present invention;
FIG. 3 is a graph showing the change of tumor volume of Balb/c mice loaded with 4T1 tumor treated with the drug-loaded hydrogel of example 12 of the present invention;
FIG. 4 is a graph showing the H & E staining of the heart, liver, spleen, lung and kidney after the treatment period of Balb/c mice bearing the 4T1 tumor in example 12 of the present invention.
Detailed Description
To better illustrate the objects, aspects and advantages of the present invention, the following examples are further described below, wherein all reagents are commercially available reagents.
Example 1
A preparation method of redox response polypeptide hydrogel is carried out in two steps.
1. Synthesis of polypeptides
(1) Swelling of RINK resins
RINK resin was placed in a 150ml reactor and soaked with Dichloromethane (DCM). After 2 hours, the resin was washed with 3 resin volumes of N-Dimethylformamide (DMF) and then drained off until use.
(2) Removal of Fmoc protecting group
A quantity of 20% piperidine was added to the reactor and the Fmoc protecting group on the resin was removed. After deprotection, 3 resin volumes of DMF were washed and then drained.
(3) Activation and coupling of amino acids
The amino acid to be coupled is activated with the activator HOBT and added to the reactor for coupling.
(4) Peptide chain extension
Repeating the above steps of deprotection and coupling according to the amino acid sequence, and connecting the corresponding amino acids in sequence until the synthesis is completed.
(5) N-terminal acetylation
Adding a certain amount of acetic anhydride and DIEA into the reactor for reacting for half an hour, and sealing an N-terminal acetylation end.
(6) Cleavage of crude polypeptide
After deprotection, the polypeptide was cleaved from the resin using cleavage solution trifluoroacetic acid and centrifuged four times with glacial ethyl ether.
(7) Polypeptide purification
And separating and purifying the crude polypeptide product by using HPLC (high performance liquid chromatography), and freeze-drying to obtain the polypeptide with a certain purity higher than 95%.
2. Preparation of a Redox-responsive polypeptide hydrogel
Dissolving the synthesized polypeptide in 0.1% H2O2And (3) vortexing the solution to dissolve the polypeptide solution to form a polypeptide solution with the concentration of 10mg/ml, and standing the polypeptide solution at room temperature to form the redox response polypeptide hydrogel.
Example 2
The synthesis of the polypeptide was performed as in example 1. Dissolving the synthesized polypeptide in 0.1% H2O2The solution is vortexed to dissolve the polypeptide to form a polypeptide solution with a concentration of 15mg/mlAnd standing at room temperature to form the redox response polypeptide hydrogel.
Example 3
The synthesis of the polypeptide was performed as in example 1. Dissolving the synthesized polypeptide in 0.1% H2O2And (3) vortexing the solution to dissolve the polypeptide solution to form a polypeptide solution with the concentration of 20mg/ml, and standing the polypeptide solution at room temperature to form the redox response polypeptide hydrogel.
Example 4
The synthesis of the polypeptide was performed as in example 1. Dissolving the synthesized polypeptide in 0.1% H2O2And (3) vortexing the solution to dissolve the polypeptide solution to form a polypeptide solution with the concentration of 25mg/ml, and standing the polypeptide solution at room temperature to form the redox response polypeptide hydrogel.
Example 5
The synthesis of the polypeptide was performed as in example 1. Dissolving the synthesized polypeptide in 0.1% H2O2And (3) the solution is vortexed to be dissolved to form a polypeptide solution with the concentration of 30mg/ml, and the polypeptide solution is stood at room temperature to form the redox response polypeptide hydrogel.
Example 6
The synthesis of the polypeptide was performed as in example 1. Dissolving the synthesized polypeptide in 0% H2O2And (3) vortexing the solution to dissolve the polypeptide solution to form a polypeptide solution with the concentration of 20mg/ml, and standing the polypeptide solution at room temperature to form the redox response polypeptide hydrogel.
Example 7
The synthesis of the polypeptide was performed as in example 1. Dissolving the synthesized polypeptide in 0.03% H2O2And (3) vortexing the solution to dissolve the polypeptide solution to form a polypeptide solution with the concentration of 20mg/ml, and standing the polypeptide solution at room temperature to form the redox response polypeptide hydrogel.
