CN107794280B - Targeted cell-penetrating peptide gene vector and application thereof - Google Patents
Targeted cell-penetrating peptide gene vector and application thereof Download PDFInfo
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- CN107794280B CN107794280B CN201710883839.8A CN201710883839A CN107794280B CN 107794280 B CN107794280 B CN 107794280B CN 201710883839 A CN201710883839 A CN 201710883839A CN 107794280 B CN107794280 B CN 107794280B
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- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/87—Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation
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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
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
- A61K48/0008—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition
- A61K48/0025—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition wherein the non-active part clearly interacts with the delivered nucleic acid
- A61K48/0041—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition wherein the non-active part clearly interacts with the delivered nucleic acid the non-active part being polymeric
Abstract
The invention discloses a targeting cell-penetrating peptide gene vector and application thereof, wherein the amino acid sequence of the targeting cell-penetrating peptide gene vector is as follows: REDV-Gm‑YGRKKRRQRRR‑Gn-PKKKRKV, wherein: m is 1-4, n is 1-4. The targeting cell-penetrating peptide gene vector has better biocompatibility and basically has no toxicity to endothelial cells. The targeting cell-penetrating peptide gene carrier carries genes to selectively enter endothelial cells, thereby promoting the proliferation and migration of the endothelial cells and being beneficial to the formation of blood vessels. The targeting cell-penetrating peptide gene vector has the functions of cell-penetrating peptide and nuclear localization signals, and is favorable for carrying genes to efficiently enter cells and cell nucleuses, so that the gene delivery effect is greatly improved, and the purpose of gene therapy is achieved. The invention improves the gene delivery effect and promotes the angiogenesis at the position of defective vascular tissues.
Description
Technical Field
The invention belongs to the field of molecular biology, and relates to a targeted cell-penetrating peptide gene vector and application thereof.
Background
At present, cardiovascular diseases are increasingly prevalent. Cardiovascular diseases remain one of the leading causes of death worldwide due to poor clinical efficacy and significant cost of treatment. Currently, gene therapy has attracted increasing attention from researchers in methods for treating congenital and acquired cardiovascular diseases. With the identification of the pathophysiological molecular pathways of heart failure and related cardiovascular diseases, preclinical tests of gene therapy are developed in small and large animal models and gradually become clinical, however, the initial clinical effects do not reach the expected targets. Viral vectors are controversial for their safety issues. The non-viral gene vector well avoids the problem of the viral vector, but the main problems of high cytotoxicity, poor selectivity, low cellular uptake efficiency, difficulty in entering cell nucleus, poor transfection efficiency, low gene expression level and the like are that the therapeutic gene carried by the gene vector cannot be accumulated in target tissues or cells.
An effective gene delivery system is the key of gene therapy, and how to obtain a safe and efficient gene vector is very important research content. In recent years, cationic polymer gene vectors have attracted much attention because of their easy preparation and modification, high transfection efficiency, and other features. But has high cell transfection efficiency and high cytotoxicity due to the high charge density. Therefore, how to obtain a targeting gene vector with low toxicity and high efficiency is still the direction of the researchers. The gene delivery process is very complex, needs to cross multiple barriers, and how to efficiently cross cell membranes, efficiently escape from endosomes and efficiently enter cell nuclei remains the key point for designing gene vectors. The gene vector based on the cell-penetrating peptide has high biocompatibility and special cell-penetrating effect, has great development potential in the aspect of gene vector design, but the research of the gene vector is limited due to the lack of specificity. Therefore, the design of safe, efficient and specific gene vectors still faces great challenges.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a targeting cell-penetrating peptide gene vector which has good biocompatibility, high-efficiency gene delivery effect and targeting property on endothelial cells.
The second purpose of the invention is to provide the application of the targeting cell-penetrating peptide gene vector.
The third purpose of the invention is to provide a second targeting cell-penetrating peptide gene vector.
The fourth purpose of the invention is to provide the application of the second targeting cell-penetrating peptide gene vector.
The technical scheme of the invention is summarized as follows:
a targeted cell-penetrating peptide gene vector, wherein the amino acid sequence of the vector is as follows:
REDV-YGRKKRRQRRR-PKKKRKV, shown in SEQ ID NO. 1;
the application of the targeting cell-penetrating peptide gene vector delivery gene is provided.
