KR20170002983A - Drug composite having anti-cancer and anti-inflammation activity - Google Patents
Drug composite having anti-cancer and anti-inflammation activity Download PDFInfo
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- KR20170002983A KR20170002983A KR1020150093008A KR20150093008A KR20170002983A KR 20170002983 A KR20170002983 A KR 20170002983A KR 1020150093008 A KR1020150093008 A KR 1020150093008A KR 20150093008 A KR20150093008 A KR 20150093008A KR 20170002983 A KR20170002983 A KR 20170002983A
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Abstract
Description
The present invention relates to a drug complex having anti-cancer and anti-inflammatory activity.
A receptor for advanced glycation endproducts (RAGE) is an immunoglobulin-based transmembrane protein that possesses the ability to bind to the final glycation end product. In addition, advanced glycation endproducts (AGEs) are produced in the body or in vitro, and are produced by the glycation of saccharides by binding to proteins. The final glycation products are key substances involved in the onset and aggravation of various degenerative diseases such as diabetes, arteriosclerosis, chronic renal nitrification and Alzheimer's disease, and are also known to be widely involved in aging and aging-related diseases.
The interaction between the receptor RAGE and its ligand, AGE, is well known to promote activation of inflammatory genes (Nawroth PP et al., Diabetes-associated sustained activation of the transcription factor nuclear factor-kappaB,
Thus, as part of efforts to suppress the onset of various diseases caused by RAGE, studies have been reported to inhibit RAGE-mediated signal transduction by binding to RAGE. For example, Korean Patent Laid-Open Publication No. 2013-0082474 discloses a pharmaceutical composition for preventing or treating myocarditis comprising sAGE (soluble RAGE) lacking the transmembrane domain and cytoplasmic domain of RAGE as an active ingredient . In addition, techniques using an antibody that specifically binds RAGE are also known (for example, as anti-RAGE antibody, ab89911 antibody from abcam).
However, the above-described techniques are based on large proteins having large molecular weights, and they have a problem that their stability is relatively lowered, and productivity is also very low due to the characteristics of production in animal cells. In addition, all of the above-mentioned techniques are intended to suppress only the signal transduction of RAGE and do not have any other function than the protein therapeutic agent.
Korean Patent Laid-Open Publication No. 2011-0136504 discloses a drug complex for promoting the transition to the brain of a brain disease treatment agent or the like by binding a therapeutic agent for brain disease or a diagnostic agent for brain disease to a RAGE receptor target peptide. However, this technique also shows the possibility that RAGE receptor target peptide can be used as a drug carrier, and does not provide a base technology for stable complex formation.
Thus, the present invention is based on a RAGE-binding peptide capable of targeting RAGE, which not only inhibits the RAGE signal transduction process of a RAGE-binding peptide, but also provides a gene therapy gene, which can effectively treat a target disease, And to further improve the stability of the final complex, there is an urgent need to develop a drug complex.
Accordingly, the present invention not only effectively inhibits the signal transduction system mediated by RAGE, but also imparts the ability to bind to RAGE-binding peptide through electrostatic attraction with DNA and nuclear orientation, And to provide a drug complex capable of mass production by bacteria such as Escherichia coli as well as animal cells.
Therefore, in order to solve the above problems,
A RAGE binding peptide, a disease-treating gene, and a cationic polymer.
According to an embodiment of the present invention, the RAGE-binding peptide may be a peptide represented by SEQ ID NO: 1.
According to another embodiment of the present invention, the RAGE-binding peptide may be contained in an amount of 4 to 10 parts by weight based on 1 part by weight of the disease-treating gene.
According to another embodiment of the present invention, the cationic polymer may be contained in an amount of 1 part by weight to 30 parts by weight based on 1 part by weight of the disease-treating gene.
According to another embodiment of the present invention, the disease-treating gene may be an anti-cancer gene.
According to another embodiment of the present invention, the anti-cancer gene may be a gene selected from the group consisting of HSV-TK gene, PTEN gene, PDCD4 gene and APC gene.
