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Double receptor identified serial cell-penetrating peptide modified tumor targeted nano drug delivery system

A nano-drug delivery system and tumor-targeting technology, applied in the direction of anti-tumor drugs, peptides, hybrid peptides, etc., can solve the problems of limiting the application of membrane-penetrating peptides

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, as a non-specific "functional molecule", the penetrating peptide can non-selectively mediate the carrier's penetration into all tissues and cells, resulting in the toxicity of the drug to normal tissues. Application in systemic drug delivery

Method used

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  • Double receptor identified serial cell-penetrating peptide modified tumor targeted nano drug delivery system
  • Double receptor identified serial cell-penetrating peptide modified tumor targeted nano drug delivery system
  • Double receptor identified serial cell-penetrating peptide modified tumor targeted nano drug delivery system

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] The preparation of embodiment 1 R8-dGR

[0033] (1) Take 1g of 2-CL-Trt Resin resin and place it in a solid-phase reactor, add 15ml of dichloromethane (DCM) to swell for 30min, and then drain the DCM;

[0034] (2) Weigh 0.9 g of arginine protected by fluorenylmethoxycarbonyl (Fmoc) at the N-terminal, add it to the swollen resin, add N,N-diisopropylethylamine (DIEA), dimethylamide ( DMF), DCM nitrogen bubbling reaction at room temperature for 2.5 hours, drain the reaction solution after the reaction, add 20ml of ethyl acetate to wash, then add 20% hexahydropyridine / DMF solution to remove the Fmoc protecting group, add ethyl acetate after removing the protecting group 20ml wash;

[0035] (3) Weigh 0.67 g of glycine protected by fluorenylmethoxycarbonyl (Fmoc) at the N-terminal, add it to the reactor, and then add benzotriazole-N,N,N',N'-tetramethyluronium hexafluoro Phosphate ester (HBTU), DIEA, react at room temperature for 2 hours with nitrogen gas bubbling, add 20ml ...

Embodiment 2

[0040] Example 2. DSPE-PEG 2000 - Preparation of R8-dGR

[0041] In a 25ml round bottom flask, add 10ml chloroform followed by DSPE-PEG 2000 -Mal 15.0mg (5.1umol), triethylamine 3ul (17.9mmol), then R8-dGR 13.1mg (7.7umol) was dissolved in 5ml of methanol and added to a round bottom flask. Press and spin dry to get the initial product, add chloroform to dissolve, filter, and spin dry under reduced pressure to get DSPE-PEG 2000 -R8-dGR 21.8 mg (92.0%), a colorless oily compound.

[0042] Based on the method of this embodiment, when PEG is selected from 200-50000, R X When selected from R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, when DGR is selected from DGR, dGR, DGr, dGr (lowercase letters represent D-type amino acids), Lipid is selected from DSPE , PE, DOPE, DPPE, DMPE, DEPE, each specific Lipid-PEG-R can be similarly prepared X -DGR.

Embodiment 3

[0043] Example 3. R X - Preparation of DGR (X=2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) modified liposomes

[0044] With phospholipids, cholesterol, DSPE-PEG 2000 、DSPE-PEG 2000 -R X -DGR is used as material to prepare double receptor recognition tumor targeting liposome. Weigh 1.4mg of phospholipids, 0.4mg of cholesterol, DSPE-PEG 2000 0.3mg, DSPE-PEG 2000 -R X -DGR 0.2mg, dissolved in an appropriate amount of chloroform, in a water bath at 37°C, remove the chloroform by rotary evaporation under reduced pressure to form a uniform lipid film, add 1ml of PBS buffer for hydration for 1h, and ultrasonically (10s, 10s, 15 times) with the probe. Then extrude through 400nm, 200nm and 100nm polycarbonate films in turn to obtain R X - DGR modified liposomes.

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Abstract

The invention provides a serial cell-penetrating peptide modified tumor targeted and tumor penetrated nano drug delivery system capable of simultaneously identifying an integrin receptor and a transmembrane protein receptor, wherein the serial cell-penetrating peptide is mainly formed by connecting a DGR polypeptide fragment covalently at the C-tail end of polyarginine of the cell-penetrating peptide. The polypeptide not only can selectively identify two highly expressed receptors on the surfaces of the tumor cells, but also can be efficiently mediated into the cells. The nano drug delivery system mainly consists of a nano carrier, a drug and a lipid-polyethylene glycol-serial cell-penetrating peptide ligand interstitial compound and is a potential tumor targeted treatment carrier.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical preparations, in particular to a tumor-targeted nano-drug delivery system, which covalently links a linear aspartic acid-glycine-arginine (DGR) sequence to a cell-penetrating peptide Polyarginine (R X ) to obtain a tandem penetrating peptide with both integrin receptor and transmembrane protein receptor dual recognition ability and high-efficiency mediation of cell transduction ability, and modify the peptide on the surface of the nano drug delivery system to obtain A tumor-targeted nano-drug delivery system. Background technique [0002] Malignant tumors are one of the major diseases that seriously threaten human health. Chemotherapy is the most commonly used method for clinical treatment of tumors. However, chemotherapy drugs generally have low selectivity and large toxic and side effects, making the therapeutic effect of tumors very limited. In recent years, the research on tumor-tar...

Claims

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Application Information

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IPC IPC(8): C07K19/00A61K47/42A61K47/48A61K9/14A61K9/127A61K9/107A61P35/00
Inventor 何勤刘亚圆高会乐
Owner SICHUAN UNIV
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