KR20140025657A - Novel amphiphilic cyclic peptides,??method for the preparation thereof and stable self-assembly nano-carrier comprising the same - Google Patents
Novel amphiphilic cyclic peptides,??method for the preparation thereof and stable self-assembly nano-carrier comprising the same Download PDFInfo
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Abstract
The present invention relates to a novel amphipathic cyclic peptide, a stable self-assembled nanostructure comprising the same, and a method for producing the same. The self-assembled nanostructure comprising the cyclic amphipathic peptide according to the present invention has excellent thermal stability, Conventional linear peptide can have a constrained structure that is not observed in the amphipathic substance, so that specific nano-magnetic assemblage can be made, and thus can be usefully used as a carrier for various drugs.
Description
The present invention relates to novel amphipathic cyclic peptides, stable self-assembled nanostructures comprising the same, and methods of making the same.
Particulate drug delivery systems are structures in the form of emulsions, liposomes, and nanoparticles that are prepared using oils, lipids, surfactants, or natural and synthetic polymers. Numerous studies on the manufacture, characterization and drug encapsulation of particulate drug delivery systems And the possibility as a drug delivery vehicle has been sufficiently proved. As a representative example, liposome and polymerome are most commonly used. In addition, there are nano emulsion, solid lipid nanoparticle, and supergroup modified nano particle, and in recent years, there have been used a dispersion system, a supramolecule, a polymer, Studies on the nanostructure formation and function expression of soft materials such as liquid crystal have been actively conducted.
Self-assembly is a fundamental technology of nanotechnology, which allows the reproducible nanostructures to be spontaneously formed by artificially controlling the forces that push or pull each other among molecules. These self-assembly techniques are likely to be developed through technological convergence in the fields of biochips, nanotubes, electronic materials and new materials used in disease diagnosis, and nanostructures necessary for the manufacture of highly integrated semiconductors.
Peptide-based self-assembly materials are expected to be used in the development of new nanomaterials, particularly in the field of nanobiotechnology, because of their excellent cognitive ability to specific molecules, various chemical properties, and biocompatibility. In addition, peptides have the same chemical structure as proteins, but have several advantages, including the fact that they are shorter in length, easier to synthesize and mass-produce than proteins, and have wider chemical diversity. However, peptides and peptide epitopes are not typically structured due to short chain lengths and thermodynamic instability, which may limit their usefulness when accurate and stable bases are required, such as in the case of specific molecular recognition.
On the other hand, macrocyclic molecules with a cyclic structure can have a significant effect on the chemical, physical and biological properties of macrocyclic molecules, and in particular, they may be more rigid and morphologic than linear molecules corresponding to cyclic molecules There is an advantage that the constrained structure can be maintained more effectively.
Various types of peptide amphipathic substances have been developed to date and have been reported to be useful in many biological applications. Despite the unique properties of the cyclic molecule, all peptide amphoteric substances developed so far have a linear peptide molecule Is used. However, nanostructures self-assembled from linear peptide amphipathic substances also tend to be limited in their structural stability because the linear peptides generally have unstable bases.
Therefore, the inventors of the present invention prepared an amphipathic substance using a cyclic peptide to prepare a stable self-assembling peptide nano-structure, that is, Or peptidic nano structure capable of mimicking or replacing various biological functions of natural proteins through the improvement and enhancement of existing properties and can be used as a drug carrier.
The present invention provides a novel cyclic amphipathic peptide and a method for producing the same.
The present invention also provides a self assembled double nanocarrier capable of being used as various drug delivery systems including the above-mentioned cyclic amphipathic peptide, and a imaging agent for diagnosing a disease including the nanotransporter.
In order to solve the above problems,
The present invention provides a cyclic amphipathic peptide consisting of the following structural formula 1:
[Structural formula 1]
R 1 -X m -W n -Y o
In the
Each of X and Y is the same or different and is selected from arginine, tryptophan, cysteine, histidine, isoleucine, methionine, serine, valine, alanine, glycine, leucine, proline, phenylalanine, tyrosine, asparagine and glutamine,
Wherein R is arginine,
Wherein W is tryptophan,
Each of l, m, n and o is independently an integer of 2 to 20.
Further, in order to solve the above problems,
(a) synthesizing a peptide linked to a solid phase, comprising the steps of: preparing Arg (pbf) -OH or Gly-OH in which the amino terminal of the first amino acid sequence is protected with a protecting group;
(b) sequentially synthesizing amino acids at the ends of the Arg (pbf) -OH or Gly-OH to produce a chain-like peptide comprising the peptide represented by the
(c) removing the protecting group at the terminal of the last amino acid of the chain-like peptide sequence and cyclizing the cyclic amphipathic peptide.
