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A tumor-targeted nano-drug delivery system modified by tandem penetrating peptides recognized by dual receptors

A penetrating peptide and tandem technology, which is applied in the field of tumor-targeted nano-drug delivery systems modified by tandem penetrating peptides recognized by dual receptors, can solve problems such as limiting the application of penetrating peptides.

Inactive Publication Date: 2018-07-03
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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  • A tumor-targeted nano-drug delivery system modified by tandem penetrating peptides recognized by dual receptors
  • A tumor-targeted nano-drug delivery system modified by tandem penetrating peptides recognized by dual receptors
  • A tumor-targeted nano-drug delivery system modified by tandem penetrating peptides recognized by dual receptors

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 -DGR0.2mg, 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 1 hour, 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 present invention provides a tandem penetrating peptide modified tumor targeting and tumor penetrating nano drug delivery system that simultaneously recognizes integrin receptors and transmembrane protein receptors. The tandem penetrating peptide is mainly a DGR polypeptide. The fragment is formed by covalently connecting to the C-terminus of the penetrating peptide polyarginine, and the polypeptide can not only selectively recognize receptors highly expressed on the surface of two types of tumor cells, but also efficiently mediate into cells. The nano-drug delivery system is mainly composed of nano-carriers, drugs and lipid-polyethylene glycol-tandem transmembrane peptide ligand chimeras, and is a potential tumor-targeted therapy 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-targe...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K19/00A61K47/42A61K47/64A61K9/14A61K9/127A61K9/107A61P35/00
Inventor 何勤刘亚圆高会乐
Owner SICHUAN UNIV
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