VAP POLYPEPTIDE AND USE THEREOF IN PREPARATION OF DRUG FOR TARGETED DIAGNOSIS AND TREATMENT OF TUMOR

• US 20190314446A1
• Filed: 12/06/2017
• Published: 10/17/2019
• Est. Priority Date: 12/07/2016
• Status: Active Grant

• Current Assignee: Fudan University
• Original Assignee: Fudan University
• Inventors: Lu, Weiyue, Ran, Danni, Mao, Jiani, Xie, Cao
• Granted Patent: US 11,622,990 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 31/337 having four-membered rings, e.g. taxol
• CPC Class Codes: A61K 31/42 Oxazoles
• CPC Class Codes: A61K 31/64 Sulfonylureas, e.g. glibenclamide, tolbutamide, chlorpropamide
• CPC Class Codes: A61K 31/704 attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin digitoxin A61K31/7048
• CPC Class Codes: A61K 38/05 Dipeptides
• CPC Class Codes: A61K 38/08 Peptides having 5 to 11 amino acids A61K38/043 - A61K38/046 take precedence
• CPC Class Codes: A61K 39/0011 Cancer antigens
• CPC Class Codes: A61K 47/34 Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers A61K47/10 takes precedence
• CPC Class Codes: A61K 47/62 the modifying agent being a protein, peptide or polyamino acid
• CPC Class Codes: A61K 47/64 Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent peptidic linkers A61K47/65
• CPC Class Codes: A61K 47/6907 the form being a microemulsion, nanoemulsion or micelle
• CPC Class Codes: A61K 49/0032 Methine dyes, e.g. cyanine dyes
• CPC Class Codes: A61K 49/0043 Fluorescein, used in vivo
• CPC Class Codes: A61K 49/0056 Peptides, proteins, polyamino acids
• CPC Class Codes: A61K 49/14 Peptides, e.g. proteins
• CPC Class Codes: A61K 9/107 Emulsions ; Emulsion preconcentrates; Micelles composition of emulsions A61K47/00
• CPC Class Codes: A61K 9/1075 Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers A61K9/0026 takes precedence
• CPC Class Codes: A61K 9/127 Liposomes
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07K 7/06 having 5 to 11 amino acids

Abstract

Provided in the present invention are highly stable D-configuration polypeptides DVAP and SVAP having a high binding activity to the GRP78 protein, and also provided are an L-configuration polypeptide LVAP and a DVAP-or SVAP-modified model drug and a macromolecule carrier material, and the use thereof in the construction of a tumour image and a drug-delivery system for targeted treatment.

Claims

1. A D-configuration peptide, characterized in that, the D-configuration peptide is ^DVAP, or ^SVAP, and the amino acid sequence of the ^DVAP is ^DP^DA^DV^DR^DT^DN^DS, and the amino acid sequence of the ^SVAP is ^DS^DN^DT^DR^DV^DA^BP.

2. A peptide complex of ^DVAP, ^SVAP, or both, wherein the ^DVAP and/or ^SVAP peptide complex is maleimide-group-contained imaging substance modified by the ^DVAP and/or ^SVAP of claim 1, wherein the structure of the ^DVAP and/or ^SVAP peptide complex is ^DVAP-X and/or ^SVAP-X, X is the image substance;

wherein the X is one or more selected from of the group consisting of a fluorescent substance, a near-infrared dye, a magnetic resonance imaging agent, and a radiographic agent.

4. A peptide complex of ^DVAP, ^SVAP, or both, wherein the ^DVAP and/or ^SVAP peptide complex is antitumor drug modified by the ^DVAP and/or ^SVAP peptide of claim 1, wherein the structure of the ^DVAP and/or ^SVAP peptide complex is ^DVAP-Y and/or ^SVAP-Y, Y is the antitumor drug;

wherein the antitumor drug is one or more selected from of the group consisting of anthracyclines, doxorubicin or epirubicin, taxanes, such as taxol, docetaxel, cabazitaxel, camptothecins, camptothecin, hydroxycamptothecin, irinotecan, vinblastines, vincristine, vinorelbine, proteasome inhibitors, bortezomib, carfilzomib, lactones, parthenolide, peptide drugs, p53 activating peptide, melittin, scorpion venom peptide and antimicrobial peptides.

6. A peptide complex of ^DVAP, ^SVAP, or both, wherein, the ^DVAP and/or ^SVAP peptide complex is polymer carrier material modified by the ^DVAP and/or ^SVAP of claim 1, wherein the structure of the ^DVAP and/or ^SVAP peptide complex is ^DVAP-polyethylene glycol-Z and/or ^SVAP-polyethylene glycol-Z, Z is the polymer carrier material;

wherein the polymer carrier material is one or more selected from of the group consisting of phospholipids, polylactic acid, poly lactic-co-glycolic acid, and polycaprolactones.

8. A drug delivery system, characterized in that, the drug delivery system comprises:

D-configuration peptide according to claim 1; and

/or

^DVAP, ^SVAP and/or ^LVAP peptide complex,

wherein the drug delivery system is a liposome delivery system, a polymer micelle delivery system, a polymer disc delivery system or a nanoparticle delivery system.

9. The drug delivery system according to claim 8, characterized in that, besides the ^DVAP, ^SVAP and/or ^LVAP peptide complex, the drug delivery system further comprises (1) a diagnostic drug (2) an antitumor drug, or both;

wherein the (1) diagnostic drug is one or more selected from of the group consisting of fluorescent substance, near-infrared dye and magnetic resonance imaging agent, and/or

the (2) anti-tumor drug is one or more selected from of the group consisting of anthracyclines, such as doxorubicin or epirubicin, taxanes, such as taxol, docetaxel cabazitaxel, camptothecins, camptothecin, hydroxycamptothecin, irinotecan, vinblastines, vincristine and vinorelbine, proteasome inhibitors, bortezomib, carfilzomib, lactones, parthenolide, peptide drugs, p53 activating peptide, melittin, peptide drugs, scorpion venom peptide and antimicrobial peptides.