In addition, the present invention provides a self assembled double nanocarrier capable of being used as a drug delivery vehicle including the cyclic amphipathic peptide, and further provides a imaging agent for diagnosing diseases including the nanocarrier.
The self-assembled nanostructure comprising the cyclic amphipathic peptide according to the present invention has excellent thermal stability and can have a constrained structure that is not observed in the conventional linear peptide amphipathic substance, so that a specific nano-magnetic assembly can be produced , And can be usefully used as a carrier of various drugs.
1 is a conceptual diagram showing a nanostructure molecular model of an embodiment according to the present invention.
Figure 2 is a TEM and AFM image showing the nanostructure geometry of an underwater peptide amphipathic material according to one embodiment of the present invention.
FIG. 3 is a graph comparing the self-assembly behavior characteristics of the cyclic peptide amphipathic material of one embodiment of the present invention.
FIG. 4 is a graph comparing cytotoxic patterns in HeLa cells according to an embodiment of the present invention. FIG.
Hereinafter, the present invention will be described in more detail.
An aspect of the present invention relates to a cyclic amphipathic peptide comprising the following structural formula (1).
[Structural formula 1]
R 1 -X m -W n -Y o
In the
Each of X and Y is the same or different and is selected from arginine, tryptophan, cysteine, histidine, isoleucine, methionine, serine, valine, alanine, glycine, leucine, proline, phenylalanine, tyrosine, asparagine and glutamine, Glutamine, and serine,
Wherein R is arginine,
W is tryptophan,
Each of l, m, n and o is independently an integer of 2 to 20.
According to the present invention, the cyclic amphipathic peptide comprising the [structural formula 1] is more preferably an amino acid sequence of SEQ ID NO: 1 or 2.
Further, a method for producing a cyclic amphipathic peptide according to the present invention is characterized by comprising the following steps.
(a) synthesizing a peptide linked to a solid phase, the method comprising the steps of: preparing Arg (pbf) -OH or Gly-OH in which the amino acid sequence of the first amino acid sequence is protected with a protecting group;
(b) synthesizing an amino acid at the terminal of Arg (pbf) -OH or Gly-OH in order to prepare a chain peptide comprising the peptide represented by the
(c) removing the protecting group at the terminal of the last amino acid of the chain-like peptide sequence and cyclizing it.
In the preparation method according to the present invention, the protecting group of step (a) may be 9-fluorenylmethoxycarbonyl (Fmoc), 2- (phenylsulfonyl) ethoxycarbonyl, trimethylsilylethoxycarbonyl ), 4-methoxy-2,3,6-trimethylphenylsulfonyl (Mtr), formyl, acetyl, propionyl, butyryl, phenylacetyl, benzoyl, tolyl, phenoxyacetyl, methoxycarbonyl, Butylcarbamate (t-Boc), 2-iodoethoxycarbonyl, aryloxycarbonyl (Aloc), carboxybenzyl (CBZ) , 4-methoxybenzyloxycarbonyl (MOZ) and 4-nitrobenzyloxycarbonyl, and more preferably 9-fluorenylmethoxycarbonyl (Fmoc).
In addition, in the production method according to the present invention, the chain-like peptide of step (b) may have the amino acid sequence of SEQ ID NO: 1 or 2.
Furthermore, in the preparation method according to the present invention, the method of synthesizing the amino acid at the terminal of Arg (pbf) -OH or Gly-OH protected with the protecting group of step (b) can be carried out through repetition of the amide bond. Specifically, water (H 2 O) molecules are released between the amino terminal (N-terminal) of the first amino acid connected to the solid phase and the carboxy terminal (C-terminal) of the newly introduced amino acid, Type peptide can be produced.
In addition, in the production method according to the present invention, the reaction for removing the terminal protecting group of the last amino acid for cyclizing the chain-like peptide of the step (c) can be removed by using piperidine. Specifically, the cyclic amphipathic peptide can be obtained by removing the chain-like peptide connected to the solid phase from the resin and then removing the protecting group at the terminal amino acid.
Meanwhile, the method of removing the chain-like peptide from the resin may be a mixed solvent in which acetic acid, trifluoroethanol, and dichloromethane are mixed at a ratio of 2: 2: 6.
