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Preparation and application of cathepsin B activation type targeted anti-tumor polypeptide

A cathepsin and anti-tumor technology, which is applied in the preparation and application of polypeptide m-iRGD, can solve the problems of unseen enzyme-activated targeted anti-tumor polypeptides, achieve good application and promotion value, and the preparation method is convenient and easy. Inhibition of growth and metastasis

Inactive Publication Date: 2016-12-14
SUN YAT SEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] So far, there have been no reports on the synthesis of enzyme-activated targeting anti-tumor polypeptides carrying selective hydrolysis in tumor cells using chain iRGD peptide-guided technology and peptide modification technology

Method used

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  • Preparation and application of cathepsin B activation type targeted anti-tumor polypeptide
  • Preparation and application of cathepsin B activation type targeted anti-tumor polypeptide
  • Preparation and application of cathepsin B activation type targeted anti-tumor polypeptide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment example 1

[0032] Example 1: Synthesis and purification of m(KLA)-iRGD and reference peptides

[0033] 1. Put 2-Chlorotrityl Chloride Resin resin into the reaction tube, add DCM (15ml / g), shake for 30min;

[0034] 2. Filter out the solvent through the sand core, add 3 times molar excess of Fmoc-L-Cys(Trt)-OH, then add 10 times molar excess of DIEA, and finally add DMF to dissolve, shake for 30 minutes, cap with methanol for 30 minutes;

[0035] 3. Remove the solvent, add 20% piperidine / DMF solution (15ml / g) for 5min, remove and add 20% piperidine / DMF solution (15ml / g) for 15min;

[0036] 4. Take out the piperidine solution, take more than a dozen resins, wash them three times with ethanol, add ninhydrin, KCN, and phenol solution one drop each, heat at 105°C-110°C for 5min, and turn dark blue as a positive reaction;

[0037] 5. DMF (10ml / g) twice, methanol (10ml / g) twice, DMF (10ml / g) twice;

[0038] 6. Protect amino acid Fmoc-L-Asp(OtBu)-OH in three times excess, HBTU in three times ex...

Embodiment example 2

[0067] Implementation Case 2: Research on the Anti-tumor Effect of m(KLA)-iRGD

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Abstract

The invention discloses a novel cathepsin B activation type targeted anti-tumor polypeptide m(KLA)-iRGD, the molecular weight is 2570, and the amino acid sequence is D(KLAKLAKKLAKLA)KGGCRGDKGPDC. The polypeptide is formed by KLA peptide and iRGD peptide through flexible connexon Gly-Gly. The sequence of the KLA peptide is KLAKLAKKLAKLAK, and amino acids of the KLAKLAKKLAKLA sequence at the N terminal of the polypeptide are all D-amino acids. The sequence of the iRGD peptide is CRGDKGPDC. The polypeptide has the advantage that the tumor targeted peptide iRGD and the apoptosis promoting peptide KLA are connected into the new polypeptide m(KLA)-iRGD for the first time. The polypeptide m(KLA)-iRGD can be specifically combined with alphaVbeta3 and NRP-1 receptors and enter tumor cells, mitochondrial apoptosis is initiated after the polypeptide is activated by intracellular cathepsin B (CTSB), tumor cells are selectively killed, and growth and migration of tumors are remarkably inhibited. Under the same concentration, a polypeptide m(KLA)-iRGD comparison peptide has higher tumor targeting and higher capacity of inhibiting tumor growth and migration. Meanwhile, the polypeptide m(KLA)-iRGD has no obvious toxicity on mouse weight and vital organs, and a solid foundation is laid for further clinical research and application.

Description

technical field [0001] The invention belongs to the technical field of biology and medicine, and specifically relates to the preparation and application of a polypeptide m(KLA)-iRGD with anticancer activity. Background technique [0002] Chemotherapy is one of the main ways to treat tumors clinically. However, most chemotherapeutic drugs cause serious side effects due to lack of tumor targeting, and their clinical application is limited. Sexual drugs appear very urgent. [0003] Tumor-targeting peptides are a class of polypeptides that can selectively deliver drugs to the tumor microenvironment. By targeting specific receptors in tumor sites, they can mediate targeted delivery of drugs, improve drug efficacy and reduce damage to normal tissues. side effect. Tumor targeting polypeptides can be divided into three types: (i) targeting peptides; (ii) penetrating peptides; (iii) targeting penetrating peptides. The iRGD peptide belongs to the above-mentioned third category of p...

Claims

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Application Information

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IPC IPC(8): C07K19/00A61K38/10A61K47/48A61P35/00
Inventor 张革王启帆郭松鹤杜军
Owner SUN YAT SEN UNIV
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