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Whole process targeting polypeptide and application in constructing tumor targeted diagnosis delivery system

A technology for targeting peptides and drug delivery systems, applied in the field of pharmacy, can solve the problems of ineffective drug treatment and no tumor stem cell targeting function.

Pending Publication Date: 2019-02-26
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

According to the data, most of the current ligands only target a certain receptor or a certain cell. However, there are tumor cells in tumor tissues, as well as tumor stem cells, tumor mimic blood vessels, tumor neovascularization and blood-tumor barrier (BTB) etc. There is also a blood-brain barrier (BBB) ​​in brain tumors, which prevents about 98% of small-molecule chemotherapy drugs and almost 100% of proteins and other macromolecular drugs from entering the brain through the BBB, resulting in almost ineffective drug treatment. Therefore, the development of Ligands that can target the whole process of tumor growth and development, especially brain tumors, have important practical significance
[0003] VAP( L VAP1 (L-type amino acid sequence is SNTRVAP) and its stable optimized polypeptide D VAP (D-type amino acid sequence D P D A D V D R D T D N D S), L VAP2 (L-type amino acid sequence is PAVRTNS) and its stable optimized polypeptide S VAP (D-type amino acid sequence D S D N D T D R D V D A D P)) is a 7-peptide that has a high binding activity to the glucose-regulating protein GRP78 verified in the early stage of this application. It can target tumor neovascularization endothelial cells and span BTB, target tumor cells and tumor stem cells, and has good targeting in vivo. target capability, but not across the BBB
[0004] WSW( L WSW (L-type amino acid sequence is SYPGWSW) and its stable optimized polypeptide D WSW (D-type amino acid sequence D W D S D W D G D P D Y D S)) is also a 7-peptide with high binding activity to quorum sensing receptors verified in the early stage of this application, which can target brain capillary endothelial cells and penetrate BBB, target tumor neovascular endothelial cells and penetrate BTB, and target To tumor cells, but no tumor stem cell targeting function

Method used

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  • Whole process targeting polypeptide and application in constructing tumor targeted diagnosis delivery system
  • Whole process targeting polypeptide and application in constructing tumor targeted diagnosis delivery system
  • Whole process targeting polypeptide and application in constructing tumor targeted diagnosis delivery system

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0087] D WVAP1-Cys, D WVAP1-Fluorescein, D WVAP1-Cy7, D WVAP1-drug, D Synthesis and Characterization of WVAP1-PEG-PLA

[0088] 1) D Synthesis and Characterization of WVAP1-Cys

[0089] Using solid-phase peptide synthesis method, synthesized D WVAP1-Cys (sequence is D S D N D T D R D V D A D P D C-Aminocaproic acid- D W D S D W D G D P D Y D S), the specific method: insert amino acids in sequence on the Boc-Cys PAM resin, react with HBTU / DIEA as the condensing agent and TFA as the deprotecting agent. After the reaction was completed, the resin was cut with hydrogen fluoride containing P-cresol, and stirred in an ice bath for 1 h. After the reaction, the hydrogen fluoride in the tube was removed under reduced pressure, the precipitate was precipitated with glacial ether and washed 3 times, the precipitate was redissolved with 20% acetonitrile, and the filtrate was collected and then rotary evaporated to obtain a crude polypeptide solution. The crude polypep...

Embodiment 2

[0101] Example 2 D Binding activity experiment of WVAP1 and glucose regulatory protein GRP78

[0102] Pre-binding analysis was carried out by the biacore system, and pH 5.0 was selected as the optimal pH for the combination of GRP78 and CM5 chips. The recombinant human GRP78 was coupled to the CM5 chip, and the RU value reached the target value. D WVAP1 is configured into sample solutions of different concentrations, injected sequentially from low to high, and analyzed by Biacore T200Evaluation software D The binding activity between WVAP1 and protein, and their K were calculated respectively D value, and with D VAP and D WSW comparison (eg Figure 5 shown).

Embodiment 3

[0103] Example 3 D Serum stability test of WVAP1

[0104] Will D Prepare 1 mg / mL aqueous solution of WVAP1, take 0.1 mL and add it to 0.9 mL of 25% mouse serum, incubate at 37°C, take out 100 μL of reaction solution at 0 and 15 min, 0.5, 1, 2 and 4 h, and add 20 μL of trichloroacetic acid ( TCA) to precipitate proteins in serum, let stand at 4°C for 20min, centrifuge at 12000rpm for 10min, take 20μL of supernatant for HPLC analysis, serum stability results (such as Image 6 shown) shows that, D WVAP1 has good serum stability.

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Abstract

The invention belongs to the field of pharmacy, and particularly relates to whole process targeting polypeptide molecule targeting a brain capillary vessel endothelial cell, a tumor neovascular endothelial cell, a tumor mimic blood vessel, a tumor cell and a tumor stem cell, and a stable optimized polypeptide molecule thereof, and an application of modified compound and a drug delivery system in the diagnosis and treatment of tumors. The invention relates to the application of the whole process targeting polypeptide WVAP and a WVAP modified drug and a polymer carrier material, and the application thereof in the construction of tumor imaging and a targeted therapy delivery system, the results show that WVAP can cross a blood-brain barrier, can target tumor neovascularization and cross blood-tumor barrier, and target tumor mimicry blood vessels, the tumor cells and the cancer stem cells; the nano drug delivery system constructed by the WVAP modified polymer carrier material can effectively deliver the encapsulated drug into the brain, targets the tumor tissue, and significantly improves the antitumor efficacy.

Description

technical field [0001] The invention belongs to the field of pharmacy, relates to whole-process targeting polypeptides and uses thereof, in particular to whole-process target polypeptides that can cross the blood-brain barrier and cross the blood-tumor barrier, and target tumor new blood vessels, tumor mimic blood vessels, tumor cells and tumor stem cells. To polypeptide molecules, their drug complexes and modified nano drug delivery systems. Background technique [0002] The prior art discloses that the mortality rate of tumor ranks first among all diseases, and it is a disease that seriously threatens human life and health. In clinical treatment, traditional chemotherapy, as the main means of tumor drug treatment, has defects such as poor selectivity to tumor tissue, high toxicity, narrow therapeutic window, and multi-drug resistance. Therefore, in order to overcome the limitations of traditional treatment methods, active targeting has become an important strategy to impr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K19/00A61K31/704A61K31/337A61K38/05A61K31/365A61K31/37A61P35/00
CPCA61K31/337A61K31/365A61K31/37A61K31/704A61K38/05C07K7/06C07K2319/00
Inventor 陆伟跃冉丹妮谢操占昌友毛佳妮
Owner FUDAN UNIV
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