CN116650672A - Active targeting response type self-assembled imaging probe and preparation method and application thereof - Google Patents
Active targeting response type self-assembled imaging probe and preparation method and application thereof Download PDFInfo
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- CN116650672A CN116650672A CN202210149574.XA CN202210149574A CN116650672A CN 116650672 A CN116650672 A CN 116650672A CN 202210149574 A CN202210149574 A CN 202210149574A CN 116650672 A CN116650672 A CN 116650672A
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- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
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- A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
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- A61K49/04—X-ray contrast preparations
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/10—Organic compounds
- A61K49/14—Peptides, e.g. proteins
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
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- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Chemical & Material Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
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- Physics & Mathematics (AREA)
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- Engineering & Computer Science (AREA)
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- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
The invention belongs to the technical field of medical use, and particularly relates to an active targeting response type self-assembled imaging probe, and a preparation method and application thereof. The active targeting response type self-assembled imaging probe comprises an active targeting peptide segment, a response type segment, a self-assembled segment and an imaging probe group which are sequentially connected, and the active targeting self-assembled imaging probe is based on cathepsin B and a polypeptide segment with molecular specific response, not only has the capability of actively targeting an affected part, but also can spontaneously form a nano structure after the enrichment of a tumor part, and enhances the enrichment and retention of the probe at the target focus part so as to enhance the sensitivity of the probe.
Description
Technical Field
The invention belongs to the technical field of medical use, and particularly relates to an active targeting response type self-assembled imaging probe, and a preparation method and application thereof.
Background
The complexity of tumor makes the development of high-sensitivity tumor imaging probes facing a difficult task, most of the imaging probes used in clinic at present are small molecular probes, the main problems of the imaging probes are that the efficiency of reaching disease sites is low, and unavoidable side effects can be caused to other organs, and active targeting probes are that probes are directionally distributed in target tissues or target cells by utilizing molecular affinity effects such as antigen-antibody or receptor, and active ingredients are accumulated or released at target sites.
Neuropeptide Y (NPY) is a peptide chemical messenger secreted by hypothalamus, and studies have been carried out at present to show that neuropeptide Y is found in clinical cases of breast cancer, brain cancer, ovarian cancer, renal cancer and other diseases 1 Overexpression of the receptor, and low expression of this receptor in normal tissue organs. This indicates neuropeptide Y 1 Is a potential target point for tumor targeting diagnosis and treatment.
Chinese patent application (publication No. CN 111744022A) discloses an active targeting response type imaging probe, a preparation method and application thereof, but the active targeting response type imaging probe cannot respond to cell targeting and subcellular organelles to realize accurate imaging of the probe, and cannot generate self-assembly effect on specific subcells to cause certain side effects of the probe.
Disclosure of Invention
The invention aims at overcoming the defects in the prior art, and provides an active targeting response type self-assembled imaging probe which can spontaneously form a nano structure after enrichment of a tumor part and enhance enrichment and retention of the target focus part.
The above object of the present invention is achieved by the following means: an active targeting responsive self-assembled imaging probe comprises an active targeting peptide segment, a responsive segment, a self-assembled segment and an imaging probe group which are connected in sequence.
In the above-mentioned active targeting responsive self-assembled imaging probe, the active targeting peptide segment is selected from the group consisting of: [ Arg ] 6 ,Pro 34 ]pNPY、[Phe 6 ,Pro 34 ]pNPY、[Asn 6 ,Pro 34 ]pNPY、[Cys 6 ,Pro 34 ]pNPY、[D-His 26 ,Pro 34 ]NPY、[Phe 7 ,Pro 34 ]pNPY、[Pro 30 ,Nal 32 ,Leu 34 ]NPY(28-36)、[Pro 30 ,Nle 31 ,Nal 32 ,Leu 34 ]NPY(28-36)、NPY(28-36)、[Pro 30 ,Tyr 32 ,Pro 34 ]NPY(25-36)、[Pro 30 ,Tyr 32 ]NPY(25-36)、[Pro 30 ,Trp 32 ]NPY(25-36)、[Asn 28 ,Pro 30 ,Trp 32 ]NPY(25-36)、[Tyr 32 ,Pro 34 ]NPY(25-36)、[Pro 30 ,Tyr 31 ,Trp 32 ]NPY(25-36)、[Pro 30 ,Nle 31 ,Bpa 32 ,Leu 34 ]At least one of NPY (28-36) and NPY (25-36).
In the active targeting responsive self-assembled imaging probe, the amino acid sequence of the responsive fragment comprises at least one of SEQ ID No. 1-368.
In the active targeting responsive self-assembled imaging probe, the responsive enzyme and molecule corresponding to the responsive fragment are selected from the group consisting of: at least one of cathepsin B, cathepsin E, cathepsin L, cathepsin C, cathepsin D, cathepsin K, carboxypeptidase, papain, chymotrypsin, kallikrein, collagenase, endopeptidase.
In the active targeting responsive self-assembled imaging probe, the self-assembled fragment amino acid sequence comprises at least one of SEQ ID No. 369-403.
In the active targeting response type self-assembled imaging probe, after reaching tumor cells, the active targeting response type self-assembled imaging probe responds by enzymes in a cell lysosome to form a nanostructure;
preferably, the nanostructure is at least one of a nanoparticle, a polyhedral structure, a nanowire, a nanorod, a nanofiber, a nanotube, a nanodisk, a nanosheet, a two-dimensional nanodendrite, a porous structure, a nanobranch, a nano-frame, a nanoflower, and an aerogel.
In the active targeting responsive self-assembled imaging probe, the probe is at least one selected from a fluorescent probe, a CT probe, a nuclide probe and a magnetic resonance imaging probe;
preferably, the fluorescent probe is at least one selected from the group consisting of Cy3, cy5, cy3.5, cy5.5, cy7, cy7.5, ICG, IR-780, IR-783, IR775, IR-792, IR-808, IR-820, IR-825, IR-1048, IR-1064 and derivatives thereof;
preferably, the CT probe is selected from at least one of iopamidol, iohexol, iopamidol, iopromide, ioversol, lopyr, iodixanol, and iomeprol;
preferably, the nuclide probe is selected from 18 F、 99m Tc、 131 I、 133 Xe、 32 P、 3 H、 109 Cd、 111 Zn、 141 Ce、 153 Sm、 198 At least one of Au;
preferably, the magnetic resonance imaging probe is selected from at least one of gadodiamide, gadodiamide disodium, gadofoshan, gadodiamide and cadinamine sodium, gadofoshan, gadoteridol, and ferroferric oxide.
The invention also provides a preparation method of the active targeting response type self-assembled imaging probe, which at least comprises the following steps:
s1, sequentially coupling an active targeting peptide segment, a response type fragment and a self-assembly fragment on resin 0 through a polypeptide automatic synthesizer to obtain resin 1;
s2, adding an imaging group into the resin 1 for reaction to obtain resin 2;
s3, cutting the resin 2 to remove the protection of the amino acid side chain, and purifying to obtain the active targeting response type self-assembled polypeptide drug.
S4, cutting the obtained resin to remove the protection of the amino acid side chain, and purifying to obtain the active targeting response type self-assembled imaging probe.
The invention also provides the active targeting response type self-assembled imaging probe and application of the active targeting response type self-assembled imaging probe prepared according to the preparation method in preparation of antitumor drugs;
preferably, the use in the preparation of a medicament for breast cancer, brain cancer, kidney cancer, endometrial cancer, ovarian cancer and ewing's sarcoma.
The invention also provides an imaging agent, which comprises the active targeting response type self-assembled imaging probe.
The invention also provides application of the imaging agent in preparing a medicament for diagnosing tumor diseases;
preferably, the use in the preparation of a medicament for diagnosing breast cancer, brain cancer, kidney cancer, endometrial cancer, ovarian cancer and ewing's sarcoma.
The amino acid sequence of SEQ ID No.1 is GRRGKGG;
the amino acid sequence of SEQ ID No.2 is GFLG;
the amino acid sequence of SEQ ID No.3 is ALAL;
the amino acid sequence of SEQ ID No.4 is AFK;
the amino acid sequence of SEQ ID No.5 is KGRR;
the amino acid sequence of SEQ ID No.6 is CKF;
the amino acid sequence of SEQ ID No.7 is AGFSLPAKR;
the amino acid sequence of SEQ ID No.8 is FFRIKFERQ;
the amino acid sequence of SEQ ID No.9-28 is YX (X is any natural amino acid);
the amino acid sequence of SEQ ID No.29-48 is GX (X is any natural amino acid);
the amino acid sequence of SEQ ID No.49-68 is SX (X is any natural amino acid);
the amino acid sequence of SEQ ID No.69-88 is VX (X is any natural amino acid);
the amino acid sequence of SEQ ID No.89-108 is FX (X is any natural amino acid);
the amino acid sequence of SEQ ID No.109-128 is MX (X is any natural amino acid);
the amino acid sequence of SEQ ID No.129-148 is WX (X is any natural amino acid);
the amino acid sequence of SEQ ID No.149-168 is AX (X is any natural amino acid);
the amino acid sequence of SEQ ID No.169-188 is LX (X is any natural amino acid);
the amino acid sequence of SEQ ID Nos. 189-208 is KX (X is any natural amino acid);
the amino acid sequence of SEQ ID No.209-228 is RX (X is any natural amino acid);
the amino acid sequence of SEQ ID No.229-248 is FFX (X is any natural amino acid);
the amino acid sequence of SEQ ID Nos. 249-268 is TTX (X is any natural amino acid);
the amino acid sequence of SEQ ID No.269-288 is YTX (X is any natural amino acid);
the amino acid sequence of SEQ ID No.289-308 is RRX (X is any natural amino acid);
the amino acid sequence of SEQ ID No.309-328 is PXGP (X is any natural amino acid);
the amino acid sequence of SEQ ID No.329-348 is DDX (X is any natural amino acid);
the amino acid sequence of SEQ ID No.349-368 is KKX (X is any natural amino acid);
the amino acid sequence of SEQ ID No.369 is KLVFF;
the SEQ ID No.370 amino acid sequence is KLVFFAECG;
the amino acid sequence of SEQ ID No.371 is FF;
the SEQ ID No.372 amino acid sequence is FFEFKFE;
the amino acid sequence of SEQ ID No.373 is FFKY;
the amino acid sequence of SEQ ID No.374 is GFFYE;
the amino acid sequence of SEQ ID No.375 is ILQINS;
the SEQ ID No.376 amino acid sequence is ILVAV;
the amino acid sequence of SEQ ID No.377 is RADA;
the SEQ ID No.378 amino acid sequence is EAKA;
the SEQ ID No.379-398 has the amino acid sequence XAAA (X is any natural amino acid);
the amino acid sequence of SEQ ID No.399 is YPGDV;
the amino acid sequence of SEQ ID No.400 is WYFRRGK;
the SEQ ID No.401 amino acid sequence is VEALYL;
the amino acid sequence of SEQ ID No.402 is VIA;
the amino acid sequence of SEQ ID No.403 is GGAAVV.