In addition, it is preferable that the protecting group of the amino acid terminal is removed by adding piperidine to dimethylformamide (DMF).
Another aspect of the present invention relates to a self assembled double nanocarrier comprising the cyclic amphipathic peptide, wherein the form is characterized by being in the form of micelles or vesicles.
Conventional linear peptide amphipathic substances tend to agglomerate into irregular entities whereas the amphiphilic cyclic peptides of the present invention form an extended basin along the axis so that hydrophilic and hydrophobic units are stacked together in a two- By connecting the indole rings, regular spheres in the form of micelles or vesicles are formed.
The self-assembled double-nanotransporter has a diameter of 10 to 100 nm. When the size is less than 10 nm, there is a problem that the nanotransducer exits the intravascular space or is easily discharged through elongation. It is accumulated in the liver or the nanocransporter can be removed by macrophages.
The self assembled two-nanotransporter can be used as a drug delivery system capable of delivering various drugs. The self assembled double nanocatalyst according to the present invention is composed of a double membrane having hydrophilic and hydrophobic characteristics and is formed in a structure capable of supporting a hydrophobic drug on the double membrane of the nanocatalyst.
Therefore, the self-assembled double-nanocatalyst according to the present invention may contain a nucleic acid, a protein, a polypeptide, a carbohydrate, an inorganic substance, an antibiotic, an anticancer agent, an antimicrobial agent, a steroid, a antiinflammatory agent, a sex hormone, an immunosuppressant, an antiviral agent, . A group consisting of antihistamines, local anesthetics, anti-angiogenic agents, angiostatic agents, anticoagulants, immunomodulators, cytotoxic agents, antibodies, neurotransmitters, mental actions, oligonucleotides, lipids, cells, tissues, cancer chemotherapeutics, And the like can be enclosed.
Particularly, the drug is preferably a hydrophobic drug, and examples thereof include paclitaxel, docetaxel, doxorubicin, cisplatin, carboplatinum, 5-FU, etoposide, anticancer agent of camptothecin; Sex hormones of testosterone, estrogen, and estradiol; Steroid derivatives of triamcinolone acetonide, hydrocortisone, dexamethasone, prednisolone, betamethasone; Cyclosporine; Or a hydrophobic drug such as prostaglandin may be loaded into the hydrophobic portion of the micelle. At this time, when the hydrophobic drug is loaded, the delivery efficiency of the drug is further improved as a carrier of the drug.
Another aspect of the present invention relates to the imaging agent for diagnosing a disease comprising the self-assembled two-nanocatalyst.
The imaging agent may be used by enclosing one species selected from the group consisting of MRI and CT contrast agents in the nanocarrier.
At this time, the MRI contrast agent is a complex substance of a paramagnetic substance, gadolinium and manganese, and one kind selected from the group consisting of Gd-DTPA, Gd-DTPA-BMA, Gd-DOTA, Gd- , The PET contrast agent is one species selected from the group consisting of radioactive isotopes 18 F, 124 I, 64 Cu, 99 m Tc and 11 In, and can be introduced into the nanotransporter as a chelate DOTA and DTPA complex.
Hereinafter, the present invention will be described in detail with reference to the following examples and experimental examples. It will be apparent to those skilled in the art that the present invention is not limited by the following examples and experimental examples, but the following examples and experimental examples are illustrative of the present invention.
< Example 1> Cyclophilin A-1 ( CyPA -1)
Step 1: Fmoc - Arg ( pbf ) - OH or Gly - OH Manufacturing
The first amino acid of the peptide sequence of the present invention, Fmoc-Arg (pbf) -OH or Gly-OH, was preferentially synthesized in the solid phase 2-chlorotrityl resin.