The second targeting cell-penetrating peptide gene vector has the amino acid sequence as follows:
REDV-Gm-YGRKKRRQRRR-Gn-PKKKRKV, wherein: m is 1-4, n is 1-4.
Preferably: m is 4 and n is 4.
When m is 1 and n is 1, REDV-Gm-YGRKKRRQRRR-GnPKKKRKV is shown in SEQ ID NO. 2;
when m is 4, n is 4, REDV-Gm-YGRKKRRQRRR-GnPKKKRKV is shown in SEQ ID NO. 3;
the second targeting cell-penetrating peptide gene vector target and the application of preferably delivering genes to the cell-penetrating peptide gene vector.
The invention has the advantages that:
(1) the targeting cell-penetrating peptide gene vector adopts polypeptide as the gene vector, has better biocompatibility and basically has no toxicity to endothelial cells.
(2) The targeting cell-penetrating peptide gene carrier carries genes to selectively enter endothelial cells, thereby promoting the proliferation and migration of the endothelial cells and being beneficial to the formation of blood vessels.
(3) The targeting cell-penetrating peptide gene vector has the functions of cell-penetrating peptide and nuclear localization signals, and is favorable for carrying genes to efficiently enter cells and cell nucleuses, so that the gene delivery effect is greatly improved, and the purpose of gene therapy is achieved.
(4) The invention adopts the cell-penetrating peptide TAT as a load gene part, reduces the toxicity of a gene vector, and improves the biocompatibility and the cell uptake rate of the gene vector. In addition, the REDV polypeptide and the nuclear localization sequence NLS are integrated into the TAT sequence, the endothelial cell selectivity and the nuclear localization function of the gene vector are endowed, and in order to enable the three polypeptide sequences to better exert the respective functions, flexible glycine is introduced among the three polypeptide sequences, so that the gene delivery effect is improved, and the angiogenesis at the position of a defective vascular tissue is promoted.
Drawings
FIG. 1 is a diagram of relative cellular activities of a targeting cell-penetrating peptide gene vector and its gene complex.
FIG. 2(1) is a graph of cell migration at 6 hours.
FIG. 2(2) is the number of cell migrations calculated from Image-Pro Plus 6.0.
FIG. 3(1) is an in vitro blood vessel mapping.
FIG. 3(2) shows the number of vascular structures counted from Image-Pro Plus 6.0.
In vitro blood vessel mapping.
Detailed Description
The present invention will be further described with reference to the following examples. It should be understood that the examples of the present invention are illustrative only and are not intended to limit the scope of the present invention. Further, after reading the teaching of the present invention, the skilled person can make changes or modifications to the invention, and such equivalent forms also fall within the scope defined by the claims of the present application.
Hy926 cells were purchased from the cell bank of the chinese academy of sciences (shanghai research and development public service platform).
The targeting cell-penetrating peptide gene vector of the invention comprises the following components:
REDV-YGRKKRRQRRR-PKKKRKV and REDV-Gm-YGRKKRRQRRR-Gn-PKKKRKV：
Wherein the sequence REDV is derived from a polypeptide sequence of natural fibronectin and has the function of specific selective adhesion to endothelial cells.
The sequence YGRKKRRQRRR(TAT) is derived from a polypeptide sequence of human immunodeficiency virus (HIV-1) and has the function of transferring to cytoplasm and nucleus through a membrane.
The sequence pkkkrkv (nls) is derived from the large T antigen of simian virus 40(SV 40).
Example 1
A targeted cell-penetrating peptide gene vector has an amino acid sequence of REDV-YGRKKRRQRRR-PKKKRKV (REDV-TAT-NLS) (shown in SEQ ID NO. 1).
Example 2
A targeted cell-penetrating peptide gene vector has an amino acid sequence of REDV-G-YGRKKRRQRRR-G-PKKKRKV (REDV-G-TAT-G-NLS) (shown in SEQ ID NO. 2).