Compared with the prior art, the invention has the following beneficial effects:
1. the active targeting response type self-assembled imaging probe is used for more sensitive imaging probes, and has good biocompatibility and toxicological acceptability.
2. The active targeting response type self-assembled imaging probe can be used for preparing a long-time enhanced imaging pharmaceutical preparation.
3. The active targeting response type self-assembled imaging probe provided by the invention is based on the cathepsin B and a polypeptide chain segment with molecular specific response, has the capability of actively targeting an affected part, can spontaneously form a nano structure after enrichment of a tumor part, and can enhance enrichment and retention of the probe at a target focus part so as to enhance the sensitivity of the probe.
Drawings
FIG. 1 is a graph showing the results of targeting cancer cells with the imaging probe prepared in example 1.
FIG. 2 is a graph showing the results of in vitro cell slicing of the imaging probe prepared in example 1 (FIG. 2-1: control group, FIG. 2-2: imaging probe).
FIG. 3 is a graph showing the in vivo fluorescence imaging results of the imaging probe prepared in example 1. (FIG. 3-1: IR808, FIG. 3-2: imaging probe).
Detailed Description
The following are specific examples of the present invention, and the technical solutions of the present invention are further described, but the present invention is not limited to these examples.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.
The active targeting peptide segment is synthesized by a resin solid phase synthesis mode.
Example 1:
preparing raw materials R1, R2, R3 and F1, wherein R1 is peptide [ Pro ] 30 ,Nle 31 ,Bpa 32 ,Leu 34 ]NPY (28-36), R2 is responsive fragment KGRRG, R3 is self-assembled fragment FF, F1 is imaging probe group IR808.
PEG-1000 polyurethane resin is selected as a substrate, activated raw materials (Boc type) of peptide fragments are placed in a material box of an automatic polypeptide synthesizer one by one according to a sequence order, the polypeptide synthesizer is started, and a small amount of resin is taken for cutting analysis after the raw materials are reacted.
After the required polypeptide is identified, the polypeptide and IR808 with activated carboxyl are placed at a material tank for reaction, and a small amount of resin is taken for detection after the reaction is finished.
After confirming the product, the synthesized resin was cleaved with 1% TFA and the amino acid side chain protection was removed, followed by purification to a purity of 96% using preparative chromatography, the purification process was monitored by preparative chromatography itself, the purified solution was spin-distilled, re-melted with deionized water, and freeze-dried by filtration to give a probe compound [ Pro ] 30 ,Nle 31 ,Bpa 32 ,Leu 34 ]NPY(28-36)-KGRRG-FF-IR-808。
Examples 2 to 17:
the difference from example 1 is only that the amino acid sequences of the starting materials R1, R2, R3 and the F1 imaging probe groups are shown in Table 1.
Table 1: examples 2-17 Probe Compounds starting materials R1, R2, R3 amino acid sequences and F1 imaging Probe groups
| Examples | R1 | R2 | R3 | F1 |
| Example 2 | [Arg 6 ,Pro 34 ]pNPY | KGRR | FF | IR-808 |
| Example 3 | [Phe 6 ,Pro 34 ]pNPY | KGRR | FF | IR-808 |
| Example 4 | [Asn 6 ,Pro 34 ]pNPY | KGRR | FF | IR-808 |
| Example 5 | [Cys 6 ,Pro 34 ]pNPY | KGRR | FF | Cy5 |
| Example 6 | [D-His 26 ,Pro 34 ]NPY | KGRR | FF | Cy5 |
| Example 7 | [Phe 7 ,Pro 34 ]pNPY | KGRR | FF | Cy5 |
| Example 8 | [Pro 30 ,Nal 32 ,Leu 34 ]NPY(28-36) | KGRR | FF | Cy5 |
| Example 9 | [Pro 30 ,Nle 31 ,Nal 32 ,Leu 34 ]NPY(28-36) | KGRR | FF | IR-783 |
| Example 10 | NPY(28-36) | KGRR | FF | IR-783 |
| Example 11 | [Pro 30 ,Tyr 32 ,Pro 34 ]NPY(25-36) | KGRR | FF | IR-783 |
| Example 12 | [Pro 30 ,Tyr 32 ]NPY(25-36) | KGRR | FF | IR-783 |
| Example 13 | [Pro 30 ,Trp 32 ]NPY(25-36) | KGRR | FF | IR-783 |
| Example 14 | [Tyr 32 ,Pro 34 ]NPY(25-36) | KGRR | FF | Cy7 |
| Example 15 | [Pro 30 ,Tyr 31 ,Trp 32 ]NPY(25-36) | KGRR | FF | Cy7 |
| Example 16 | NPY(25-36) | KGRR | FF | Cy7 |
| Example 17 | [Asn 28 ,Pro 30 ,Trp 32 ]NPY(25-36) | KGRR | FF | Cy7 |
Wherein KGRR is the amino acid sequence of SEQ ID No. 5; FF is the amino acid sequence of SEQ ID No. 371.
Example 18:
preparing raw materials R1, R2, R3 and F1, wherein R1 is peptide fragment [ Arg ] 6 ,Pro 34 ]pNPY, R2 is responsive fragment GFLG, R3 is self-assembled fragment GFFYE, F1 is imaging probe group iohexol.
PEG-1000 polyurethane resin is selected as a substrate, activated raw materials (Boc type) of peptide fragments are placed in a material box of an automatic polypeptide synthesizer one by one according to a sequence order, the polypeptide synthesizer is started, and a small amount of resin is taken for cutting analysis after the raw materials are reacted.
After the required polypeptide is identified, the polypeptide and the iohexol with activated carboxyl are placed at a material tank for reaction, and a small amount of resin is taken for detection after the reaction is finished.
After confirming the product, the synthesized resin was cleaved with 1% TFA and the amino acid side chain protection was removed, followed by purification to a purity of 96% using preparative chromatography, the purification process was monitored by preparative chromatography itself, the purified solution was spin-distilled, re-melted with deionized water, and freeze-dried by filtration to give a probe compound [ Arg ] 6 ,Pro 34 ]pNPY-GFLG-GFFYE-iohexol.
Examples 19 to 34:
the difference from example 2 is only that the amino acid sequences of the starting materials R1, R2, R3 and the F1 imaging probe groups are shown in Table 2.
Table 2: examples 19-34 Probe Compounds starting materials R1, R2, R3 amino acid sequences and F1 imaging Probe groups
Wherein GFLG is the amino acid sequence of SEQ ID No. 2; GFFYE is the amino acid sequence of SEQ ID No. 374.
Example 35:
preparing raw materials R1, R2, R3 and F1, wherein R1 is peptide fragment [ Phe ] 6 ,Pro 34 ]pNPY, R2 is responsive fragment AFK, R3 is self-assembled fragment ILVAV, F1 is imaging probe group 18F-deoxyglucose.
PEG-1000 polyurethane resin is selected as a substrate, activated raw materials (Boc type) of peptide fragments are placed in a material box of an automatic polypeptide synthesizer one by one according to a sequence order, the polypeptide synthesizer is started, and a small amount of resin is taken for cutting analysis after the raw materials are reacted.
After the required polypeptide is identified, the polypeptide and 18F-substituted deoxyglucose with activated carboxyl are placed at a material tank for reaction, and a small amount of resin is taken for detection after the reaction is finished.
After confirming the product, the synthesized resin was cleaved with 1% TFA and the amino acid side chain protection was removed, followed by purification to a purity of 96% using preparative chromatography, the purification process was monitored by preparative chromatography itself, the purified solution was spin-distilled, re-melted with deionized water, and freeze-dried by filtration to give a probe compound [ Phe ] 6 ,Pro 34 ]pNPY-AFK-ILVAV-18F deoxyglucose.
Examples 36 to 51:
the difference from example 3 is only that the amino acid sequences of R1, R2, R3 and the F1 imaging probe groups of the raw materials of examples 36 to 51 are shown in Table 3.
Table 3: examples 36-51 Probe Compounds starting materials R1, R2, R3 amino acid sequences and F1 imaging Probe groups
Wherein AFK is SEQ ID No.4 amino acid sequence; ILVAV is SEQ ID No.376 amino acid sequence.
Example 52:
preparing raw materials R1, R2, R3 and F1, wherein R1 is peptide fragment [ Asn ] 6 ,Pro 34 ]pNPY, R2 is a responsive fragment ALAL, R3 is a self-assembled fragment ILVAV, and F1 is an imaging probe group gadodiamide.
PEG-1000 polyurethane resin is selected as a substrate, activated raw materials (Boc type) of peptide fragments are placed in a material box of an automatic polypeptide synthesizer one by one according to a sequence order, the polypeptide synthesizer is started, and a small amount of resin is taken for cutting analysis after the raw materials are reacted.