Step 2: Linear Fmoc - Arg - Arg - Arg - Gly - Ser - Tri - Ser - Gly Manufacturing
The synthesis of amino acids using the amino bond after the Fmoc-Arg (pbf) -OH obtained in the
In this step, peptides were synthesized using amino acids with Fmoc and a protecting group. Particularly, an amide bond (H 2 O) is bonded between the amino terminal (N-terminal / -NH 2 ) of the amino acid synthesized in the resin and the carboxy terminal (C-terminal / -COOH) (-CO-NH-). ≪ / RTI >
Step 3: annular Of peptide Produce
The Fmoc protecting group at the amino terminus of the last amino acid of the chain-like peptide sequence is removed in order to synthesize the synthesized chain peptide as a cyclic peptide. (AcOH) / trifluoroethanol (TFE) / dichloromethane (MC) were mixed at a ratio of 2: 2: 6 in order to separate the peptide from the resin. After 1-2 hours, the solvent was filtered through the filtration method, and the remaining solid resin was discarded and only the filtrate was taken. The same procedure was repeated 3 times. Hexane was added to the filtrate, and acetic acid remaining in the filtrate was removed by azeotropic distillation. The peptide with a protecting group is obtained by adding MC and hexane and evaporating it in the form of a white powder while sequentially repeating the process. Thereafter, a linear peptide and a peptide having a protecting group attached thereto in order to cyclize the peptide of the
< Example 2> Cyclophilin A-2 ( CyPA -2)
Instead of using the structural formula R 1 -X m -W n -Y o in the first embodiment, a new integer value such as l + 1 or l-1, n + 1 or n-1 is assigned to the l and n values Cyclophilin A-2 was prepared by the same method except that
< Experimental Example 1> Characteristic experiment
(1) Transmission electron microscopy ( TEM )
The cyclic peptide of Example 1 according to the present invention was dissolved in water (5-50 [mu] M) and the nanostructure of these peptides was examined by transmission electron microscopy (TEM).
As shown in FIG. 2, it can be seen that as the
Also, as
However, aggregates of the control (liPA-2) exhibited an irregular shape, whereas agglomerates of Example 2 (cyPA-2) were observed to have a homogeneous population of spherical bodies (diameter of about 11 nm).
(2) Atomic force microscope ( AFM ) Measure
The atomic force microscope (AFM) was used to investigate whether chain length affects self-assembly behavior.
Examination by atomic force microscopy (AFM) further proved the shape and homogeneity of the spheres (Figure 2e).
Thus, it can be clearly seen from this that the self-assembly behavior of the linear and cyclic peptide amphipathic substances is significantly different from each other. Linear Peptide Amphipathic materials tend to agglomerate into irregular bodies, while cyclic peptide amphipathic materials form regular spheres.
(3) Circular light dichromaticity Spectroscopy ( CD ) Measure
In order to examine the self-assembling behavior of the cyclic peptide amphipathic substances of Examples 1 and 2 and the linear peptide amphoteric substances of
As a result, as shown in FIG. 3, it was confirmed that the circular dichroism spectroscopic spectrum of Example 2 (cyPA-2) and control (liPA-2) according to the present invention had a definite minimum ellipticity of 200-203 nm . This means that the peptides are present mainly in disordered coil states and do not have a well defined secondary structure, and the two peptides strongly represent the negative band at about 223-224 nm. These bands are judged to be the behavior of tryptophan expected from the exciton bond generated by aromatic chromophores in which indoles are stacked together.
In particular, as shown in FIG. 3A, the temperature-dependent CD spectra of control group 2 (liPA-2) showed a sharp linear decrease of the average residue ellipticity at 224 nm. At the high temperature (84 ° C), the normalized cohesion was reduced to 62% compared to the normalized cohesion at 4 ° C, whereas the ellipticity at 223 nm for Example 2 (cyPA-2) And the cohesion was maintained at about 82% even at a high temperature of 84 DEG C (see FIG. 3B).
Thus, it has been found that the cyclic peptide amphipathic material according to the present invention forms nanostructures that are more rigid and superior in thermal stability than linear peptide amphipathic materials, even though they use the same cohesive mechanism as linear peptide amphipathic materials.
(4) Fluorescence spectroscopy ( Fluorescence spectroscopy )
On the other hand, since the indole chromophore in tryptophan is very sensitive to the characteristics of the local environment, the intrinsic fluorescence of tryptophan can be used to investigate changes in the protein conformation and interaction with other molecules. In order to measure the fluorescence generated from the tryptophan residue, fluorescence generated by excitation at 280 nm was measured. This was done by using fluorescence spectrophotometry at various concentrations of peptides to determine the minimum threshold concentration at which peptides synthesized nanostructures begin to self-assemble.
As a result of graphically showing fluorescence intensities at 350 nm as a function of peptide concentration in the graphs of FIGS. 3C and 3D, both of the control 2 (liPA-2) and the inventive example 2 (cyPA-2) A significant increase in tryptophan fluorescence was observed at concentrations ranging from 20 μM to 20 μM. Above a certain concentration, the fluorescence intensity of the two peptides increased sharply, and it was determined that this discontinuous intensity change probably reflected the onset of aggregation and the critical aggregation concentration (CAC).