Example 8
The synthesis of the polypeptide was performed as in example 1. The synthesized polypeptide was dissolved in 0.3% H2O2And (3) vortexing the solution to dissolve the polypeptide solution to form a polypeptide solution with the concentration of 20mg/ml, and standing the polypeptide solution at room temperature to form the redox response polypeptide hydrogel.
Example 9
Comparative examples 1-8 Redox polypeptide hydrogels prepared under different conditions are shown in Table 1.
TABLE 1 comparison of Redox polypeptide hydrogels prepared under different gelling conditions
Figure BDA0002694509140000051
Results are expressed as mean±SD.
The concentration range of the polypeptide in Table 1 is 10-30mg/ml, H2O2The concentration range of the solution is 0-0.3%. As can be seen from Table 1, different gelling conditions can affect the gelling time, gelling effect and oxidation efficiency of the polypeptide solution. When fixed H2O2The concentration of the solution was 0.1%, and the gel formation time required for increasing the polypeptide solution concentration from 10mg/ml to 30mg/ml became shorter and shorter, but when the concentration was as high as 30mg/ml, the hydrogel formed was in a turbid state. Therefore, in consideration of the gelling effect and gelling time, the concentration range of the polypeptide is preferably 15-25mg/ml, the gelling time is shorter in the concentration range, and the formed hydrogel is transparent and clear.
When the concentration of the polypeptide was fixed at 20mg/ml, H2O2When the concentration of the solution is increased from 0% to 0.3%, the gelling time of the polypeptide is shortened, and the content of residual mercaptan is reduced, which indicates that more disulfide bonds are generated by oxidation and the oxidation efficiency is increased. When H is present2O2The concentration of (2) is 0%, which indicates that only air is oxidized, and the oxidation efficiency is extremely low. When H is present2O2When the concentration of (B) is 0.3%, the oxidation efficiency is high, but flocculent fibers also appear. Considering the efficiency and toxicity of oxidation, H2O2The concentration of the solution is preferably in the range of 0.03% to 0.1%.
The oxidation efficiency was measured by the Ellman experimental method.
Example 10
In a preferred range, the redox-responsive polypeptide hydrogel in example 3 is selected to prepare an anticancer drug-loaded hydrogel, and the application of the hydrogel in-vitro redox-responsive drug release is studied, wherein the selected drug is doxorubicin hydrochloride (DOX).
DOX-Supported hydrogels were prepared analogously to example 3, except that D was prepared beforehandOX dissolved in 0.1% H2O2In the solution, the concentration of DOX is 2mg/ml, and finally, DOX-loaded hydrogel is obtained. 1ml of PBS solution (0mM, 2mM, 5mM, 10mM) containing different Glutathione (GSH) concentrations at pH 7.4 was then added to the DOX-loaded hydrogel, placed in a shaker at 37 ℃ at 120rpm, the release medium was removed for a particular application at a particular time point and supplemented with the same volume of fresh release medium.
FIG. 1 is a graph showing the drug release behavior of DOX-loaded hydrogels, where the increase in the release amount of DOX, as indicated by GSH response, occurs when the concentration of GSH in the release medium increases. The hydrogel is shown to have concentration-dependent sensitivity to reducing substances, and the drug can be controllably released through redox conditions.
Example 11
In a preferred range, the redox-responsive polypeptide hydrogel in example 3 is selected to prepare an anticancer drug-loaded hydrogel, and the application of the hydrogel in vitro anticancer effect is studied, wherein the selected drug is doxorubicin hydrochloride (DOX).
The DOX loaded hydrogel was prepared as in example 10. 4T1 mouse breast cancer cells were seeded into 96-well plates and then redox-responsive hydrogels, DOX, H at different concentrations diluted in DMEM cell culture medium were added2O2Solutions and DOX-loaded hydrogels were incubated with 4T1 cells for 48h, with blank media as a control. Cell viability and IC50 values were then measured by MTT.
The results are shown in fig. 2, and the cell viability of the redox hydrogel is over 95%, indicating that the hydrogel has good cell compatibility. The DOX-loaded hydrogel was effective in inhibiting cell proliferation and had an IC50 value of 2.39 μ g/ml, which was slightly greater than the IC50 value for DOX (1.39 μ g/ml). The drug-loaded hydrogel has good effect of inhibiting cancer cells. And H of DOX2O2The cell viability of the solution was not much different from that of DOX, indicating H2O2Has no great influence on the drug effect of DOX.