After identifying the desired polypeptide, the polypeptide and gadodiamine having an activated carboxyl group are placed in a canister for reaction. And taking a small amount of resin for detection after the reflection is finished.
After confirming the product, the synthesized resin was cleaved with 1% TFA and the amino acid side chain protection was removed, followed by purification to a purity of 99% using preparative chromatography, the purification process was monitored by preparative chromatography itself, the purified solution was spin-distilled, re-melted with deionized water, and freeze-dried by filtration to give a probe compound [ Asn ] 6 ,Pro 34 ]pNPY-ALAL-ILVAV-gadodiamide.
Examples 53 to 68:
the difference from example 4 is only that the amino acid sequences of R1, R2, R3 and F1 imaging probe groups of the raw materials of examples 53 to 65 are shown in Table 4.
Table 4: examples 53-68 Probe Compounds starting materials R1, R2, R3 amino acid sequences and F1 imaging Probe groups
| Examples | R1 | R2 | R3 | F1 |
| Example 53 | [Pro 30 ,Nle 31 ,Bpa 32 ,Leu 34 ]NPY(28-36) | ALAL | ILVAV | Gadolinium diamine |
| Example 54 | [Arg 6 ,Pro 34 ]pNPY | ALAL | ILVAV | Gadolinium diamine |
| Example 55 | [Phe 6 ,Pro 34 ]pNPY | ALAL | ILVAV | Gadolinium diamine |
| Example 56 | [Cys 6 ,Pro 34 ]pNPY | ALAL | ILVAV | Gadolinium diamine |
| Example 57 | [D-His 26 ,Pro 34 ]NPY | ALAL | ILVAV | Gadocetetic acid disodium salt |
| Example 58 | [Phe 7 ,Pro 34 ]pNPY | ALAL | ILVAV | Gadocetetic acid disodium salt |
| Example 59 | [Pro 30 ,Nal 32 ,Leu 34 ]NPY(28-36) | ALAL | ILVAV | Gadocetetic acid disodium salt |
| Example 60 | [Pro 30 ,Nle 31 ,Nal 32 ,Leu 34 ]NPY(28-36) | ALAL | ILVAV | Gadocetetic acid disodium salt |
| Example 61 | NPY(28-36) | ALAL | ILVAV | Gadocetetic acid disodium salt |
| Example 62 | [Pro 30 ,Tyr 32 ,Pro 34 ]NPY(25-36) | ALAL | ILVAV | Gadoteric acid meglumine |
| Example 63 | [Pro 30 ,Tyr 32 ]NPY(25-36) | ALAL | ILVAV | Gadoteric acid meglumine |
| Example 64 | [Pro 30 ,Trp 32 ]NPY(25-36) | ALAL | ILVAV | Gadoteric acid meglumine |
| Example 65 | [Tyr 32 ,Pro 34 ]NPY(25-36) | ALAL | ILVAV | Gadoteric acid meglumine |
| Example 66 | [Pro 30 ,Tyr 31 ,Trp 32 ]NPY(25-36) | ALAL | ILVAV | Gadoteric acid meglumine |
| Example 67 | NPY(25-36) | ALAL | ILVAV | Gadofoshan |
| Example 68 | [Asn 28 ,Pro 30 ,Trp 32 ]NPY(25-36) | ALAL | ILVAV | Gadofoshan |
Wherein ALAL is the amino acid sequence of SEQ ID No. 3; ILVAV is SEQ ID No.376 amino acid sequence.
Application example 1:
the sample probe compounds prepared in examples 1 to 68 were subjected to phagocytosis experiments of human breast cancer cells, and the specific procedures were as follows:
one million MDA-MB-231 human breast cancer cells were seeded in 6-well plates at 37℃with 5% CO 2 Incubate overnight. The free IR-808 of IR-808 and the probe sample prepared in example 5 were then added thereto at equimolar concentrations. Cells were collected after 12h of co-administration, resuspended after three rinsing passes with PBS, and the average fluorescence intensity of 10000 individual macrophages was examined by flow cytometry (manufacturer BD, model FACSCalibur), 550nm excitation, 610nm collection signal, respectively.
FIG. 1 is a graph showing the results of targeting cancer cells with the probe compound prepared in example 1. It can be seen from the figure that the synthesized imaging probe has the property of actively targeting human breast cancer tumor cells. Other example test results were similar to those described above, and all that the synthesized probe compounds had the conclusion of actively targeting human breast cancer tumor cells.
Application example 2:
the probe compound samples prepared in examples 1 to 68 were subjected to a cell slice experiment of human breast cancer cells, and the specific steps are as follows:
one million MDA-MB-231 human breast cancer cells were seededIn a 6-well plate at 37℃in 5% CO 2 Incubate overnight. Then, a sample of free IR-808 having an equimolar concentration of IR-808 and the probe compound prepared in example 5 were added thereto, and after 12 hours, the cells were collected, washed three times with PBS, and then fixed with 4% paraformaldehyde for 15 minutes, and then sectioned for preparation and observation by a biological transmission electron microscope.
FIG. 2 is a graph showing the results of in vitro cell slicing of the imaging probe prepared in example 1 (FIG. 2-1: control group, FIG. 2-2: imaging probe). From the figure, it can be seen that the probe compound sample prepared in example 1 is capable of undergoing morphological transformation in breast cancer cells, and self-assembling to form nanofibers. Other examples test results were similar to those described above, and all that resulted in the synthesized compounds having the ability to undergo morphological transformation in breast cancer cells, self-assembly into nanofibers.
Application example 3:
the probe compound samples prepared in examples 1 to 17 were subjected to a fluorescent imaging experiment of a human breast cancer tumor mouse, and the specific steps are as follows:
the probe compound sample prepared in example 1 was prepared to 2mg/mL with pure water, and 100. Mu.L was injected into the body of the mouse by tail vein, and after 72 hours, the anesthetized tumor mouse was imaged.
FIG. 3 is a graph showing the in vivo fluorescence imaging results of the imaging probe prepared in example 1. (FIG. 3-1: IR808, FIG. 3-2: imaging probe). From the graph, the tumor part still has obvious fluorescence, and the signal ratio of the tumor part to normal tissue is 3.43. Other examples test results are similar to those described above, demonstrating that the probe compound samples prepared according to the present invention can actively target tumor sites of tumor mice and perform long-term precise imaging.
Application example 4:
CT imaging experiments were performed on the probe compound samples prepared in examples 18 to 34 on human breast cancer tumor mice, and the specific procedures were as follows:
the probe compound sample prepared in example 19 was prepared to 2mg/mL with pure water, 100 μl was injected into the body of the mouse via tail vein, and after 72 hours, the anesthetized tumor mouse was imaged, and it was found that the tumor portion thereof still had an obvious CT-enhanced imaging effect, and the signal ratio of the tumor portion to surrounding normal tissues was 1.57. Other examples test results are similar to those described above, demonstrating that the probe compound samples prepared according to the present invention can actively target tumor sites of tumor mice and perform long-term precise imaging.
Application example 5:
the probe compound samples prepared in examples 35 to 51 were subjected to PET imaging experiments of human breast cancer tumor mice, and the specific steps are as follows:
the probe compound sample prepared in example 35 was prepared to 2mg/mL with pure water, and 100. Mu.L was injected into the body of the mouse by tail vein, and after 72 hours, the anesthetized tumor mouse was imaged. The tumor part of the tumor part is found to have obvious PET imaging effect, and the signal ratio of the tumor part to surrounding normal tissues is 2.65. Other examples test results are similar to those described above, demonstrating that the probe compound samples prepared according to the present invention can actively target tumor sites of tumor mice and perform long-term precise imaging.
Application example 6:
the probe compound samples prepared in examples 52 to 68 were subjected to magnetic resonance imaging experiments of human breast cancer tumor mice, and the specific procedures are as follows:
the probe compound sample prepared in example 52 was prepared to 2mg/mL with PBS water, 100 μl was injected into the body of the mouse via tail vein, and after 72 hours, the anesthetized tumor mouse was imaged, and it was found that the tumor portion still had obvious T1 enhanced imaging, and the signal ratio of the tumor portion to normal tissue was 3.76. Other examples test results are similar to those described above, demonstrating that the probe compound samples prepared according to the present invention can actively target tumor sites of tumor mice and perform long-term precise imaging.
Table 5: examples 1-68 in vivo imaging experiments with mastadenoma mice signal-to-noise ratio test results
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Wherein, the liquid crystal display device comprises a liquid crystal display device, ++ + + and representation letter the noise ratio is greater than 3.5; ++ + representation letter the noise ratio is 2.5-3.5; ++ means a signal to noise ratio of 1.5-2.5; + means a signal to noise ratio of 1-1.5.
Table 6: examples 1-68 in vivo imaging experiments on mastadenoma-bearing mice test results of effective imaging time
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Wherein, the liquid crystal display device comprises a liquid crystal display device, +++++ representation effective formation the imaging time is longer than 12 hours; ++ means that the effective imaging time is 8-12h; ++ means that the effective imaging time is 4-8h; + indicates that the effective imaging time is less than 4 hours.
In conclusion, the active targeting response type self-assembled imaging probe disclosed by the invention is based on the cathepsin B and the polypeptide chain segment with molecular specific response, has the capability of actively targeting an affected part, can spontaneously form a nano structure after enrichment of a tumor part, and enhances enrichment and retention of the probe at a target focus part so as to enhance the sensitivity of the probe.
The specific embodiments described herein are offered by way of example only to illustrate the spirit of the invention. Various modifications or additions to the described embodiments may be made by those skilled in the art to which the invention pertains or may be substituted in a similar manner without departing from the spirit of the invention or beyond the scope of the appended claims.
While the invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof.
