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Integrin-targetable polypeptide mn and application thereof in preparing tumor targeting drugs

An integrin and targeting technology, applied in the field of pharmacy, can solve problems such as insufficient stability, and achieve the effects of overcoming insufficient stability, improving binding activity, and improving tumor targeting and diagnosis and treatment in vivo

Pending Publication Date: 2020-06-05
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The invention provides a novel polypeptide targeting integrins highly expressed in various tumors, and is used for the diagnosis and treatment of tumor targeted drug delivery. The binding activity of protein integrin can improve the immunogenicity of the existing ligand polypeptide c(RGDyK), RW, etc. used to modify the carrier system, and achieve better tumor targeting and diagnosis and treatment effects in vivo

Method used

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  • Integrin-targetable polypeptide mn and application thereof in preparing tumor targeting drugs
  • Integrin-targetable polypeptide mn and application thereof in preparing tumor targeting drugs
  • Integrin-targetable polypeptide mn and application thereof in preparing tumor targeting drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0100] Synthesis and Characterization of Peptide, Peptide-Cys, Peptide-Fluorescein, Peptide-Drug Complex, Peptide-PEG-DSPE

[0101] Synthesis and Characterization of Peptides and Peptide-Cys:

[0102]The solid-phase peptide synthesis method was used to design and synthesize the mn polypeptide (amino acid sequence mnRwr; uppercase letters indicate amino acids in L configuration, lowercase letters indicate amino acids in D configuration) and synthesize RW polypeptides (amino acid sequence RWrNM; uppercase letters indicate amino acids in L configuration, Lowercase letters indicate D-configuration amino acids).

[0103] Specific method: use Boc solid-phase peptide synthesis method, insert amino acids in sequence on PAM-Boc resin, and react with HBTU / DIEA as condensation agent and TFA as deprotection 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 i...

Embodiment 2

[0114] Study on Serum Stability of Peptides

[0115] Make c(RGDyK), RW and mn into 1mg / mL aqueous solution, take 0.1mL and add it to 0.9mL 25% mouse serum, incubate at 37°C, at 0 and 15min, 0.5, 1, 2, 4, 8 and After 12 hours, 100 μL of the reaction solution was taken out, 20 μL of trichloroacetic acid (TCA) was added to precipitate proteins in the serum, left at 4°C for 20 min, centrifuged at 12,000 rpm for 10 min, and 20 μL of the supernatant was taken for HPLC analysis (eg Image 6 shown).

Embodiment 3

[0117] Polypeptide and Integrin α v beta 3 binding activity assay

[0118] The recombinant human GRP78 was coupled to the CM5 chip, and the RU value reached the target value. Configure c(RGDyK), RW and mn respectively as a gradient sample solution. Samples were injected sequentially from low to high, and the binding activities of c(RGDyK), RW and mn to proteins were analyzed with Biacore T200Evaluation software, and their K were calculated respectively D value (such as Figure 7 shown).

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Abstract

The present invention belongs to the field of pharmacy and relates to a highly stable multifunctional short peptide mn having high affinity with integrin and multi-functions of targeting tumor neovascularization, tumor mimic blood vessels and tumor cells, a polypeptide-modified complex, a drug delivery system and uses of the short peptide mn in preparation of drugs for tumor diagnosis and treatment. Experiment results show that mn-modified drugs are specifically taken up by integrin-expressing positive cells and tumor tissue, and have good tumor targeting and imaging functions; and a drug delivery system constructed by an mn-modified polymer carrier material effectively delivers entrapped drugs to target tissue and significantly improves the tumor diagnosis and treatment. Comparing the prepared drugs with widely used integrin ligand c (RGDyK), the mn has better stability in serum and stronger binding ability with the integrin, immunogenicity of a modified carrier system is significantly lower than a carrier system modified by the c (RGDyK), etc., mn-mediated in-vivo active targeting drug delivery effects are more effective and the mn has good application prospects in the tumor diagnosis and targeted therapy.

Description

technical field [0001] The invention belongs to the field of pharmacy, and relates to a polypeptide mn capable of targeting integrin, in particular to a highly stable multifunctional polypeptide mn and its derivatives which have high affinity with integrin and can target tumor neovascularization, tumor mimic blood vessels and tumor cells. Drug complexes of mn polypeptides and drug delivery systems modified by mn polypeptides, especially related to mn (amino acid sequence mnRwr; uppercase letters indicate amino acids in L configuration, lowercase letters indicate amino acids in D configuration) and its derivatives, diagnostic drugs and therapeutic drugs complexes, their modified polymer carrier materials and their drug delivery systems such as liposomes, micelles, discs, nanoparticles and biofilm-coated nanoparticles, as well as in the preparation of tumor diagnosis and targeted therapy drugs in the application. Background technique [0002] The prior art discloses that tumo...

Claims

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Application Information

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IPC IPC(8): C07K7/06A61K47/42A61K9/127
CPCC07K7/06C07K19/00A61K47/42A61K9/127
Inventor 陆伟跃李锦阳谢操
Owner FUDAN UNIV
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