Example 3
A targeted cell-penetrating peptide gene vector, the amino acid sequence of which is REDV-G4-YGRKKRRQRRR-G4-PKKKRKV(REDV-G4-TAT-G4-NLS) (shown in SEQ ID NO. 3).
Example 4
Targeting cell-penetrating peptide gene vector (hereinafter referred to as gene vector) and ZNF580 gene (the ZNF580 gene is taken as an example in the invention, but the gene is not limited to the invention) to prepare a gene compound with the N/P molar ratio of 30, and the method comprises the following steps:
an aqueous solution of ZNF580 gene (shown in SEQ ID No. 4) at a concentration of 0.10 mg/ml was added dropwise to the aqueous solution of the gene vector at a ratio of N/P (nitrogen in the gene vector/phosphorus in ZNF580 gene) of 30 under stirring, and stirred for 1 hour to obtain a gene complex.
A control cell-penetrating peptide gene vector (hereinafter referred to as a control gene vector) having a sequence of YGRKKRRQRRR-PKKKRKV (TAT-NLS) and ZNF580 gene was prepared as a control gene complex having an N/P molar ratio of 30, comprising the steps of:
an aqueous solution of ZNF580 gene (shown in SEQ ID No. 4) at a concentration of 0.10 mg/ml was added dropwise to the aqueous solution of the control gene vector at a ratio of N/P (nitrogen in the control gene vector/phosphorus in ZNF580 gene) of 30 under stirring, and stirred for 1 hour to obtain a control gene complex.
The cytotoxicity of the gene vector and the gene compound is evaluated by an MTT (3- (4, 5-dimethylthiazole-2) -2, 5-diphenyl tetrazolium bromide) colorimetric method, and the method comprises the following steps:
seeding of Hy926 cells into 96-well plates (1X 10)4Cell/well) DMEM cell culture medium, after the cells were grown to 90%, the DMEM cell culture medium was changed to serum-free DMEM medium, and starvation was performed for 12 hours. The medium was then changed to fresh 10% FBS DMEM growth medium.
Adding the aqueous solution of the gene vector into 10% FBS DMEM growth medium to ensure that the concentration of the gene vector is 5, 10, 15, 20, 30, 40, 60, 80, 100 and 120 micrograms/ml respectively; adding the aqueous solution of the gene complex into a 10% FBS DMEM growth medium to ensure that the concentration of the gene complex is 5, 10, 15, 20, 30, 40, 60, 80, 100 and 120 micrograms/milliliter respectively; after mixing, the supernatant was discarded after 24 hours, 20. mu.l of 5 mg/ml MTT solution (PBS buffer solution as a solvent) was added to each well, and incubation was continued for 4 hours to crystallize formazan. After incubation, the medium was carefully discarded from the wells, 150. mu.l DMSO was added to the wells and the wells were shaken on a shaker for 10 minutes at low speed to dissolve the crystals sufficiently. The Optical Density (OD) of each well was measured at 490 nm wavelength with an enzyme linked immunosorbent detector. Relative cell activity (%) was calculated using the following formula:
wherein, OD 490': absorbance values, avg (OD 490C'), of the experimental group minus the zeroing group: and (5) corrected average value of absorbance of the control group.
FIG. 1 shows cell activities of the gene vectors and their gene complexes prepared in example 1, example 2 and example 3, respectively.
The targeted cell-penetrating peptide gene vector has low toxicity, high cell activity and high cell activity at high concentration of 120 microgram/ml. Compared with a gene vector, the gene complex has higher cellular activity, which is because the ZNF580 gene can promote the proliferation and migration of endothelial cells. Moreover, the relative cell activity does not show a trend of obviously reducing along with the increase of the concentration, which indicates that the gene vector and the gene compound thereof are basically non-toxic to endothelial cells.
Example 5
Ea.hy926 cells were evaluated for their ability to migrate following transfection with the gene complex using a cell migration assay.