Sequence listing
<110> Ningbo Material technology and engineering institute of China academy of sciences
Ningbo Cixi biomedical engineering institute
<120> an active targeting responsive self-assembled imaging probe, and preparation method and application thereof
<141> 2022-02-09
<160> 403
<170> SIPOSequenceListing 1.0
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Gly Arg Arg Gly Lys Gly Gly
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<210> 2
<211> 4
<212> PRT
<213> Unknown
<400> 2
Gly Phe Leu Gly
1
<210> 3
<211> 4
<212> PRT
<213> Unknown
<400> 3
Ala Leu Ala Leu
1
<210> 4
<211> 3
<212> PRT
<213> Unknown
<400> 4
Ala Phe Lys
1
<210> 5
<211> 4
<212> PRT
<213> Unknown
<400> 5
Lys Gly Arg Arg
1
<210> 6
<211> 3
<212> PRT
<213> Unknown
<400> 6
Cys Lys Phe
1
<210> 7
<211> 9
<212> PRT
<213> Unknown
<400> 7
Ala Gly Phe Ser Leu Pro Ala Lys Arg
1 5
<210> 8
<211> 9
<212> PRT
<213> Unknown
<400> 8
Phe Phe Arg Ile Lys Phe Glu Arg Gln
1 5
<210> 9
<211> 2
<212> PRT
<213> Unknown
<400> 9
Tyr Ala
1
<210> 10
<211> 2
<212> PRT
<213> Unknown
<400> 10
Tyr Arg
1
<210> 11
<211> 2
<212> PRT
<213> Unknown
<400> 11
Tyr Asn
1
<210> 12
<211> 2
<212> PRT
<213> Unknown
<400> 12
Tyr Asp
1
<210> 13
<211> 2
<212> PRT
<213> Unknown
<400> 13
Tyr Cys
1
<210> 14
<211> 2
<212> PRT
<213> Unknown
<400> 14
Tyr Gln
1
<210> 15
<211> 2
<212> PRT
<213> Unknown
<400> 15
Tyr Glu
1
<210> 16
<211> 2
<212> PRT
<213> Unknown
<400> 16
Tyr Gly
1
<210> 17
<211> 2
<212> PRT
<213> Unknown
<400> 17
Tyr His
1
<210> 18
<211> 2
<212> PRT
<213> Unknown
<400> 18
Tyr Ile
1
<210> 19
<211> 2
<212> PRT
<213> Unknown
<400> 19
Tyr Leu
1
<210> 20
<211> 2
<212> PRT
<213> Unknown
<400> 20
Tyr Lys
1
<210> 21
<211> 2
<212> PRT
<213> Unknown
<400> 21
Tyr Met
1
<210> 22
<211> 2
<212> PRT
<213> Unknown
<400> 22
Tyr Phe
1
<210> 23
<211> 2
<212> PRT
<213> Unknown
<400> 23
Tyr Pro
1
<210> 24
<211> 2
<212> PRT
<213> Unknown
<400> 24
Tyr Ser
1
<210> 25
<211> 2
<212> PRT
<213> Unknown
<400> 25
Tyr Thr
1
<210> 26
<211> 2
<212> PRT
<213> Unknown
<400> 26
Tyr Trp
1
<210> 27
<211> 2
<212> PRT
<213> Unknown
<400> 27
Tyr Tyr
1
<210> 28
<211> 2
<212> PRT
<213> Unknown
<400> 28
Tyr Val
1
<210> 29
<211> 2
<212> PRT
<213> Unknown
<400> 29
Gly Ala
1
<210> 30
<211> 2
<212> PRT
<213> Unknown
<400> 30
Gly Arg
1
<210> 31
<211> 2
<212> PRT
<213> Unknown
<400> 31
Gly Asn
1
<210> 32
<211> 2
<212> PRT
<213> Unknown
<400> 32
Gly Asp
1
<210> 33
<211> 2
<212> PRT
<213> Unknown
<400> 33
Gly Cys
1
<210> 34
<211> 2
<212> PRT
<213> Unknown
<400> 34
Gly Gln
1
<210> 35
<211> 2
<212> PRT
<213> Unknown
<400> 35
Gly Glu
1
<210> 36
<211> 2
<212> PRT
<213> Unknown
<400> 36
Gly Gly
1
<210> 37
<211> 2
<212> PRT
<213> Unknown
<400> 37
Gly His
1
<210> 38
<211> 2
<212> PRT
<213> Unknown
<400> 38
Gly Ile
1
<210> 39
<211> 2
<212> PRT
<213> Unknown
<400> 39
Gly Leu
1
<210> 40
<211> 2
<212> PRT
<213> Unknown
<400> 40
Gly Lys
1
<210> 41
<211> 2
<212> PRT
<213> Unknown
<400> 41
Gly Met
1
<210> 42
<211> 2
<212> PRT
<213> Unknown
<400> 42
Gly Phe
1
<210> 43
<211> 2
<212> PRT
<213> Unknown
<400> 43
Gly Pro
1
<210> 44
<211> 2
<212> PRT
<213> Unknown
<400> 44
Gly Ser
1
<210> 45
<211> 2
<212> PRT
<213> Unknown
<400> 45
Gly Thr
1
<210> 46
<211> 2
<212> PRT
<213> Unknown
<400> 46
Gly Trp
1
<210> 47
<211> 2
<212> PRT
<213> Unknown
<400> 47
Gly Tyr
1
<210> 48
<211> 2
<212> PRT
<213> Unknown
<400> 48
Gly Val
1
<210> 49
<211> 2
<212> PRT
<213> Unknown
<400> 49
Ser Ala
1
<210> 50
<211> 2
<212> PRT
<213> Unknown
<400> 50
Ser Arg
1
<210> 51
<211> 2
<212> PRT
<213> Unknown
<400> 51
Ser Asn
1
<210> 52
<211> 2
<212> PRT
<213> Unknown
<400> 52
Ser Asp
1
<210> 53
<211> 2
<212> PRT
<213> Unknown
<400> 53
Ser Cys
1
<210> 54
<211> 2
<212> PRT
<213> Unknown
<400> 54
Ser Gln
1
<210> 55
<211> 2
<212> PRT
<213> Unknown
<400> 55
Ser Glu
1
<210> 56
<211> 2
<212> PRT
<213> Unknown
<400> 56
Ser Gly
1
<210> 57
<211> 2
<212> PRT
<213> Unknown
<400> 57
Ser His
1
<210> 58
<211> 2
<212> PRT
<213> Unknown
<400> 58
Ser Ile
1
<210> 59
<211> 2
<212> PRT
<213> Unknown
<400> 59
Ser Leu
1
<210> 60
<211> 2
<212> PRT
<213> Unknown
<400> 60
Ser Lys
1
<210> 61
<211> 2
<212> PRT
<213> Unknown
<400> 61
Ser Met
1
<210> 62
<211> 2
<212> PRT
<213> Unknown
<400> 62
Ser Phe
1
<210> 63
<211> 2
<212> PRT
<213> Unknown
<400> 63
Ser Pro
1
<210> 64
<211> 2
<212> PRT
<213> Unknown
<400> 64
Ser Ser
1
<210> 65
<211> 2
<212> PRT
<213> Unknown
<400> 65
Ser Thr
1
<210> 66
<211> 2
<212> PRT
<213> Unknown
<400> 66
Ser Trp
1
<210> 67
<211> 2
<212> PRT
<213> Unknown
<400> 67
Ser Tyr
1
<210> 68
<211> 2
<212> PRT
<213> Unknown
<400> 68
Ser Val
1
<210> 69
<211> 2
<212> PRT
<213> Unknown
<400> 69
Val Ala
1
<210> 70
<211> 2
<212> PRT
<213> Unknown
<400> 70
Val Arg
1
<210> 71
<211> 2
<212> PRT
<213> Unknown
<400> 71
Val Asn
1
<210> 72
<211> 2
<212> PRT
<213> Unknown
<400> 72
Val Asp
1
<210> 73
<211> 2
<212> PRT
<213> Unknown
<400> 73
Val Cys
1
<210> 74
<211> 2
<212> PRT
<213> Unknown
<400> 74
Val Gln
1
<210> 75
<211> 2
<212> PRT
<213> Unknown
<400> 75
Val Glu
1
<210> 76
<211> 2
<212> PRT
<213> Unknown
<400> 76
Val Gly
1
<210> 77
<211> 2
<212> PRT
<213> Unknown
<400> 77
Val His
1
<210> 78
<211> 2
<212> PRT
<213> Unknown
<400> 78
Val Ile
1
<210> 79
<211> 2
<212> PRT
<213> Unknown
<400> 79
Val Leu
1
<210> 80
<211> 2
<212> PRT
<213> Unknown
<400> 80
Val Lys
1
<210> 81
<211> 2
<212> PRT
<213> Unknown
<400> 81
Val Met
1
<210> 82
<211> 2
<212> PRT
<213> Unknown
<400> 82
Val Phe
1
<210> 83
<211> 2
<212> PRT
<213> Unknown
<400> 83
Val Pro
1
<210> 84
<211> 2
<212> PRT
<213> Unknown
<400> 84
Val Ser
1
<210> 85
<211> 2
<212> PRT
<213> Unknown
<400> 85
Val Thr
1
<210> 86
<211> 2
<212> PRT
<213> Unknown
<400> 86
Val Trp
1
<210> 87
<211> 2
<212> PRT
<213> Unknown
<400> 87
Val Tyr
1
<210> 88
<211> 2
<212> PRT
<213> Unknown
<400> 88
Val Val
1
<210> 89
<211> 2
<212> PRT
<213> Unknown
<400> 89
Phe Ala
1
<210> 90
<211> 2
<212> PRT
<213> Unknown
<400> 90
Phe Arg
1
<210> 91
<211> 2
<212> PRT
<213> Unknown
<400> 91
Phe Asn
1
<210> 92
<211> 2
<212> PRT
<213> Unknown
<400> 92
Phe Asp
1
<210> 93
<211> 2
<212> PRT
<213> Unknown
<400> 93
Phe Cys
1
<210> 94
<211> 2
<212> PRT
<213> Unknown
<400> 94
Phe Gln
1
<210> 95
<211> 2
<212> PRT
<213> Unknown
<400> 95
Phe Glu
1
<210> 96
<211> 2
<212> PRT
<213> Unknown
<400> 96
Phe Gly
1
<210> 97
<211> 2
<212> PRT
<213> Unknown
<400> 97
Phe His
1
<210> 98
<211> 2
<212> PRT
<213> Unknown
<400> 98
