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Method for enhancing targeting selectivity of administration system by modifying cell penetrating peptide

A drug delivery system, a technology for penetrating peptides, applied in pharmaceutical formulations, chemical instruments and methods, peptides, etc., can solve the problems of cytotoxicity, limited application, lack of cell selectivity, etc.

Inactive Publication Date: 2012-07-11
PEKING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the field of anti-tumor therapy, one of the more prominent problems is that the cell-penetrating peptide lacks cell selectivity after the drug or drug delivery system enters the body, and at the same time, the positive charge it carries can cause cytotoxicity to a certain extent, thus limiting its clinical application

Method used

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  • Method for enhancing targeting selectivity of administration system by modifying cell penetrating peptide
  • Method for enhancing targeting selectivity of administration system by modifying cell penetrating peptide
  • Method for enhancing targeting selectivity of administration system by modifying cell penetrating peptide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Example 1: Enzymatic hydrolysis of cell-penetrating peptides that can activate

[0026] Design and synthesis of activating cell penetrating peptide, the sequence of activating cell penetrating peptide is EEEEEXPLGLAGRRRRRRXKC. Enzymatic hydrolysis of synthetic activatable cell penetrating peptides. Reversed-phase high performance liquid chromatography was used to monitor the enzymatic hydrolysis of type IV collagenase (containing MMP-2 and 9) on activating cell penetrating peptides at 37°C. Collect the enzymolysis components for matrix-assisted laser analysis and ionization time-of-flight mass spectrometry detection, and compare the sequence of the speculated enzymatic fragments. HPLC detects the peak position of the activatable cell-penetrating peptide and the changes in the spectrum after enzymatic hydrolysis. The activatable cell-penetrating peptide solutions of different concentrations all have an absorption peak at about 14.8 min (MALDI-TOF-MS detects the molecular w...

Embodiment 2

[0027] Example 2: Investigation on the anti-proliferation effect of activating cell penetrating peptide-doxorubicin copolymer on tumor cells

[0028] Can activate cell penetrating peptide, the sequence is DGDGDGDGGDGPLGLAGrrrrrrrrrC, and adriamycin through the intermediate linker 3-maleimidopropionic acid N-hydroxysuccinimide ester (CAS: 55750-62-4) chemical bond and form a copolymer (As attached figure 2 Shown). The specific process is as follows: dimethylformamide dissolves adriamycin and 3-maleimidopropionate N-hydroxysuccinimide ester respectively, adds triethylamine to adjust the pH value, stirs at room temperature and reacts for 2 hours and then pour In 50ml ether, wash the precipitated precipitate with anhydrous ether twice, centrifuge the precipitate and vacuum dry; take the precipitate and activating cell penetrating peptide to dissolve in dimethylformamide, add triethylamine, stir at room temperature for 2 hours Then it was poured into 10 ml of ether, the precipitated...

Embodiment 3

[0030] Example 3: Inhibitory effect of activating cell penetrating peptide-methotrexate copolymer on tumor cells

[0031] It can activate the cell penetrating peptide, the sequence is DGDDGGDGGDGPLGLAGrrrrrrrrrC, which forms a copolymer with methotrexate (as attached Figure 4 Shown).

[0032] Human fibrosarcoma cell HT-1080, MMP enzyme is highly expressed, and has a specific degradation effect on the peptide PLGLAG; human breast cancer cell MCF-7, MMP enzyme expression is less. The two kinds of cells were cultured in appropriate culture medium to investigate the cytotoxicity of activating cell-penetrating peptide-methotrexate copolymer in HT-1080 and MCF-7 cells. The results showed that the free drug methotrexate has a strong cytotoxic effect in both types of cells, inhibiting cell growth; it can activate the cell penetrating peptide-methotrexate copolymer in HT-1080 cells and incubate The cell inhibition rate of 2h reached 20%, and the cell inhibition rate of 24h incubation was ...

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Abstract

The invention relates to modification of a cell penetrating peptide for realizing a low-toxicity administration system with a positive targeting selecting function. A shielding peptide, an enzymolysis substrate peptide and a cell-penetrating peptide are connected in sequence, so that an activatable cell penetrating peptide is formed; and a medicament and / or a tracer and / or a medicament carrier is connected or embedded or adsorbed to the cell penetrating peptide, so that an administration system is constructed. According to a shielding peptide sequence, positive charges carried on the surface of the administration system can be reduced or completely neutralized, the cell penetrating capability of the cell penetrating peptide is shielded, and the toxicity of the administration system on normal cells of an organism is lowered; and an enzymolysis substrate peptide sequence can be identified by enzyme systems secreted specifically by different pathological change tissue cells and fractured by enzyme hydrolysis, so that a cell penetrating peptide is released and is used for carrying a medicament and / or a medicament carrier through a cell membrane, and the medicament enters cells and is brought into play. The invention aims to actively convey an antitumor medicament to tumor tissues in a targeted way and make the antitumor medicament enter tumor cells to a larger extent by using the administration system which can be used for activating a cell penetrating function, so that the toxicity at a non-tumor position is lowered while the antitumor effect of the medicament is enhanced.

Description

Technical field [0001] The present invention relates to the modification of cell penetrating peptides to achieve a low-toxic drug delivery system with active target selection function, and its technical field is related to life science and biomedical technology. technical background [0002] The peptide chain with cell penetrating activity separated from the protein is called cell penetrating peptide. It is generally composed of peptide chains of less than 30 amino acids and is positively charged under physiological pH conditions. At present, there are three types of cell penetrating peptides: protein-derived peptide chains, model peptide chains and designed peptide chains. There are more than one hundred amino acid sequences with penetrating function reported so far. [0003] At present, the research on the mechanism of cell penetrating peptide into the cell mainly includes transduction mode and endocytosis mode. Among them, the transduction modes include direct transmembrane an...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/48A61K47/42A61K45/00A61K49/00A61K51/00A61K48/00A61K38/00A61P35/00C07K14/00C07K7/06
CPCY02A50/30
Inventor 齐宪荣董达文王鹏程时念秋向柏马冬旭
Owner PEKING UNIV
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