In addition, the CAC of the peptides was calculated using the intersection of the linear regression lines. As a result, the CAC values for liPA-2 and cyPA-2 were 5.7 μM and 3.3 μM, respectively. The CAC values for the cyclic peptide amphipathic material were slightly lower than the CAC values for the corresponding linear peptide amphoteric material, but the difference was not significant.
Meanwhile, in the case of Example 2 according to the present invention, the molecular length is about 2.5-3.0 nm, which depends on the peptide donor. When the molecular length is fitted to the spherical micelle model, the diameter of the observed spherical nano- ) Of about 5-6 nm in diameter. Also, the diameter of the self-assembled spherical nano-body of Example 1 (cyPA-1) according to the present invention is also well suited to the vesicle model.
The follicular model is in good agreement with the molecular length of the peptides. The cyclic peptides form a basin extending along the axis, linking the hydrophilic and hydrophobic units and the indole rings of tryptophan stacked on each other in a bilayer structure, Were found to be in good agreement with the CD data.
Thus, in view of the molecular length of the cyclic peptide amphipathic substance according to the present invention, not only is it self-assembled into a specifically small two-ply follicular nanostructure, but also the unique self-assembly of the cyclic peptide amphipathic substance according to the present invention, The assembly behavior, the high thermal stability and the formation of a considerably small follicle structure appears to be due to their constrained structure and the entropy advantage of the ring phase during the self-assembly process.
< Experimental Example 2> Cytotoxicity test ( Cytotoxicity Assay )
After identifying the self-assembly behavior of linear and cyclic peptide amphipathic substances, it is important to examine how these amphipathic substances interact with mammalian cells and to obtain their differentiated cytotoxicity patterns in potential cellular applications Do. For this purpose, in order to confirm the presence or absence of toxicity in the cells of the synthesized peptides, WST-1 assay was used in HeLa cells.
Cell lines of subcultured HeLa cells were subjected to cytotoxicity tests. HeLa cells were subcultured in DMEM supplemented with 10% FBS (Fetal Bovine Serum) to obtain 10 4 cells. Various concentrations of peptides were added thereto, followed by incubation. After a certain period of time, WST-1 solution was added , And the cytotoxicity was obtained by measuring the absorbance at 450 nm after 4 hours.
As a result, as shown in Fig. 4, both the cyclic peptide cyPA-2 according to the present invention and the linear peptide, liPA-2, as a control group, were not found to be toxic within the test concentration range, .
It has been found that this similar level of cytotoxicity prevents the free diffusion of each of the amphipathic components to the cell surface and that the cytotoxicity of the peptide amphipathic substances is highly proportional to their CAC, It is believed that the CACs of the amphipathic cyclic peptide and the linear peptide are similar.
<110> Yonsei University
<120> Novel amphiphilic cyclic peptides, method for the preparation
and stable self-assembly nano-carrier comprising the same
<130> HPC-3212
<160> 2
<170> Kopatentin 2.0
<210> 1
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> cyPA-1
<400> 1
Arg Arg Arg Gly Ser Trp Trp Trp
Claims (10)
[Structural formula 1]
R 1 -X m -W n -Y o
In the above formula 1,
X and Y are the same or different, respectively, and are selected from arginine, tryptophan, cysteine, histidine, isoleucine, methionine, serine, valine, alanine, glycine, leucine, proline, phenylalanine, tyrosine, asparagine and glutamine,
R is arginine,
W is tryptophan,
Each of l, m, n and o is independently an integer of 2 to 20.
The cyclic amphiphilic peptide is a cyclic amphiphilic peptide comprising the amino acid sequence of SEQ ID NO: 1 or 2.
(a) synthesizing a peptide linked to a solid phase, the method comprising the steps of: preparing Arg (pbf) -OH or Gly-OH in which the amino acid sequence of the first amino acid sequence is protected with a protecting group;
(b) preparing a chain peptide comprising a peptide represented by the following [Formula 1] by sequentially synthesizing amino acids at the Arg (pbf) -OH or Gly-OH ends; And
(c) removing the protecting group at the terminal of the last amino acid of the chained peptide sequence to cyclize the cyclic amphiphilic peptide.
[Structural formula 1]
R 1 -X m -W n -Y o
In the above formula 1,
X and Y are the same or different, respectively, and are selected from arginine, tryptophan, cysteine, histidine, isoleucine, methionine, serine, valine, alanine, glycine, leucine, proline, phenylalanine, tyrosine, asparagine and glutamine,
R is arginine,
W is tryptophan,
Each of l, m, n and o is independently an integer of 2 to 20.