Phe Ile
1
<210> 99
<211> 2
<212> PRT
<213> Unknown
<400> 99
Phe Leu
1
<210> 100
<211> 2
<212> PRT
<213> Unknown
<400> 100
Phe Lys
1
<210> 101
<211> 2
<212> PRT
<213> Unknown
<400> 101
Phe Met
1
<210> 102
<211> 2
<212> PRT
<213> Unknown
<400> 102
Phe Phe
1
<210> 103
<211> 2
<212> PRT
<213> Unknown
<400> 103
Phe Pro
1
<210> 104
<211> 2
<212> PRT
<213> Unknown
<400> 104
Phe Ser
1
<210> 105
<211> 2
<212> PRT
<213> Unknown
<400> 105
Phe Thr
1
<210> 106
<211> 2
<212> PRT
<213> Unknown
<400> 106
Phe Trp
1
<210> 107
<211> 2
<212> PRT
<213> Unknown
<400> 107
Phe Tyr
1
<210> 108
<211> 2
<212> PRT
<213> Unknown
<400> 108
Phe Val
1
<210> 109
<211> 2
<212> PRT
<213> Unknown
<400> 109
Met Ala
1
<210> 110
<211> 2
<212> PRT
<213> Unknown
<400> 110
Met Arg
1
<210> 111
<211> 2
<212> PRT
<213> Unknown
<400> 111
Met Asn
1
<210> 112
<211> 2
<212> PRT
<213> Unknown
<400> 112
Met Asp
1
<210> 113
<211> 2
<212> PRT
<213> Unknown
<400> 113
Met Cys
1
<210> 114
<211> 2
<212> PRT
<213> Unknown
<400> 114
Met Gln
1
<210> 115
<211> 2
<212> PRT
<213> Unknown
<400> 115
Met Glu
1
<210> 116
<211> 2
<212> PRT
<213> Unknown
<400> 116
Met Gly
1
<210> 117
<211> 2
<212> PRT
<213> Unknown
<400> 117
Met His
1
<210> 118
<211> 2
<212> PRT
<213> Unknown
<400> 118
Met Ile
1
<210> 119
<211> 2
<212> PRT
<213> Unknown
<400> 119
Met Leu
1
<210> 120
<211> 2
<212> PRT
<213> Unknown
<400> 120
Met Lys
1
<210> 121
<211> 2
<212> PRT
<213> Unknown
<400> 121
Met Met
1
<210> 122
<211> 2
<212> PRT
<213> Unknown
<400> 122
Met Phe
1
<210> 123
<211> 2
<212> PRT
<213> Unknown
<400> 123
Met Pro
1
<210> 124
<211> 2
<212> PRT
<213> Unknown
<400> 124
Met Ser
1
<210> 125
<211> 2
<212> PRT
<213> Unknown
<400> 125
Met Thr
1
<210> 126
<211> 2
<212> PRT
<213> Unknown
<400> 126
Met Trp
1
<210> 127
<211> 2
<212> PRT
<213> Unknown
<400> 127
Met Tyr
1
<210> 128
<211> 2
<212> PRT
<213> Unknown
<400> 128
Met Val
1
<210> 129
<211> 2
<212> PRT
<213> Unknown
<400> 129
Trp Ala
1
<210> 130
<211> 2
<212> PRT
<213> Unknown
<400> 130
Trp Arg
1
<210> 131
<211> 2
<212> PRT
<213> Unknown
<400> 131
Trp Asn
1
<210> 132
<211> 2
<212> PRT
<213> Unknown
<400> 132
Trp Asp
1
<210> 133
<211> 2
<212> PRT
<213> Unknown
<400> 133
Trp Cys
1
<210> 134
<211> 2
<212> PRT
<213> Unknown
<400> 134
Trp Gln
1
<210> 135
<211> 2
<212> PRT
<213> Unknown
<400> 135
Trp Glu
1
<210> 136
<211> 2
<212> PRT
<213> Unknown
<400> 136
Trp Gly
1
<210> 137
<211> 2
<212> PRT
<213> Unknown
<400> 137
Trp His
1
<210> 138
<211> 2
<212> PRT
<213> Unknown
<400> 138
Trp Ile
1
<210> 139
<211> 2
<212> PRT
<213> Unknown
<400> 139
Trp Leu
1
<210> 140
<211> 2
<212> PRT
<213> Unknown
<400> 140
Trp Lys
1
<210> 141
<211> 2
<212> PRT
<213> Unknown
<400> 141
Trp Met
1
<210> 142
<211> 2
<212> PRT
<213> Unknown
<400> 142
Trp Phe
1
<210> 143
<211> 2
<212> PRT
<213> Unknown
<400> 143
Trp Pro
1
<210> 144
<211> 2
<212> PRT
<213> Unknown
<400> 144
Trp Ser
1
<210> 145
<211> 2
<212> PRT
<213> Unknown
<400> 145
Trp Thr
1
<210> 146
<211> 2
<212> PRT
<213> Unknown
<400> 146
Trp Trp
1
<210> 147
<211> 2
<212> PRT
<213> Unknown
<400> 147
Trp Tyr
1
<210> 148
<211> 2
<212> PRT
<213> Unknown
<400> 148
Trp Val
1
<210> 149
<211> 2
<212> PRT
<213> Unknown
<400> 149
Ala Ala
1
<210> 150
<211> 2
<212> PRT
<213> Unknown
<400> 150
Ala Arg
1
<210> 151
<211> 2
<212> PRT
<213> Unknown
<400> 151
Ala Asn
1
<210> 152
<211> 2
<212> PRT
<213> Unknown
<400> 152
Ala Asp
1
<210> 153
<211> 2
<212> PRT
<213> Unknown
<400> 153
Ala Cys
1
<210> 154
<211> 2
<212> PRT
<213> Unknown
<400> 154
Ala Gln
1
<210> 155
<211> 2
<212> PRT
<213> Unknown
<400> 155
Ala Glu
1
<210> 156
<211> 2
<212> PRT
<213> Unknown
<400> 156
Ala Gly
1
<210> 157
<211> 2
<212> PRT
<213> Unknown
<400> 157
Ala His
1
<210> 158
<211> 2
<212> PRT
<213> Unknown
<400> 158
Ala Ile
1
<210> 159
<211> 2
<212> PRT
<213> Unknown
<400> 159
Ala Leu
1
<210> 160
<211> 2
<212> PRT
<213> Unknown
<400> 160
Ala Lys
1
<210> 161
<211> 2
<212> PRT
<213> Unknown
<400> 161
Ala Met
1
<210> 162
<211> 2
<212> PRT
<213> Unknown
<400> 162
Ala Phe
1
<210> 163
<211> 2
<212> PRT
<213> Unknown
<400> 163
Ala Pro
1
<210> 164
<211> 2
<212> PRT
<213> Unknown
<400> 164
Ala Ser
1
<210> 165
<211> 2
<212> PRT
<213> Unknown
<400> 165
Ala Thr
1
<210> 166
<211> 2
<212> PRT
<213> Unknown
<400> 166
Ala Trp
1
<210> 167
<211> 2
<212> PRT
<213> Unknown
<400> 167
Ala Tyr
1
<210> 168
<211> 2
<212> PRT
<213> Unknown
<400> 168
Ala Val
1
<210> 169
<211> 2
<212> PRT
<213> Unknown
<400> 169
Leu Ala
1
<210> 170
<211> 2
<212> PRT
<213> Unknown
<400> 170
Leu Arg
1
<210> 171
<211> 2
<212> PRT
<213> Unknown
<400> 171
Leu Asn
1
<210> 172
<211> 2
<212> PRT
<213> Unknown
<400> 172
Leu Asp
1
<210> 173
<211> 2
<212> PRT
<213> Unknown
<400> 173
Leu Cys
1
<210> 174
<211> 2
<212> PRT
<213> Unknown
<400> 174
Leu Gln
1
<210> 175
<211> 2
<212> PRT
<213> Unknown
<400> 175
Leu Glu
1
<210> 176
<211> 2
<212> PRT
<213> Unknown
<400> 176
Leu Gly
1
<210> 177
<211> 2
<212> PRT
<213> Unknown
<400> 177
Leu His
1
<210> 178
<211> 2
<212> PRT
<213> Unknown
<400> 178
Leu Ile
1
<210> 179
<211> 2
<212> PRT
<213> Unknown
<400> 179
Leu Leu
1
<210> 180
<211> 2
<212> PRT
<213> Unknown
<400> 180
Leu Lys
1
<210> 181
<211> 2
<212> PRT
<213> Unknown
<400> 181
Leu Met
1
<210> 182
<211> 2
<212> PRT
<213> Unknown
<400> 182
Leu Phe
1
<210> 183
<211> 2
<212> PRT
<213> Unknown
<400> 183
Leu Pro
1
<210> 184
<211> 2
<212> PRT
<213> Unknown
<400> 184
Leu Ser
1
<210> 185
<211> 2
<212> PRT
<213> Unknown
<400> 185
Leu Thr
1
<210> 186
<211> 2
<212> PRT
<213> Unknown
<400> 186
Leu Trp
1
<210> 187
<211> 2
<212> PRT
<213> Unknown
<400> 187
Leu Tyr
1
<210> 188
<211> 2
<212> PRT
<213> Unknown
<400> 188
Leu Val
1
<210> 189
<211> 2
<212> PRT
<213> Unknown
<400> 189
Lys Ala
1
<210> 190
<211> 2
<212> PRT
<213> Unknown
<400> 190
Lys Arg
1
<210> 191
<211> 2
<212> PRT
<213> Unknown
<400> 191
Lys Asn
1
<210> 192
<211> 2
<212> PRT
<213> Unknown
<400> 192
Lys Asp
1
<210> 193
<211> 2
<212> PRT
<213> Unknown
<400> 193
Lys Cys
1
<210> 194
<211> 2
<212> PRT
<213> Unknown
<400> 194
Lys Gln
1
<210> 195
<211> 2
<212> PRT
<213> Unknown
<400> 195
Lys Glu
1
<210> 196
<211> 2
<212> PRT
<213> Unknown
<400> 196
Lys Gly
1
<210> 197
<211> 2
<212> PRT
<213> Unknown
<400> 197
Lys His
1
<210> 198
<211> 2
<212> PRT
<213> Unknown
<400> 198
Lys Ile
1
<210> 199
<211> 2
<212> PRT
<213> Unknown
<400> 199
Lys Leu
1
<210> 200
<211> 2
<212> PRT
<213> Unknown
<400> 200
Lys Lys
1
<210> 201