The method comprises the following steps: ea.hy926 cells were serum-free starved for 12 hours 48 hours after transfection with the control gene complex, example 1, example 2, example 3 gene complex (N/P ═ 30), and ZNF580 gene in 24-well plates. The cells were digested and washed 3 times with D-Hanks and redispersed in serum-free DMEM medium, and 200. mu.l of the cell suspension was seeded onto the upper chamber of a transwell (1.2X 10)5Cells/well), 500 microliters of complete medium was added to the lower chamber of the transwell. The cells were placed in an incubator and incubated for 6 hours. The upper transwell chamber was removed and washed 3 times with D-Hanks to remove non-adherent cells, followed by fixation with 4% paraformaldehyde. Sterility of cells in the upper chamber of the transwellThe cotton swab was gently wiped off and adherent cells that migrated through the bottom filter of the upper chamber to the lower surface were stained with eosin for 8 minutes. After washing off the color with D-Hanks, the color was observed under an upright microscope and recorded by photography. Three replicates were performed in 6 fields and the migration capacity of ea.hy926 cells after transfection of different gene complexes was statistically analyzed by Image-Pro Plus 6.0 software.
And (3) analysis results: FIG. 2 is a graph showing cell migration at 6 hours (1) and the number of cell migrations calculated from Image-Pro Plus 6.0 (2). Wherein the content of the first and second substances,
a is the migration number of cells transfected with the control gene complex 104;
b is the migration number 112 of the cell transfected by the gene complex prepared from the gene vector of example 1;
c is the migration number 138 of the cell transfected by the gene complex prepared by the gene vector of example 2;
d is the migration number 179 of cells transfected with the gene complex prepared from the gene vector of example 3;
e is the migration number 63 of the ZNF580 gene transfected cells.
The number of migrating cells transfected by the gene complex formed by the gene vector and the gene in example 1, example 2 and example 3 is much higher than the migration capacity of the cells transfected by the control gene complex (104) and the ZNF580 gene (63). The result shows that the targeting cell-penetrating peptide gene vector can effectively carry ZNF580 gene to transfect endothelial cells, thereby greatly improving the proliferation and migration capacity of the endothelial cells.
Example 6
The vascularization ability of the transfected human umbilical vein endothelial cells was evaluated by an in vitro vascularization assay.
The method comprises the following steps: the experimental procedures were performed according to Corning Matrigel Matrix instructions. The Matrigel gel was first thawed well overnight at 4 ℃. 50 μ l of diluted Matrigel (final concentration of 10 mg/ml) was slowly added dropwise to the wells of a 96-well plate, taking care to avoid the formation of air bubbles. The 96-well plate was then placed in an incubator and incubated for 1 hour to allow the Matrigel gel to gel sufficiently. The reference gene complex, the gene complex prepared from the gene vector of example 1, and examples2 Gene Complex prepared by Gene vector, example 3 Gene Complex prepared by Gene vector and human umbilical vein endothelial cells transfected by ZNF580 Gene were uniformly seeded on Matrigel gel surface (4X 10)4Cells/well) were cultured at 37 ℃ under 5% carbon dioxide. After 6 hours the vascularization was observed under an optical microscope and recorded photographically. Each sample was subjected to 3 replicates and the number of vascular loops was counted by Image-Pro Plus 6.0 software.
And (3) analysis results: in FIG. 3, (1) is an in vitro blood vessel map and the number of blood vessel-like structures calculated from Image-Pro Plus 6.0 (2). Wherein the content of the first and second substances,
a is the number of vascular ring structures of cells transfected by the control gene complex 15;
b is the number of vascular ring structures 20 of the cells transfected by the gene complex prepared by the gene vector of example 1;
c is the number of vascular ring structures 21 of the cells transfected by the gene complex prepared by the gene vector of example 2;
d is the number of vascular ring structures 25 of the cells transfected by the gene complex prepared by the gene vector of example 3;
e is the number of vascular ring structures of ZNF580 gene transfected cells 10.
The number of vascular ring structures generated by the cells transfected by the gene vector formed by the gene and the gene complex formed by the example 1, the example 2 and the example 3 is far higher than that of the cells transfected by the control gene complex and the ZNF580 gene. Studies have shown that the vascularization process is closely related to the migration and proliferation of endothelial cells, the growth of capillaries, and the formation of vascular ring structures. The targeting cell-penetrating peptide gene vector can effectively carry genes to transfect endothelial cells and express the genes into corresponding proteins, thereby greatly improving the proliferation and migration capacity of the endothelial cells and the formation of a vascular ring structure and further promoting the vascularization of defective vascular tissues.