The protecting groups of step (a) are 9-fluorenylmethoxycarbonyl (Fmoc), 2- (phenylsulfonyl) ethoxycarbonyl, trimethylsilylethoxy carbonyl (Teoc), 4-methoxy-2, 3,6-trimethyl phenylsulfonyl (Mtr), formyl, acetyl, propionyl, butyryl, phenylacetyl, benzoyl, toluyl, phenoxyacetyl, methoxycarbonyl, ethoxycarbonyl, 2,2,2 -Trichloroethoxycarbonyl, tert-butylcarbamate (t-Boc), 2-iodoethoxycarbonyl, aryloxycarbonyl (Aloc), carboxybenzyl (CBZ), 4-methoxybenzyl oxycarbonyl (MOZ) and 4-nitrobenzyloxycarbonyl. The method for producing a cyclic amphiphilic peptide, characterized in that one.
The method for synthesizing an amino acid at the Arg (pbf) -OH (or Gly-OH) terminus of step (b) is performed by repeating amide bonds.
Wherein the removal of the protecting group at the end of the last amino acid to cyclize the chain-like peptide of step (c) is carried out using diisopropylethylamine (DIPEA).
Wherein the nanotransporter comprises a nucleic acid, a protein, a polypeptide, a carbohydrate, an inorganic substance, an antibiotic, an anticancer agent, an antibacterial agent, a steroid, an antiinflammatory agent, a sex hormone, an immunosuppressant, an antiviral agent, A group consisting of antihistamines, local anesthetics, anti-angiogenic agents, angiostatic agents, anticoagulants, immunomodulators, cytotoxic agents, antibodies, neurotransmitters, mental actions, oligonucleotides, lipids, cells, tissues, cancer chemotherapeutics, Wherein the drug is capable of enclosing one kind of drug selected from the group consisting of:
The imaging agent for diagnosing a disease includes an MRI or PET contrast agent in the self assembled double nanocatalyst,
The MRI contrast agent is a complex of gadolinium and manganese and is one kind selected from the group consisting of Gd-DTPA, Gd-DTPA-BMA, Gd-DOTA, Gd-DO3A and iron oxide,
Wherein the PET contrast agent is in the form of a chelate DOTA or DTPA complex comprising at least one member selected from the group consisting of radioactive isotopes 18 F, 124 I, 64 Cu, 99 m Tc and 11 In.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| KR101581926B1 (en) * | 2014-09-23 | 2016-01-04 | 연세대학교 산학협력단 | self-assembly peptide nano-capsule and drug-delivery carrier comprising the same |
| KR20160136695A (en) * | 2015-05-20 | 2016-11-30 | 연세대학교 산학협력단 | The synthesis method of cyclic peptide by pre-activation cyclization and cyclic peptide synthesized thereby |
| CN109589308A (en) * | 2019-01-18 | 2019-04-09 | 陕西科技大学 | One kind is based on low immunogenicity polypeptide micron vesica and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US8324154B2 (en) * | 2005-12-22 | 2012-12-04 | Novabiotics, Ltd. | Treatment of fungal infections with cyclic antimicrobial peptides |
| KR100943043B1 (en) | 2008-02-05 | 2010-02-24 | 전북대학교산학협력단 | A hydrophilic chitosan-hydrophobic linoleic acid nanoparticles loading iron oxide nanoparticles, a preparation method of thereof and a contrast agent for diagnosing liver diseases including the same |
| KR101032922B1 (en) * | 2008-12-24 | 2011-05-06 | 연세대학교 산학협력단 | Nanostructure having stabilized multiple alpha-helical structure, self-assembling macrocyclic compound for forming the nanosructure, and the method of preparing the compound |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101581926B1 (en) * | 2014-09-23 | 2016-01-04 | 연세대학교 산학협력단 | self-assembly peptide nano-capsule and drug-delivery carrier comprising the same |
| KR20160136695A (en) * | 2015-05-20 | 2016-11-30 | 연세대학교 산학협력단 | The synthesis method of cyclic peptide by pre-activation cyclization and cyclic peptide synthesized thereby |
| CN109589308A (en) * | 2019-01-18 | 2019-04-09 | 陕西科技大学 | One kind is based on low immunogenicity polypeptide micron vesica and preparation method thereof |
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| KR101502797B1 (en) | 2015-03-17 |
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