<211> 2
<212> PRT
<213> Unknown
<400> 201
Lys Met
1
<210> 202
<211> 2
<212> PRT
<213> Unknown
<400> 202
Lys Phe
1
<210> 203
<211> 2
<212> PRT
<213> Unknown
<400> 203
Lys Pro
1
<210> 204
<211> 2
<212> PRT
<213> Unknown
<400> 204
Lys Ser
1
<210> 205
<211> 2
<212> PRT
<213> Unknown
<400> 205
Lys Thr
1
<210> 206
<211> 2
<212> PRT
<213> Unknown
<400> 206
Lys Trp
1
<210> 207
<211> 2
<212> PRT
<213> Unknown
<400> 207
Lys Tyr
1
<210> 208
<211> 2
<212> PRT
<213> Unknown
<400> 208
Lys Val
1
<210> 209
<211> 2
<212> PRT
<213> Unknown
<400> 209
Arg Ala
1
<210> 210
<211> 2
<212> PRT
<213> Unknown
<400> 210
Arg Arg
1
<210> 211
<211> 2
<212> PRT
<213> Unknown
<400> 211
Arg Asn
1
<210> 212
<211> 2
<212> PRT
<213> Unknown
<400> 212
Arg Asp
1
<210> 213
<211> 2
<212> PRT
<213> Unknown
<400> 213
Arg Cys
1
<210> 214
<211> 2
<212> PRT
<213> Unknown
<400> 214
Arg Gln
1
<210> 215
<211> 2
<212> PRT
<213> Unknown
<400> 215
Arg Glu
1
<210> 216
<211> 2
<212> PRT
<213> Unknown
<400> 216
Arg Gly
1
<210> 217
<211> 2
<212> PRT
<213> Unknown
<400> 217
Arg His
1
<210> 218
<211> 2
<212> PRT
<213> Unknown
<400> 218
Arg Ile
1
<210> 219
<211> 2
<212> PRT
<213> Unknown
<400> 219
Arg Leu
1
<210> 220
<211> 2
<212> PRT
<213> Unknown
<400> 220
Arg Lys
1
<210> 221
<211> 2
<212> PRT
<213> Unknown
<400> 221
Arg Met
1
<210> 222
<211> 2
<212> PRT
<213> Unknown
<400> 222
Arg Phe
1
<210> 223
<211> 2
<212> PRT
<213> Unknown
<400> 223
Arg Pro
1
<210> 224
<211> 2
<212> PRT
<213> Unknown
<400> 224
Arg Ser
1
<210> 225
<211> 2
<212> PRT
<213> Unknown
<400> 225
Arg Thr
1
<210> 226
<211> 2
<212> PRT
<213> Unknown
<400> 226
Arg Trp
1
<210> 227
<211> 2
<212> PRT
<213> Unknown
<400> 227
Arg Tyr
1
<210> 228
<211> 2
<212> PRT
<213> Unknown
<400> 228
Arg Val
1
<210> 229
<211> 3
<212> PRT
<213> Unknown
<400> 229
Phe Phe Ala
1
<210> 230
<211> 3
<212> PRT
<213> Unknown
<400> 230
Phe Phe Arg
1
<210> 231
<211> 3
<212> PRT
<213> Unknown
<400> 231
Phe Phe Asn
1
<210> 232
<211> 3
<212> PRT
<213> Unknown
<400> 232
Phe Phe Asp
1
<210> 233
<211> 3
<212> PRT
<213> Unknown
<400> 233
Phe Phe Cys
1
<210> 234
<211> 3
<212> PRT
<213> Unknown
<400> 234
Phe Phe Gln
1
<210> 235
<211> 3
<212> PRT
<213> Unknown
<400> 235
Phe Phe Glu
1
<210> 236
<211> 3
<212> PRT
<213> Unknown
<400> 236
Phe Phe Gly
1
<210> 237
<211> 3
<212> PRT
<213> Unknown
<400> 237
Phe Phe His
1
<210> 238
<211> 3
<212> PRT
<213> Unknown
<400> 238
Phe Phe Ile
1
<210> 239
<211> 3
<212> PRT
<213> Unknown
<400> 239
Phe Phe Leu
1
<210> 240
<211> 3
<212> PRT
<213> Unknown
<400> 240
Phe Phe Lys
1
<210> 241
<211> 3
<212> PRT
<213> Unknown
<400> 241
Phe Phe Met
1
<210> 242
<211> 3
<212> PRT
<213> Unknown
<400> 242
Phe Phe Phe
1
<210> 243
<211> 3
<212> PRT
<213> Unknown
<400> 243
Phe Phe Pro
1
<210> 244
<211> 3
<212> PRT
<213> Unknown
<400> 244
Phe Phe Ser
1
<210> 245
<211> 3
<212> PRT
<213> Unknown
<400> 245
Phe Phe Thr
1
<210> 246
<211> 3
<212> PRT
<213> Unknown
<400> 246
Phe Phe Trp
1
<210> 247
<211> 3
<212> PRT
<213> Unknown
<400> 247
Phe Phe Tyr
1
<210> 248
<211> 3
<212> PRT
<213> Unknown
<400> 248
Phe Phe Val
1
<210> 249
<211> 3
<212> PRT
<213> Unknown
<400> 249
Thr Thr Ala
1
<210> 250
<211> 3
<212> PRT
<213> Unknown
<400> 250
Thr Thr Arg
1
<210> 251
<211> 3
<212> PRT
<213> Unknown
<400> 251
Thr Thr Asn
1
<210> 252
<211> 3
<212> PRT
<213> Unknown
<400> 252
Thr Thr Asp
1
<210> 253
<211> 3
<212> PRT
<213> Unknown
<400> 253
Thr Thr Cys
1
<210> 254
<211> 3
<212> PRT
<213> Unknown
<400> 254
Thr Thr Gln
1
<210> 255
<211> 3
<212> PRT
<213> Unknown
<400> 255
Thr Thr Glu
1
<210> 256
<211> 3
<212> PRT
<213> Unknown
<400> 256
Thr Thr Gly
1
<210> 257
<211> 3
<212> PRT
<213> Unknown
<400> 257
Thr Thr His
1
<210> 258
<211> 3
<212> PRT
<213> Unknown
<400> 258
Thr Thr Ile
1
<210> 259
<211> 3
<212> PRT
<213> Unknown
<400> 259
Thr Thr Leu
1
<210> 260
<211> 3
<212> PRT
<213> Unknown
<400> 260
Thr Thr Lys
1
<210> 261
<211> 3
<212> PRT
<213> Unknown
<400> 261
Thr Thr Met
1
<210> 262
<211> 3
<212> PRT
<213> Unknown
<400> 262
Thr Thr Phe
1
<210> 263
<211> 3
<212> PRT
<213> Unknown
<400> 263
Thr Thr Pro
1
<210> 264
<211> 3
<212> PRT
<213> Unknown
<400> 264
Thr Thr Ser
1
<210> 265
<211> 3
<212> PRT
<213> Unknown
<400> 265
Thr Thr Thr
1
<210> 266
<211> 3
<212> PRT
<213> Unknown
<400> 266
Thr Thr Trp
1
<210> 267
<211> 3
<212> PRT
<213> Unknown
<400> 267
Thr Thr Tyr
1
<210> 268
<211> 3
<212> PRT
<213> Unknown
<400> 268
Thr Thr Val
1
<210> 269
<211> 3
<212> PRT
<213> Unknown
<400> 269
Tyr Thr Ala
1
<210> 270
<211> 3
<212> PRT
<213> Unknown
<400> 270
Tyr Thr Arg
1
<210> 271
<211> 3
<212> PRT
<213> Unknown
<400> 271
Tyr Thr Asn
1
<210> 272
<211> 3
<212> PRT
<213> Unknown
<400> 272
Tyr Thr Asp
1
<210> 273
<211> 3
<212> PRT
<213> Unknown
<400> 273
Tyr Thr Cys
1
<210> 274
<211> 3
<212> PRT
<213> Unknown
<400> 274
Tyr Thr Gln
1
<210> 275
<211> 3
<212> PRT
<213> Unknown
<400> 275
Tyr Thr Glu
1
<210> 276
<211> 3
<212> PRT
<213> Unknown
<400> 276
Tyr Thr Gly
1
<210> 277
<211> 3
<212> PRT
<213> Unknown
<400> 277
Tyr Thr His
1
<210> 278
<211> 3
<212> PRT
<213> Unknown
<400> 278
Tyr Thr Ile
1
<210> 279
<211> 3
<212> PRT
<213> Unknown
<400> 279
Tyr Thr Leu
1
<210> 280
<211> 3
<212> PRT
<213> Unknown
<400> 280
Tyr Thr Lys
1
<210> 281
<211> 3
<212> PRT
<213> Unknown
<400> 281
Tyr Thr Met
1
<210> 282
<211> 3
<212> PRT
<213> Unknown
<400> 282
Tyr Thr Phe
1
<210> 283
<211> 3
<212> PRT
<213> Unknown
<400> 283
Tyr Thr Pro
1
<210> 284
<211> 3
<212> PRT
<213> Unknown
<400> 284
Tyr Thr Ser
1
<210> 285
<211> 3
<212> PRT
<213> Unknown
<400> 285
Tyr Thr Thr
1
<210> 286
<211> 3
<212> PRT
<213> Unknown
<400> 286
Tyr Thr Trp
1
<210> 287
<211> 3
<212> PRT
<213> Unknown
<400> 287
Tyr Thr Tyr
1
<210> 288
<211> 3
<212> PRT
<213> Unknown
<400> 288
Tyr Thr Val
1
<210> 289
<211> 3
<212> PRT
<213> Unknown
<400> 289
Arg Arg Ala
1
<210> 290
<211> 3
<212> PRT
<213> Unknown
<400> 290
Arg Arg Arg
1
<210> 291
<211> 3
<212> PRT
<213> Unknown
<400> 291
Arg Arg Asn
1
<210> 292
<211> 3
<212> PRT
<213> Unknown
<400> 292
Arg Arg Asp
1
<210> 293
<211> 3
<212> PRT
<213> Unknown
<400> 293
Arg Arg Cys
1
<210> 294
<211> 3
<212> PRT
<213> Unknown
<400> 294
Arg Arg Gln
1
<210> 295
<211> 3
<212> PRT
<213> Unknown
<400> 295
Arg Arg Glu
1
<210> 296
<211> 3
<212> PRT
<213> Unknown
<400> 296
Arg Arg Gly
1
<210> 297
<211> 3
<212> PRT
<213> Unknown
<400> 297
Arg Arg His
1
<210> 298
<211> 3
<212> PRT
<213> Unknown
<400> 298
Arg Arg Ile
1