According to another embodiment of the present invention, the disease-treating gene may be an anti-inflammatory gene.
According to another embodiment of the present invention, the anti-inflammatory gene may be a gene selected from the group consisting of the HO-1 gene, the adiponectin gene and the TGF-beta gene.
According to another embodiment of the present invention, the cationic polymer is selected from the group consisting of poly-L-lysine, poly (N-ethyl-4-vinylpyridinium bromide), polyethyleneimine, chitosan, poly (dimethylaminoethylmethylacrylate) And polyamidoamines. ≪ / RTI >
According to another embodiment of the present invention, the cationic polymer may be a polyethyleneimine having a molecular weight of 2 kDa to 25 kDa.
According to the present invention, it is possible not only to effectively interfere with the signal transduction system mediated by RAGE, but also to achieve a combined therapeutic effect of a peptide and a gene by including a gene for treating a disease, A drug complex capable of being produced can be provided.
FIGS. 1A to 1D are schematic diagrams (a and b) of an expression vector for mass production of a RAGE-binding peptide according to the present invention, a graph (c) showing a result of purification of a peptide, and a RAGE- (D). Fig.
Figure 2 is a graph showing the results of an experiment to confirm whether the RAGE binding peptide of SEQ ID NO: 1 inhibits TNF- [alpha] release by S100B by binding to RAGE.
3 is a graph showing the results of an experiment to confirm whether the RAGE binding peptide of SEQ ID NO: 1 inhibits VEGF production by S100B by binding to RAGE.
FIG. 4 is a schematic view illustrating a process for preparing a complex comprising a RAGE-binding peptide, a DNA encoding luciferase, and a polyethyleneimine according to an embodiment of the present invention.
FIG. 5 shows the results of performing gel delay analysis on the agarose gel in order to measure the mobility according to the weight ratio of DNA and RAGE binding peptide and the mobility according to the weight ratio of DNA, RAGE binding peptide and polyethyleneimine .
FIG. 6A is a graph showing the results of measurement of relative luciferase units for complexes having various ratios of DNA: polyethyleneimine weight ratio, and FIG. 6B is a graph showing the ratio of DNA: RAGE binding peptide: polyethyleneimine Lt; RTI ID = 0.0 > luciferase < / RTI > units.
FIG. 7 is a graph showing the results of measuring the size and surface charge of each of DNA + RAGE binding peptide complex, DNA + polyethyleneimine complex, and DNA + RAGE binding peptide + polyethyleneimine complex.
FIG. 8 is a graph showing the results of comparing the gene transfer efficiency of the drug complex according to the present invention with other drug delivery vehicles using a luciferase assay method through a transfection experiment using a C6 glioblastoma cell line.
FIG. 9 is a graph showing the results of comparative evaluation of intracellular toxicity of a drug complex according to the present invention with other drug carriers using an MTT assay through a transfection infection experiment using a C6 glioblastoma cell line. FIG.
FIGS. 10A to 10E show the results of comparative evaluation of the cancer cell killing effect of the drug complex according to the present invention through a transfection infection experiment using a C6 glioblastoma cell line using a complex of an HSV-TK gene and various gene carriers Graph.
FIGS. 11A and 11B are graphs showing the percentage of tumors in whole brain tissues after treatment of an animal model into which a C6 glial cell line was injected into various complexes, and actual brain tissue images. FIG.
Hereinafter, the present invention will be described in more detail with reference to the drawings and examples.
It is well known that a sufficient therapeutic effect can not be achieved by a single treatment method in order to treat inflammatory diseases and cancer and an excellent therapeutic effect can be attained only when a variety of therapeutic methods are applied in combination.
Accordingly, in the present invention, RAGE-binding peptides and RACE-binding peptides are used as a component that effectively inhibits the signal transduction pathway mediated by RAGE by binding to RAGE and exhibits therapeutic effects such as anti-cancer or anti- The present invention also relates to a gene for treating a disease which is transferred into a cell and exhibits a therapeutic effect on a target disease, and a cationic polymer for forming a stable complex with the RACE-binding peptide and a gene for disease treatment to enable high- To provide drug complexes.
