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A kind of anti-tumor polypeptide with double effect and its application

A dual-efficiency, anti-tumor technology, applied in the field of biomedicine, can solve the problems of poor prognosis of patients, achieve the effect of short research and development cycle, strong selectivity, and broad market development prospects

Active Publication Date: 2021-09-07
HARBIN MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Clinical studies have found that a variety of digestive system tumors, including pancreatic cancer, gastric cancer, liver cancer, and cholangiocarcinoma, highly express NRP-1, and its expression level is positively correlated with clinicopathological features. Patients with high expression of NRP-1 have a poor prognosis

Method used

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  • A kind of anti-tumor polypeptide with double effect and its application
  • A kind of anti-tumor polypeptide with double effect and its application
  • A kind of anti-tumor polypeptide with double effect and its application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] The preparation of embodiment 1TMD6-D polypeptide

[0066] Proceed as follows:

[0067] 1. Resin swelling: Weigh 0.6g of CTC resin with a substitution degree of 1.0mmol / g, place it in a reaction tube, add DCM (15ml / g), and shake for 30min.

[0068] 2. Deprotection: Remove DCM, add 20% piperidine DMF solution (15ml / g), shake for 5min, remove piperidine solution, add fresh 20% piperidine DMF solution (15ml / g), shake for 15min.

[0069] 3. Detection: Take out the piperidine solution, take a small amount of resin (about 20 resins), wash it three times with ethanol, add one drop of ninhydrin, KCN, and phenol solution, heat (105-110°C) for 5 minutes, and it turns blue .

[0070] Four. Washing for the first time: wash twice with DMF solution (10ml / g), then wash twice with methanol (10ml / g), and finally wash twice with DMF solution (10ml / g).

[0071] 5. Condensation: Three-fold excess of protected amino acids and three-fold excess of HBTU were dissolved with as little DMF as...

Embodiment 2

[0079] Example 2 Detection of Permeability of Vascular Endothelial Cells in Vitro

[0080] Human umbilical vein endothelial cells (HUVECs) or siRNA-transfected HUVECs (1×10 5 ) were inoculated in 12-well transwell chambers (0.4 micron pore size), and cultured in DMEM (Dulbecco's modified Eagle's medium) medium containing 10% fetal bovine serum (FBS). at 37°C and 5% CO 2 After 48-96 hours of incubation under conditions, when HUVECs formed a mature monolayer of cells and covered the bottom membrane of the upper chamber, the culture solution was aspirated, and serum-free DMEM culture solution was added, and VEGF recombinant protein (50ng / ml) was added, Or eight kinds of polypeptides (the concentration is 25nM), or different concentrations of TMD6-D polypeptides. After incubation for 30 minutes, 50 mg of fluorescein isothiocyanate (FITC)-conjugated dextran (molecular weight 40 kDa, 1 mg / mL) was added to the upper chamber. After continuing to incubate for 30 minutes, the lower c...

Embodiment 3

[0085] Example 3 Detection of tumor tissue permeability in vivo

[0086] Female BALB / c nude mice (6-8 weeks old) received subcutaneous injection of human pancreatic cancer BxPC-3 cells (2×10 6 ), to establish subcutaneous pancreatic cancer tumors. Three weeks later, when the tumor had grown to a diameter of about 1 cm, the animals were divided into three groups (3 nude mice in each group). Control group: inject 1 mg of Evans Blue (Evans Blue) (dissolved in 200 μl of PBS) through the tail vein; positive control group: inject a mixture of 1 mg of Evans Blue and VEGF recombinant protein (400 ng) through the tail vein (dissolved in 200 μl of PBS); TMD6-D group: a mixture of 1 mg of Evans blue and TMD6-D polypeptide (500 μg) was injected via the tail vein (dissolved in 200 μl of PBS). Thirty minutes later, anesthesia was induced by intraperitoneal injection of a mixture of ketamine and xylazine, and circulatory lavage with 1% BSA (bovine serum albumin, bovineserum albumin) (disso...

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Abstract

The invention discloses an anti-tumor polypeptide with dual functions and its application. The anti-tumor polypeptide with dual functions has the amino acid sequence shown in SEQ ID NO.4. The polypeptide of the present invention can specifically target NRP-1 molecules expressed on endothelial cells and tumor cells, improve the permeability of vascular endothelial cells and increase the permeability of tumor tissue, thereby improving the penetration of drugs through vascular barrier and tumor tissue Ability. At the same time, it can also inhibit the proliferation of cancer cells and promote the apoptosis of cancer cells by blocking the downstream cell signaling pathways regulated by NRP-1. The polypeptide of the present invention can be used for the treatment of various solid tumors including pancreatic cancer, and can improve the effect of drugs, especially monoclonal antibody-targeted drugs, in treating malignant tumors.

Description

technical field [0001] The present invention relates to an anti-tumor polypeptide with dual functions and its application in the preparation of anti-tumor drugs, in particular to a polypeptide that targets solid tumor cell membranes and highly expresses NRP-1. The ability to penetrate into tumor tissue, thereby improving the anti-tumor efficacy of monoclonal antibody-targeted drugs; at the same time, it also has the activity of directly inhibiting tumor growth. The invention belongs to the technical field of biomedicine. Background technique [0002] Therapeutic monoclonal antibodies have become a hotspot in the development of new drugs worldwide. Since the first monoclonal antibody drug was launched in 1986 and the first anti-tumor monoclonal antibody drug was launched for the treatment of non-Hodgkin's lymphoma in 1997, nearly a hundred therapeutic monoclonal antibody drugs have been approved for marketing. For the treatment of tumors, autoimmune diseases and inflammator...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K7/08C12N15/11A61K38/10A61K47/42A61P35/00
CPCA61K38/00A61K47/42A61P35/00C07K7/08
Inventor 孙学英李伟东李子一姜宪乔海泉
Owner HARBIN MEDICAL UNIVERSITY
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