<210> 299
<211> 3
<212> PRT
<213> Unknown
<400> 299
Arg Arg Leu
1
<210> 300
<211> 3
<212> PRT
<213> Unknown
<400> 300
Arg Arg Lys
1
<210> 301
<211> 3
<212> PRT
<213> Unknown
<400> 301
Arg Arg Met
1
<210> 302
<211> 3
<212> PRT
<213> Unknown
<400> 302
Arg Arg Phe
1
<210> 303
<211> 3
<212> PRT
<213> Unknown
<400> 303
Arg Arg Pro
1
<210> 304
<211> 3
<212> PRT
<213> Unknown
<400> 304
Arg Arg Ser
1
<210> 305
<211> 3
<212> PRT
<213> Unknown
<400> 305
Arg Arg Thr
1
<210> 306
<211> 3
<212> PRT
<213> Unknown
<400> 306
Arg Arg Trp
1
<210> 307
<211> 3
<212> PRT
<213> Unknown
<400> 307
Arg Arg Tyr
1
<210> 308
<211> 3
<212> PRT
<213> Unknown
<400> 308
Arg Arg Val
1
<210> 309
<211> 4
<212> PRT
<213> Unknown
<400> 309
Pro Ala Gly Pro
1
<210> 310
<211> 4
<212> PRT
<213> Unknown
<400> 310
Pro Arg Gly Pro
1
<210> 311
<211> 4
<212> PRT
<213> Unknown
<400> 311
Pro Asn Gly Pro
1
<210> 312
<211> 4
<212> PRT
<213> Unknown
<400> 312
Pro Asp Gly Pro
1
<210> 313
<211> 4
<212> PRT
<213> Unknown
<400> 313
Pro Cys Gly Pro
1
<210> 314
<211> 4
<212> PRT
<213> Unknown
<400> 314
Pro Gln Gly Pro
1
<210> 315
<211> 4
<212> PRT
<213> Unknown
<400> 315
Pro Glu Gly Pro
1
<210> 316
<211> 4
<212> PRT
<213> Unknown
<400> 316
Pro Gly Gly Pro
1
<210> 317
<211> 4
<212> PRT
<213> Unknown
<400> 317
Pro His Gly Pro
1
<210> 318
<211> 4
<212> PRT
<213> Unknown
<400> 318
Pro Ile Gly Pro
1
<210> 319
<211> 4
<212> PRT
<213> Unknown
<400> 319
Pro Leu Gly Pro
1
<210> 320
<211> 4
<212> PRT
<213> Unknown
<400> 320
Pro Lys Gly Pro
1
<210> 321
<211> 4
<212> PRT
<213> Unknown
<400> 321
Pro Met Gly Pro
1
<210> 322
<211> 4
<212> PRT
<213> Unknown
<400> 322
Pro Phe Gly Pro
1
<210> 323
<211> 4
<212> PRT
<213> Unknown
<400> 323
Pro Pro Gly Pro
1
<210> 324
<211> 4
<212> PRT
<213> Unknown
<400> 324
Pro Ser Gly Pro
1
<210> 325
<211> 4
<212> PRT
<213> Unknown
<400> 325
Pro Thr Gly Pro
1
<210> 326
<211> 4
<212> PRT
<213> Unknown
<400> 326
Pro Trp Gly Pro
1
<210> 327
<211> 4
<212> PRT
<213> Unknown
<400> 327
Pro Tyr Gly Pro
1
<210> 328
<211> 4
<212> PRT
<213> Unknown
<400> 328
Pro Val Gly Pro
1
<210> 329
<211> 3
<212> PRT
<213> Unknown
<400> 329
Asp Asp Ala
1
<210> 330
<211> 3
<212> PRT
<213> Unknown
<400> 330
Asp Asp Arg
1
<210> 331
<211> 3
<212> PRT
<213> Unknown
<400> 331
Asp Asp Asn
1
<210> 332
<211> 3
<212> PRT
<213> Unknown
<400> 332
Asp Asp Asp
1
<210> 333
<211> 3
<212> PRT
<213> Unknown
<400> 333
Asp Asp Cys
1
<210> 334
<211> 3
<212> PRT
<213> Unknown
<400> 334
Asp Asp Gln
1
<210> 335
<211> 3
<212> PRT
<213> Unknown
<400> 335
Asp Asp Glu
1
<210> 336
<211> 3
<212> PRT
<213> Unknown
<400> 336
Asp Asp Gly
1
<210> 337
<211> 3
<212> PRT
<213> Unknown
<400> 337
Asp Asp His
1
<210> 338
<211> 3
<212> PRT
<213> Unknown
<400> 338
Asp Asp Ile
1
<210> 339
<211> 3
<212> PRT
<213> Unknown
<400> 339
Asp Asp Leu
1
<210> 340
<211> 3
<212> PRT
<213> Unknown
<400> 340
Asp Asp Lys
1
<210> 341
<211> 3
<212> PRT
<213> Unknown
<400> 341
Asp Asp Met
1
<210> 342
<211> 3
<212> PRT
<213> Unknown
<400> 342
Asp Asp Phe
1
<210> 343
<211> 3
<212> PRT
<213> Unknown
<400> 343
Asp Asp Pro
1
<210> 344
<211> 3
<212> PRT
<213> Unknown
<400> 344
Asp Asp Ser
1
<210> 345
<211> 3
<212> PRT
<213> Unknown
<400> 345
Asp Asp Thr
1
<210> 346
<211> 3
<212> PRT
<213> Unknown
<400> 346
Asp Asp Trp
1
<210> 347
<211> 3
<212> PRT
<213> Unknown
<400> 347
Asp Asp Tyr
1
<210> 348
<211> 3
<212> PRT
<213> Unknown
<400> 348
Asp Asp Val
1
<210> 349
<211> 3
<212> PRT
<213> Unknown
<400> 349
Lys Lys Ala
1
<210> 350
<211> 3
<212> PRT
<213> Unknown
<400> 350
Lys Lys Arg
1
<210> 351
<211> 3
<212> PRT
<213> Unknown
<400> 351
Lys Lys Asn
1
<210> 352
<211> 3
<212> PRT
<213> Unknown
<400> 352
Lys Lys Asp
1
<210> 353
<211> 3
<212> PRT
<213> Unknown
<400> 353
Lys Lys Cys
1
<210> 354
<211> 3
<212> PRT
<213> Unknown
<400> 354
Lys Lys Gln
1
<210> 355
<211> 3
<212> PRT
<213> Unknown
<400> 355
Lys Lys Glu
1
<210> 356
<211> 3
<212> PRT
<213> Unknown
<400> 356
Lys Lys Gly
1
<210> 357
<211> 3
<212> PRT
<213> Unknown
<400> 357
Lys Lys His
1
<210> 358
<211> 3
<212> PRT
<213> Unknown
<400> 358
Lys Lys Ile
1
<210> 359
<211> 3
<212> PRT
<213> Unknown
<400> 359
Lys Lys Leu
1
<210> 360
<211> 3
<212> PRT
<213> Unknown
<400> 360
Lys Lys Lys
1
<210> 361
<211> 3
<212> PRT
<213> Unknown
<400> 361
Lys Lys Met
1
<210> 362
<211> 3
<212> PRT
<213> Unknown
<400> 362
Lys Lys Phe
1
<210> 363
<211> 3
<212> PRT
<213> Unknown
<400> 363
Lys Lys Pro
1
<210> 364
<211> 3
<212> PRT
<213> Unknown
<400> 364
Lys Lys Ser
1
<210> 365
<211> 3
<212> PRT
<213> Unknown
<400> 365
Lys Lys Thr
1
<210> 366
<211> 3
<212> PRT
<213> Unknown
<400> 366
Lys Lys Trp
1
<210> 367
<211> 3
<212> PRT
<213> Unknown
<400> 367
Lys Lys Tyr
1
<210> 368
<211> 3
<212> PRT
<213> Unknown
<400> 368
Lys Lys Val
1
<210> 369
<211> 5
<212> PRT
<213> Unknown
<400> 369
Lys Leu Val Phe Phe
1 5
<210> 370
<211> 9
<212> PRT
<213> Unknown
<400> 370
Lys Leu Val Phe Phe Ala Glu Cys Gly
1 5
<210> 371
<211> 2
<212> PRT
<213> Unknown
<400> 371
Phe Phe
1
<210> 372
<211> 8
<212> PRT
<213> Unknown
<400> 372
Phe Lys Phe Glu Phe Lys Phe Glu
1 5
<210> 373
<211> 4
<212> PRT
<213> Unknown
<400> 373
Phe Phe Lys Tyr
1
<210> 374
<211> 5
<212> PRT
<213> Unknown
<400> 374
Gly Phe Phe Tyr Glu
1 5
<210> 375
<211> 6
<212> PRT
<213> Unknown
<400> 375
Ile Leu Gln Ile Asn Ser
1 5
<210> 376
<211> 5
<212> PRT
<213> Unknown
<400> 376
Ile Leu Val Ala Val
1 5
<210> 377
<211> 4
<212> PRT
<213> Unknown
<400> 377
Arg Ala Asp Ala
1
<210> 378
<211> 4
<212> PRT
<213> Unknown
<400> 378
Glu Ala Lys Ala
1
<210> 379
<211> 4
<212> PRT
<213> Unknown
<400> 379
Ala Ala Ala Ala
1
<210> 380
<211> 4
<212> PRT
<213> Unknown
<400> 380
Arg Ala Ala Ala
1
<210> 381
<211> 4
<212> PRT
<213> Unknown
<400> 381
Asn Ala Ala Ala
1
<210> 382
<211> 4
<212> PRT
<213> Unknown
<400> 382
Asp Ala Ala Ala
1
<210> 383
<211> 4
<212> PRT
<213> Unknown
<400> 383
Cys Ala Ala Ala
1
<210> 384
<211> 4
<212> PRT
<213> Unknown
<400> 384
Gln Ala Ala Ala
1
<210> 385
<211> 4
<212> PRT
<213> Unknown
<400> 385
Glu Ala Ala Ala
1
<210> 386
<211> 4
<212> PRT
<213> Unknown
<400> 386
Gly Ala Ala Ala
1
<210> 387
<211> 4
<212> PRT
<213> Unknown
<400> 387
His Ala Ala Ala
1
<210> 388
<211> 4
<212> PRT
<213> Unknown
<400> 388
Ile Ala Ala Ala
1
<210> 389
<211> 4
<212> PRT
<213> Unknown
<400> 389
Leu Ala Ala Ala
1
<210> 390
<211> 4
<212> PRT
<213> Unknown
<400> 390
Lys Ala Ala Ala
1
<210> 391
<211> 4
<212> PRT
<213> Unknown