As described in the following examples, in the present invention, an expression vector for mass production of the above-mentioned gene sequence was prepared by first securing a gene base sequence expressing a peptide binding to RAGE, To enable the mass production of the peptide.
Conventionally, ligands known to bind to RAGE include AGE, HMGB1, S100B, S100A7, S100P, amyloid-beta-protein, Mac-1 and phosphatidylserine described above. Preferably, the RAGE- 1 < / RTI > In particular, the peptide represented by SEQ ID NO: 1 contains a nucleotide sequence as well as a RAGE binding portion of HMGB1, and also includes a cysteine amino acid in order to enable chemical bonding with other carriers.
The present inventors have also found that when the content ratio of the RAGE-binding peptide and the disease-treating gene is adjusted at a proper ratio, a more stable and firm complex can be formed and consequently excellent gene transfer efficiency can be achieved, The RAGE-binding peptide may be contained in an amount of 4 to 10 parts by weight based on 1 part by weight of the disease-treating gene. When the content of the RAGE-binding peptide is less than 4 parts by weight, there is a problem that the stability of the complex to be formed and the gene transfer efficiency are poor, and even when the amount is more than 10 parts by weight, the gene transfer efficiency is low.
Furthermore, the ratio of the gene for treating disease and the cationic polymer also has a significant influence on stable complex formation and high-efficiency gene transfer. Preferably, the cationic polymer is used for 1 part by weight of the disease-treating gene May be contained in an amount of 1 part by weight to 30 parts by weight. When the content of the cationic polymer is less than 1 part by weight, the degree of positive charge distribution on the surface of the composite formed by the cationic polymer is insufficient and the efficiency of intracellular delivery is decreased. When the amount is more than 30 parts by weight, There is a problem that the efficiency may be lowered.
Meanwhile, the gene for treating diseases which can be delivered by the drug complex according to the present invention includes, but is not limited to, one or more anticancer genes such as HSV-TK gene, PTEN gene, PDCD4 gene and APC gene; Or one or more anti-inflammatory genes such as HO-1 gene, adiponectin gene and TGF-beta gene.
The cationic polymer may be selected from the group consisting of poly-L-lysine, poly (N-ethyl-4-vinylpyridinium bromide), polyethyleneimine, chitosan, poly (dimethylaminoethylmethylacrylate) And a polyethyleneimine having a molecular weight of 2 kDa to 25 kDa can be used, in consideration of biocompatibility and degradability after complex delivery.
EXAMPLES Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are intended to assist the understanding of the present invention and should not be construed as limiting the scope of the present invention.
Example One. RAGE Combination Of peptide Mass production system construction
A PCR reaction was carried out using HMGB1 DNA as a template and under conditions of DNA denaturation at 94 DEG C for 30 seconds, primer binding at 52 DEG C for 30 seconds, and DNA synthesis at 72 DEG C for 30 seconds, A large amount of the DNA sequence of SEQ ID NO: 2 encoding the RAGE binding peptide was prepared.
Then, the pET-21a vector containing the DNA sequence of SEQ ID NO: 2 and the T7 promoter and lac operator and expressing the 6-histidine tag was treated with Nhe I / Xho I restriction enzyme to express the RAGE-binding peptide Were prepared. FIGS. 1A to 1D are schematic diagrams (a and b) of the expression vector prepared by the above process, a graph (c) showing a result of purifying the peptide, and a result (d) of confirming the RAGE binding peptide through SDS- Respectively.
Example 2. RAGE Combination To peptides Of Cancer-Induced Signal Transduction Pathways
S100B is a known RAGE ligand and is known to bind RAGE and promote TNF- [alpha] release, confirming whether the RAGE binding peptide produced in Example 1 inhibits TNF- [alpha] release by S100B by binding to RAGE The experiment was carried out. (RBP) treated with only the RAGE-binding peptide according to SEQ ID NO: 1, the test group treated with S100B alone (S100B), the test group treated with S100B and SEQ ID NO: 1 (S100B + RBP) treated with RAGE-binding peptide and S100B and bovine serum albumin (S100B + BSA) were measured. The results are shown in FIG.