10. A drug or medical product for the diagnosing, tracing and/or treating a tumor with at least one of:

D-configuration peptide according to claim 1; and

/or

^DVAP, and/or ^SVAP peptide complex.

11. A method for tumor diagnosis and/or targeted therapy comprising administering to a subject in need thereof:

D-configuration peptide according to claim 1; and

/or

^DVAP, ^SVAP and/or ^LVAP peptide complex.

12. The drug delivery system according to claim 8, wherein the ^DVAP, ^SVAP and/or ^LVAP peptide complex is the peptide complex of ^DVAP and/or ^SVAP of claim 6, and the drug delivery system is a liposome delivery system, a polymer micelle delivery system, a polymer disc delivery system, or a nanoparticle delivery system.

14. The peptide complex of ^DVAP and/or ^SVAP according to claim 2, wherein the fluorescent substance is Fluorescein, the near-infrared dye is Cy7, IR820, DiR, the magnetic resonance imaging agent is Gd-DTPA, and the radiographic agent is ^99mTc-DTPA.

16. The peptide complex of ^DVAP and/or ^SVAP according to claim 4, wherein the antitumor drug is one or more selected from of the group consisting of doxorubicin or epirubicin, which containing ketone or aldehyde group;

paclitaxel, docetaxel, camptothecin, hydroxycamptothecin, 9-nitro camptothecin, vincristine, etoposide, gemcitabine, cytarabine, 5-fluorouracil, teniposide, moritinib, epothilone, vinorelbine, actinomycin D, mitoxantrone Anthraquinone, mitomycin, bleomycin, irinotecan, which containing hydroxyl or amino group;

bortezomib or carfilzomib, which containing boric acid;

peptide drugs of p53 activating peptide, melittin and scorpion venom peptide.

18. The drug delivery system according to claim 8, wherein drug delivery system is used for the diagnosing, tracing, and/or treating a tumor

19. The drug delivery system according to claim 9, wherein the fluorescent substance is Fluorescein, the near-infrared dye is selected from Cy7, IR820, DiR, and/or the magnetic resonance imaging agent is Gd-DTPA.

20. The drug or medical product according to claim 10, wherein the tumor is glucose-regulating protein GRP78 high expressed tumor.

3. A peptide complex of L-configuration peptide ^LVAP, characterized in that, the ^LVAP peptide complex is maleimide-group-contained imaging substance modified by the ^LVAP, wherein the amino acid sequence of the ^LVAP peptide is SNTRVAP, and the structure of the ^LVAP peptide complex is ^LVAP-X, X is the image substance;

wherein the X is one or more selected from of the group consisting of a fluorescent substance, a near-infrared dye, a magnetic resonance imaging agent, and a radiographic agent.

15. The peptide complex of L-configuration peptide ^LVAP according to claim 3, wherein the fluorescent substance is Fluorescein, the near-infrared dye is Cy7, IR820, DiR, the magnetic resonance imaging agent is Gd-DTPA, and the radiographic agent is ^99mTc-DTPA.

5. A peptide complex of L-configuration polypeptide ^LVAP, characterized in that, the ^LVAP peptide complex is antitumor drug modified by the ^LVAP, wherein the amino acid sequence of the ^LVAP peptide is SNTRVAP, and the structure of the ^LVAP peptide complex is ^LVAP-Y, Y is the antitumor drug;

wherein the antitumor drug is one or more selected from of the group consisting of anthracyclines, doxorubicin or epirubicin, taxanes such as taxol, docetaxel, cabazitaxel, camptothecins, camptothecin, hydroxycamptothecin, irinotecan, vinblastines, vincristine, vinorelbine, proteasome inhibitors, bortezomib, carfilzomib, lactones, parthenolide, peptide drugs, p53 activating peptide and melittin, scorpion venom peptide and antimicrobial peptides.

17. The peptide complex of L-configuration peptide ^LVAP according to claim 5, wherein the antitumor drug is one or more selected from of the group consisting of doxorubicin or epirubicin containing ketone or aldehyde group;

paclitaxel, docetaxel, camptothecin, hydroxycamptothecin, 9-nitro camptothecin, vincristine, etoposide, gemcitabine, cytarabine, 5-fluorouracil, teniposide, moritinib, epothilone, vinorelbine, actinomycin D, mitoxantrone Anthraquinone, mitomycin, bleomycin, irinotecan, which containing hydroxyl or amino;

boric acid-containing bortezomib or carfilzomib;

peptide drugs of p53 activating peptide, melittin and scorpion venom peptide.

7. An L-configuration ^LVAP peptide complex, characterized in that, the ^LVAP peptide complex is polymer carrier material modified by the ^LVAP, wherein the amino acid sequence of ^LVAP peptide is SNTRVAP, and the structure of the ^LVAP peptide complex is ^LVAP-polyethylene glycol-Z, Z is the polymer carrier material;

wherein the polymer carrier material is one or more selected from of the group consisting of phospholipids, polylactic acid, poly lactic-co-glycolic acid, and polycaprolactones.

13. The drug delivery system according to claim 8, wherein the ^DVAP, ^SVAP and/or ^LVAP peptide complex is the peptide complex of ^LVAP of claim 7, and the drug delivery system is a liposome delivery system, a polymer micelle delivery system, a polymer disc delivery system, or a nanoparticle delivery system.