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Novel polypeptide with active tumor targeting and pH sensitive cell penetratingcapability

A sensitive and new technology, applied in anti-tumor drugs, peptides, hybrid peptides, etc., can solve problems such as side effects

Inactive Publication Date: 2015-04-08
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, TH peptide, which has a strong cell-penetrating ability at the tumor site, does not have selectivity between normal cells and tumor cells, and still causes certain side effects.

Method used

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  • Novel polypeptide with active tumor targeting and pH sensitive cell penetratingcapability
  • Novel polypeptide with active tumor targeting and pH sensitive cell penetratingcapability
  • Novel polypeptide with active tumor targeting and pH sensitive cell penetratingcapability

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] Preparation and characterization of TR peptide-modified liposomes (TR-Lip)

[0020] Liposomes were prepared by thin film dispersion method. Weigh 1.2 mg of soybean lecithin, 0.4 mg of cholesterol, 0.05 mg of monomethoxy-modified polyethylene glycol and 1 mg of TR peptide-modified polyethylene glycol, dissolve them all in chloroform / methanol mixture, rotate and evaporate , to form a thin film layer, which was placed in a vacuum desiccator overnight, so that the organic solvent was fully evaporated. Add 1 ml of Hepes buffer (pH 7.4), place it on a shaker (180 rpm × 30 min, 37 °C), shake it, and sonicate it with a sonicator (5 times × 5 s × 15 s) to obtain a uniform particle size. TR-Lip. Take 100 μl TR-Lip diluted 10 times, and measure its particle size distribution and charge distribution with Zetanano particle sizer. The particle size of TR-Lip is around 150 nm. At pH 7.4, the Zeta potential of TR-Lip was around -7 mV; at pH 6.5, the Zeta potential of TR-Lip was aro...

Embodiment 2

[0022] Preparation and characterization of TR peptide-modified nanoparticles (TR-NPs)

[0023] The TR peptide-modified nanoparticles were prepared by W / O / W emulsification-solvent evaporation method. A certain amount of PLA-PLL-TR was dissolved in dichloromethane to form an organic phase, pure water was used as the water phase, the organic phase and the water phase were mixed in a certain proportion, and colostrum was formed by ultrasonication. Pour the colostrum into the outer water phase containing Poloxamer F-18 emulsifier, continue to sonicate to obtain a re-emulsion and place it in a beaker, and stir to evaporate the organic solvent to obtain a nanoparticle colloidal dispersion system. The particle size distribution and charge distribution were measured by Zetanano particle size analyzer; the binding force with integrin was measured by SPR analyzer. The particle size of TR-NPs is about 90 nm. At pH 7.4, the Zeta potential of TR-NPs was around -7.5 mV; at pH 6.5, the Zeta...

Embodiment 3

[0025] Preparation and characterization of TR peptide-modified micelles (TR-micelle)

[0026]Dissolve 10 mg DSPE-PEG-TR and 20 mg DSPE-PEG-OMe in anhydrous chloroform respectively, form a film by rotary evaporation, dry under reduced pressure overnight, add 5 ml of 20 mM Hepes buffer (pH 7.4), and shake in a water bath at 37 °C. After 20 min, filtered with a 0.22 μm microporous membrane to obtain TR peptide-modified polymer micelles (TR-micelle). The particle size distribution and charge distribution were measured by Zetanano particle size analyzer; the binding force with integrin was measured by SPR analyzer. The particle size of TR-micelle is about 112 nm. At pH 7.4, the Zeta potential of TR-micelle was around -8 mV; at pH 6.5, the Zeta potential of TR-micelle was around +4 mV. Surface plasmon resonance (SPR) was used to measure the binding ability of micelles modified with different polypeptides to integrin, and TR-micelle had the strongest binding ability to integrin.

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Abstract

The invention provides a novel polypeptide which not only can be actively targeted to highly expressed integrin receptor of tumor cells, but also can efficiently mediate cell entry. The novel polypeptide TR(c(RGDfK)-AGYLLGHINLHHLAHL(Aib)HHIL-Cys) is formed by connecting cyclic RGD peptide (c(RGDfK)) of specificity-targeted integrin receptor and non-specific pH sensitive cell penetrating peptide TH(AGYLLGHINLHHLAHL(Aib)HHIL-Cys) through covalent bonds. The novel polypeptide TR is modified onto the surface of a drug carrier system, and can mediate the drug carrier system to more efficiently deliver to the inside of the tumor, so that the tumor can be more effectively treated.

Description

technical field [0001] The present invention relates to the technical field of pharmaceutical preparations. Specifically, the present invention relates to a novel polypeptide which has both the ability to actively target the highly expressed integrin receptors of tumor cells and the ability of pH-sensitive cell membrane penetration. The novel polypeptide is modified on the surface of the drug-carrying system, and is used to mediate the drug-carrying system to efficiently and actively target tumors with high expression of integrin receptors and efficiently mediate their entry into cells, so as to achieve the purpose of improving the tumor treatment effect. Background technique [0002] 1. The incidence and mortality of cancer have been increasing year by year in recent years, which has seriously threatened human health. Although there are various treatments for cancer, chemotherapy is still the most commonly used. Because chemotherapeutic drugs often lack selectivity betwee...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K19/00A61K47/42A61P35/00
Inventor 何勤石凯荣高会乐
Owner SICHUAN UNIV
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