Referring to FIG. 2, when the RAGE binding peptide according to SEQ ID NO: 1 was treated (S100B + RBP) in comparison with the degree of TNF-α release in the case of treatment with the known TNF-α release promoting factor S100B, Which was significantly reduced.
In addition, RAGE-binding peptides according to S100B and SEQ ID NO: 1 were treated with C6 glioblastoma cell line, and the effect of angiogenesis inhibition was evaluated using VEGF ELISA. (RBP) treated with only the RAGE-binding peptide according to SEQ ID NO: 1, the test group (S100B + RBP) treated with S100B and the RAGE-binding peptide according to SEQ ID NO: 1, The degree of VEGF production in each of the experimental groups treated with the serum albumin (S100B + BSA) was measured, and the results are shown in FIG.
Referring to FIG. 3, it was confirmed that the degree of VEGF production when S100B alone was treated (S100B), and the case where RAGE-binding peptide according to SEQ ID NO: 1 was treated together (S100B + RBP).
Example 3. RAGE Combination Peptides , DNA And Cationic Manufacture of complexes containing polymers
A complex was prepared using the RAGE binding peptide prepared according to Example 1, DNA encoding luciferase, and polyethyleneimine. 4, the luciferase DNA and the RAGE-binding peptide were mixed at a predetermined ratio. After 15 minutes, the polyethyleneimine (molecular weight: 2 kDa) was mixed at a predetermined ratio, and after 30 minutes Lt; / RTI >
The complex of RAGE-binding peptide and DNA prepared as described above was electrophoresed on an agarose gel, and the change in DNA migration on the gel was analyzed through a gel retardation assay. In addition, the same analysis was performed by adding polyethyleneimine (molecular weight: 2 kDa) as a cationic polymer to RAGE-binding peptide and DNA. FIG. 5 shows mobility of DNA and RAGE binding peptide and DNA, RAGE binding peptide and polyethylene The results of measuring the mobility according to the weight ratio of immigration are shown.
Referring to FIG. 5, it can be seen that when the weight ratio of DNA: RAGE binding peptide is 1: 4 or more, a rigid complex is formed, and in addition, a harder complex is formed when polyethyleneimine is added.
Further, luciferase assays were performed to derive the optimal delivery ratio of DNA: RAGE binding peptide: polyethyleneimine complexes. This was carried out using the luciferase gene, and the expression of the luciferase gene transferred through the complex caused the production of luciferase protein, and the difference in the luciferase protein differing in the transfection efficiency was confirmed by the expression of luciferase The difference in intensity of light when treated with luciferin, a substrate, was analyzed.
FIG. 6A shows the relative luciferase unit (RLU) of the complexes when 0, 10, 15, 20, 25, and 30 times of polyethyleneimine was added to the DNA weight, respectively The measurement results are shown. Referring to FIG. 6A, it can be seen that a high RLU is measured when the weight ratio of DNA: polyethyleneimine is 1:20 or more, and the highest RLU is measured at a weight ratio of 1:20.
6B shows the results of measuring the RLU of the complexes in which the RAGE binding peptide is added to the 1:20 weight ratio complex derived from the optimum weight ratio of DNA: polyethyleneimine. Referring to FIG. 6B, it can be seen that the most optimal delivery performance is shown when the weight ratio of DNA: RAGE binding peptide: polyethyleneimine is approximately 1: 8: 20.
On the other hand, the size and surface charge of DNA + RAGE binding peptide complex, DNA + polyethyleneimine complex, and DNA + RAGE binding peptide + polyethyleneimine complex were measured and the results are shown in FIG. Referring to FIG. 7, it can be seen that the drug complex according to the present invention has a size and a positive zeta potential of 100-150 nm in diameter and has suitable size and electrical characteristics to be delivered into cells.