Example 12
In a preferred range, the redox-responsive polypeptide hydrogel in example 3 is selected to prepare an anticancer drug-loaded hydrogel, and the application of the hydrogel in vivo anticancer effect is studied, wherein the selected drug is doxorubicin hydrochloride (DOX).
The DOX loaded hydrogel was prepared as in example 10. The treatment effect of the drug-loaded hydrogel on Balb/c mice loaded with 4T1 tumor is as follows: taking 18 pieces of load 90-150mm3Balb/c mice with 4T1 tumor were divided into 3 groups, which were physiological saline group, DOX group, and DOX-loaded hydrogel group. Different solutions are injected into the tumor part for treatment, and the injection dose is 100 mu l/20 g. After the antitumor cycle was completed, the patient was sacrificed, and the heart, liver, spleen, lung and kidney were dissected and removed and fixed with formalin. Then embedding with paraffin, slicing, and carrying out H&E, staining, and observing the necrosis of the cells.
FIG. 3 is a graph showing the change in tumor volume during the treatment cycle, compared to the saline group, the DOX group and the DOX hydrogel-loaded mouse significantly inhibited the increase in tumor volume, and the DOX hydrogel-loaded group had an inhibitory effect significantly higher than that of the DOX group, indicating that the DOX hydrogel-loaded mouse had a superior inhibitory effect on 4T1 tumors.
Fig. 4 shows H & E staining conditions of organs of mice in the saline, DOX, and DOX-loaded hydrogel groups, in which both heart and kidney of the DOX group showed necrosis, and both heart, liver, spleen, lung, and kidney of the DOX-loaded hydrogel group showed no necrosis, indicating that the redox hydrogel drug delivery system can effectively reduce toxic and side effects of DOX on normal tissues.

Claims (7)

1. A self-assembling polypeptide, wherein the amino acid sequence is: Ac-Leu-Ile-Val-Ala-Gly-Orn-Cys.
2. A redox-responsive polypeptide hydrogel formed by dissolving the self-assembled polypeptide of claim 1 in H2O2A solution is formed.
3. The method for preparing a hydrogel of a redox-responsive polypeptide of claim 2, wherein the self-assembling polypeptide is dissolved in H2O2And (3) swirling the solution until the solution is dissolved to form a polypeptide solution, and standing the polypeptide solution at room temperature to form gel.
4. The method for preparing a redox-responsive polypeptide hydrogel of claim 3, wherein H is2O2The concentration of the solution is within 0.3 percent, and the concentration of the polypeptide solution is 10-30 mg/ml.
5. The method for preparing a redox-responsive polypeptide hydrogel of claim 3, wherein H is2O2The concentration of the solution is 0.03-0.1%, and the concentration of the polypeptide solution is 15-25 mg/ml.
6. Use of the redox-responsive polypeptide hydrogel of claim 2 in the preparation of an anticancer drug-loaded hydrogel.
7. The use according to claim 6, wherein the anticancer agent is doxorubicin hydrochloride.
CN202011001560.0A 2020-09-22 2020-09-22 Self-assembly polypeptide, redox response polypeptide hydrogel and preparation method and application thereof Pending CN113121642A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113754730A (en) * 2021-09-17 2021-12-07 中国药科大学 Polypeptide capable of self-assembling to form PH-responsive drug-loaded hydrogel, preparation method and application thereof
CN113956328A (en) * 2021-10-20 2022-01-21 中国药科大学 Preparation and application of polypeptide hydrogel with double enzyme responses

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CN111253481A (en) * 2020-01-19 2020-06-09 中国海洋大学 Preparation and application of bionic intelligent hydrogel
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WO2011123061A1 (en) * 2010-03-31 2011-10-06 Agency For Science, Technology And Research Amphiphilic linear peptide/peptoid and hydrogel comprising the same
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113754730A (en) * 2021-09-17 2021-12-07 中国药科大学 Polypeptide capable of self-assembling to form PH-responsive drug-loaded hydrogel, preparation method and application thereof
CN113956328A (en) * 2021-10-20 2022-01-21 中国药科大学 Preparation and application of polypeptide hydrogel with double enzyme responses

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