Sequence listing
<110> Tianjin university
<120> targeting cell-penetrating peptide gene vector and application thereof
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<170> SIPOSequenceListing 1.0
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Arg Glu Asp Val Tyr Gly Arg Lys Lys Arg Arg Gln Arg Arg Arg Pro
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Lys Lys Lys Arg Lys Val
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Arg Glu Asp Val Gly Tyr Gly Arg Lys Lys Arg Arg Gln Arg Arg Arg
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Arg Glu Asp Val Gly Gly Gly Gly Tyr Gly Arg Lys Lys Arg Arg Gln
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atgctgctgc tgcctccgcg cccaccgcat ccgcgttctt cttctccaga agcaatggac 60
ccgccgcctc cgaaagcccc accgttcccg aaagctgaag gcccgtcctc tactccgtct 120
agcgccgctg gcccgcgtcc gccacgcctg ggtcgtcacc tgctgatcga tgccaacggt 180
gtaccgtaca cctacactgt tcagctggaa gaggaaccac gtggcccgcc gcaacgtgaa 240
gcacctccgg gtgaaccggg ccctcgtaaa ggttattcct gcccggaatg tgcacgtgtg 300
ttcgcatctc cgctgcgtct gcagagccac cgcgttagcc actccgacct gaagccgttc 360
acctgcggcg cgtgcggtaa agctttcaaa cgtagctccc acctgtctcg tcaccgtgcg 420
acccaccgcg ctcgtgcggg tccgccgcat acgtgcccgc tgtgtccacg tcgctttcag 480
gatgctgcgg agctggcgca gcacgtccgc ctgcattaa 519
Claims (4)
1. A targeted cell-penetrating peptide gene vector is characterized in that the amino acid sequence of the vector is as follows:
REDV-YGRKKRRQRRR-PKKKRKV。
2. use of the targeted cell-penetrating peptide gene vector of claim 1 for the preparation of a medicament for delivering a gene.
3. A targeted cell-penetrating peptide gene vector is characterized in that the amino acid sequence of the vector is as follows:
REDV-Gm-YGRKKRRQRRR-Gn-PKKKRKV, wherein: m =1, n = 1; or m =4, n = 4.
4. The use of the targeted cell-penetrating peptide gene vector of claim 3 in the preparation of a drug for delivering a gene.
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| KR102208919B1 (en) | 2018-07-24 | 2021-01-28 | 인천대학교 산학협력단 | Cell transfection of nucleic acid using nano-assembly by fusion peptide and calcium ion and its application |
| CN110724180B (en) * | 2019-10-17 | 2021-08-20 | 山东大学 | Polypeptide for inhibiting angiogenesis and application thereof |
| CN112972701B (en) * | 2019-12-12 | 2022-09-23 | 天津大学 | Polypeptide/gene co-delivery material, preparation method and application |
| CN115594769A (en) * | 2021-06-30 | 2023-01-13 | 刘淼（Cn） | Modular assembly technology of polypeptide or micro-protein targeting chimera mediated by cell-penetrating peptide and application thereof |
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| DE102007028090A1 (en) * | 2007-06-12 | 2008-12-18 | Eberhard-Karls-Universität Tübingen Universitätsklinikum | Activatable diagnostic and therapeutic compound |
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| DE102007028090A1 (en) * | 2007-06-12 | 2008-12-18 | Eberhard-Karls-Universität Tübingen Universitätsklinikum | Activatable diagnostic and therapeutic compound |
Non-Patent Citations (1)
| Title |
|---|
| Multitargeting Gene Delivery Systems for Enhancing the Transfection of Endothelial Cells;Jing Yang等;《Macromolecular Rapid Communications，第1926-1931页》;20161215(第37期);摘要、第1927页第2-5段、第1930页第3节 * |
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Application publication date: 20180313 Assignee: TIANJIN NANOCOMY TECHNOLOGY CO.,LTD. Assignor: Tianjin University Contract record no.: X2023980031905 Denomination of invention: Targeted transmembrane peptide gene vector and its application Granted publication date: 20220211 License type: Common License Record date: 20230209 |