Example 4. Comparison of gene transfer efficiency of drug complex according to the present invention
The results of the transfection experiments using the C6 glioblastoma cell line showed that the luciferase gene transfer efficiency of the drug complex according to the present invention was compared with other drug delivery vehicles using the luciferase assay, Respectively. 8, when compared with the naked transfection efficiency, the increase in the transfection efficiency of the complex (RBP) with the RAGE-binding peptide was hardly observed, and the complex with polyethyleneimine having a molecular weight of 2 kDa (
Example 5. Intracellular toxicity of the drug complex according to the present invention
The intracellular toxicity of the drug complex according to the present invention was compared and evaluated by using MTT assay method through the transfection infection experiments using the C6 glioblastoma cell line, and the results are shown in Fig. Referring to FIG. 9, the drug complex (RBP +
Example 6. Confirmatory effect of drug complex according to the present invention
The HSV-TK gene having known activity as a cancer treatment gene was complexed with various gene carriers and transformed into C6 glioblastoma cell line. Then, HSV-TK gene was transfected in a medium supplemented with ganciclovir (10 g / ml) After incubation, cell death efficiency was assessed using Annexin V assay.
10a to 10e are respectively a control group (10a) using only the HSV-TK gene, an experimental group (10b) using a complex of a polyethyleneimine having a molecular weight of 2 kDa with the HSV-TK gene and a drug group according to the present invention, (10c) using a conjugate peptide, a polyethyleneimine having a molecular weight of 2 kDa, and a complex of an HSV-TK gene (10c), an experimental group (10d) using a complex of a polyethyleneimine having a molecular weight of 25 kDa and an HSV- The cancer cell killing effect on the experimental group (10e) using a complex of lipofectamine and the HSV-TK gene is shown in a graph.
10a to 10e, the drug complex according to the present invention shows a higher cancer cell killing effect than the experimental group (10b) using a complex of a polyethyleneimine having a molecular weight of 2 kDa and a HSV-TK gene, (10e) in the case of using lipofectamine.
Example 7. Confirmatory effect of drug complex according to the present invention in animal model
The HSV-TK gene having known activity as a cancer treatment gene was complexed with various gene carriers and treated with an animal model (Sprague dawley rat, male, 7 weeks) injected with C6 glioblastoma cell line, ganciclovir) was administered by intraperitoneal injection. The anticancer effect in animal models was evaluated by Nissl staining using animal brain tissue.
FIGS. 11A and 11B are graphs showing percentages of tumors in all brain tissues after treatment with various complexes, and actual brain tissue photographs. 11A and 11B, when the therapeutic gene is transferred using the complex (TK / RBP /
<110> IUCF-HYU
<120> Drug composite having anti-cancer and anti-inflammation activity
<130> JKP-0160
<160> 2
<170> Kopatentin 2.0
<210> 1
<211> 38
<212> PRT
<213> Artificial Sequence
<220>
<223> RAGE binding peptide
<400> 1
Lys Leu Lys Glu Lys Tyr Glu Lys Asp Ile Ala Ala Tyr
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US11407763B2 (en) | 2017-08-24 | 2022-08-09 | Gwangju Institute Of Science And Technolgy | Tryptophan hydroxylase inhibitor and pharmaceutical composition including same |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20110136504A (en) | 2010-06-15 | 2011-12-21 | 울산대학교 산학협력단 | Drug complex prepared by combining drug with rage target peptide |
| KR20130082474A (en) | 2012-01-11 | 2013-07-19 | 한국과학기술원 | Novel synthetic regulatory small rna and method of preparing the same |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| KR20110136504A (en) | 2010-06-15 | 2011-12-21 | 울산대학교 산학협력단 | Drug complex prepared by combining drug with rage target peptide |
| KR20130082474A (en) | 2012-01-11 | 2013-07-19 | 한국과학기술원 | Novel synthetic regulatory small rna and method of preparing the same |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US11407763B2 (en) | 2017-08-24 | 2022-08-09 | Gwangju Institute Of Science And Technolgy | Tryptophan hydroxylase inhibitor and pharmaceutical composition including same |
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