<400> 391
Met Ala Ala Ala
1
<210> 392
<211> 4
<212> PRT
<213> Unknown
<400> 392
Phe Ala Ala Ala
1
<210> 393
<211> 4
<212> PRT
<213> Unknown
<400> 393
Pro Ala Ala Ala
1
<210> 394
<211> 4
<212> PRT
<213> Unknown
<400> 394
Ser Ala Ala Ala
1
<210> 395
<211> 4
<212> PRT
<213> Unknown
<400> 395
Thr Ala Ala Ala
1
<210> 396
<211> 4
<212> PRT
<213> Unknown
<400> 396
Trp Ala Ala Ala
1
<210> 397
<211> 4
<212> PRT
<213> Unknown
<400> 397
Tyr Ala Ala Ala
1
<210> 398
<211> 4
<212> PRT
<213> Unknown
<400> 398
Val Ala Ala Ala
1
<210> 399
<211> 5
<212> PRT
<213> Unknown
<400> 399
Tyr Pro Gly Asp Val
1 5
<210> 400
<211> 7
<212> PRT
<213> Unknown
<400> 400
Trp Tyr Phe Arg Arg Gly Lys
1 5
<210> 401
<211> 6
<212> PRT
<213> Unknown
<400> 401
Val Glu Ala Leu Tyr Leu
1 5
<210> 402
<211> 3
<212> PRT
<213> Unknown
<400> 402
Val Ile Ala
1
<210> 403
<211> 6
<212> PRT
<213> Unknown
<400> 403
Gly Gly Ala Ala Val Val
1 5
Claims (11)
1. The active targeting response type self-assembled imaging probe is characterized by comprising an active targeting peptide segment, a response type segment, a self-assembled segment and an imaging probe group which are sequentially connected.
2. The active targeting responsive self-assembled imaging probe of claim 1, wherein the active targeting peptide fragment is selected from the group consisting of: [ Arg ] 6 ,Pro 34 ]pNPY、[Phe 6 ,Pro 34 ]pNPY、[Asn 6 ,Pro 34 ]pNPY、[Cys 6 ,Pro 34 ]pNPY、[D-His 26 ,Pro 34 ]NPY、[Phe 7 ,Pro 34 ]pNPY、[Pro 30 ,Nal 32 ,Leu 34 ]NPY(28-36)、[Pro 30 ,Nle 31 ,Nal 32 ,Leu 34 ]NPY(28-36)、NPY(28-36)、[Pro 30 ,Tyr 32 ,Pro 34 ]NPY(25-36)、[Pro 30 ,Tyr 32 ]NPY(25-36)、[Pro 30 ,Trp 32 ]NPY(25-36)、[Asn 28 ,Pro 30 ,Trp 32 ]NPY(25-36)、[Tyr 32 ,Pro 34 ]NPY(25-36)、[Pro 30 ,Tyr 31 ,Trp 32 ]NPY(25-36)、[Pro 30 ,Nle 31 ,Bpa 32 ,Leu 34 ]At least one of NPY (28-36) and NPY (25-36).
3. The active targeted responsive self-assembled imaging probe of claim 1 or 2, wherein the amino acid sequence of the responsive fragment comprises at least one of SEQ ID nos. 1-368.
4. The active targeting responsive self-assembled imaging probe of claim 3, wherein the responsive enzyme and molecule corresponding to the responsive fragment is selected from the group consisting of: at least one of cathepsin B, cathepsin E, cathepsin L, cathepsin C, cathepsin D, cathepsin K, carboxypeptidase, papain, chymotrypsin, kallikrein, collagenase, endopeptidase.
5. The active targeting responsive self-assembled imaging probe of claim 1 or 2, wherein the self-assembled fragment amino acid sequence comprises at least one of SEQ ID nos. 369-403.
6. The active targeting responsive self-assembled imaging probe according to any one of claims 1 to 5, wherein the active targeting responsive self-assembled imaging probe is formed into a nanostructure by an enzyme response in a cell lysosome after reaching a tumor cell;
preferably, the nanostructure is at least one of a nanoparticle, a polyhedral structure, a nanowire, a nanorod, a nanofiber, a nanotube, a nanodisk, a nanosheet, a two-dimensional nanodendrite, a porous structure, a nanobranch, a nano-frame, a nanoflower, and an aerogel.
7. The active targeting responsive self-assembled imaging probe according to claim 1 or 2, wherein the probe is selected from at least one of a fluorescent probe, a CT probe, a nuclear species probe, a magnetic resonance imaging probe;
preferably, the fluorescent probe is at least one selected from the group consisting of Cy3, cy5, cy3.5, cy5.5, cy7, cy7.5, ICG, IR-780, IR-783, IR775, IR-792, IR-808, IR-820, IR-825, IR-1048, IR-1064 and derivatives thereof;
preferably, the CT probe is selected from at least one of iopamidol, iohexol, iopamidol, iopromide, ioversol, lopyr, iodixanol, and iomeprol;
preferably, the nuclide probe is selected from 18 F、 99m Tc、 131 I、 133 Xe、 32 P、 3 H、 109 Cd、 111 Zn、 141 Ce、 153 Sm、 198 At least one of Au;
preferably, the magnetic resonance imaging probe is selected from at least one of gadodiamide, gadodiamide disodium, gadofoshan, gadodiamide and cadinamine sodium, gadofoshan, gadoteridol, and ferroferric oxide.
8. A method of preparing an actively targeted responsive self-assembled imaging probe according to any one of claims 1 to 7, comprising at least the steps of:
s1, sequentially coupling an active targeting peptide segment, a response type fragment and a self-assembly fragment on resin 0 through a polypeptide automatic synthesizer to obtain resin 1;
s2, adding an imaging group into the resin 1 for reaction to obtain resin 2;
s3, cutting the resin 2 to remove the protection of the amino acid side chain, and purifying to obtain the active targeting response type self-assembled polypeptide drug.
S4, cutting the obtained resin to remove the protection of the amino acid side chain, and purifying to obtain the active targeting response type self-assembled imaging probe.
9. The use of an active targeted responsive self-assembled imaging probe according to any one of claims 1 to 8 in the preparation of an anti-tumor drug;
preferably, the use in the preparation of a medicament for breast cancer, brain cancer, kidney cancer, endometrial cancer, ovarian cancer and ewing's sarcoma.
10. An imaging agent comprising the actively targeted responsive self-assembled imaging probe of any one of claims 1 to 8.
11. Use of an imaging agent according to claim 10 for the preparation of a medicament for diagnosing a neoplastic disease;
preferably, the use in the preparation of a medicament for diagnosing breast cancer, brain cancer, kidney cancer, endometrial cancer, ovarian cancer and ewing's sarcoma.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210149574.XA CN116650672A (en) | 2022-02-18 | 2022-02-18 | Active targeting response type self-assembled imaging probe and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210149574.XA CN116650672A (en) | 2022-02-18 | 2022-02-18 | Active targeting response type self-assembled imaging probe and preparation method and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN116650672A true CN116650672A (en) | 2023-08-29 |
Family
ID=87717618
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210149574.XA Pending CN116650672A (en) | 2022-02-18 | 2022-02-18 | Active targeting response type self-assembled imaging probe and preparation method and application thereof |
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