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Targeted ligand-PEG (polyethylene glycol)-cholesterol/tocopherol derivative, and preparation method and application of derivative

A technology of cholesterol derivatives and targeting ligands, which can be used in pharmaceutical formulations, medical preparations containing active ingredients, and drug combinations, etc., which can solve the problem of unsatisfactory tissue selectivity, affecting drug delivery efficiency, and weak microenvironmental responsiveness And other issues

Inactive Publication Date: 2014-03-12
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, cationic liposomes still face problems in the application of co-delivery delivery vehicles, mainly in the following aspects: (1) The ability to respond to the microenvironment of the lesion site is not strong, which affects the efficiency of drug delivery
(2) Unsatisfactory tissue selectivity, lack of specific targets only for tumor cells
[0005] The introduction of PEG chains does not affect the loading of co-delivered drugs, active targeting to tumor tissue, removal of long PEG chains triggered by tumor microenvironment, and charge reversal to positive charge before entering cells. Co-delivery of drug carriers has not been reported in relevant literature at home and abroad

Method used

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  • Targeted ligand-PEG (polyethylene glycol)-cholesterol/tocopherol derivative, and preparation method and application of derivative
  • Targeted ligand-PEG (polyethylene glycol)-cholesterol/tocopherol derivative, and preparation method and application of derivative
  • Targeted ligand-PEG (polyethylene glycol)-cholesterol/tocopherol derivative, and preparation method and application of derivative

Examples

Experimental program
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Effect test

Embodiment 1

[0057] Example 1: Synthesis of anti-EphmAb-polyethylene glycol-cholesterol and preparation of DOX / siRNA cationic liposomes and pharmacy / biological investigation

[0058] 1) Ep10mAb-PEG 2000 Synthesis of -SH

[0059] Bifunctional PEG 2000 Dissolve in water, add a certain amount of EDC and S-NHS, react at room temperature, dialyze to remove excess product, add a certain amount of Ep10mAb to the reaction solution, and react in the dark to prepare Ep10mAb-PEG 2000 -SH dialyzed to remove excess reactants, freeze-dried. After the product was purified, the structure of the product was confirmed by infrared spectroscopy and nuclear magnetic resonance spectroscopy. Then, electrophoresis and ELISA methods were used to investigate the effect of the antibody linked with PEG on its activity and the effect of the linked antibody on tumor cell proliferation.

[0060] 2) Synthesis of pH-sensitive cholesterol derivatives

[0061] Dissolve an appropriate amount of cholesterol chloroformate...

Embodiment 2

[0064] Example 2: Synthesis of folic acid-PEG-cholesterol derivatives, construction of self-assembled carriers, formulation and biological research.

[0065] 500 mg of folic acid and NHS were dissolved in 10 ml of DMSO, excess DCC was added to the solution and stirred overnight at room temperature, and the insoluble dicyclohexylurea was removed by suction filtration. Folate-NHS and bisamino-PEG were dissolved in DMSO and incubated overnight at room temperature in the dark. Pass the above product through a diethylaminoethyl-Tris anion exchange column, and use NH 4 HCO 3 Gradient elution. Combine excess cholesterol chloroformate with folic acid-PEG-NH 2Dissolve in chloroform and react overnight at room temperature according to the above reaction conditions, and detect the progress of the reaction by ninhydrin reaction. The reaction product was dried under vacuum, washed with ether to remove unreacted cholesterol chloroformate, and the purity of the product was analyzed throu...

Embodiment 3

[0067] Example 3: Synthesis of Glycyrrhetinic Acid-PEG-Tocopherol Derivatives and Construction and Preparation of Self-Assembled Carriers and Biological Research

[0068] Appropriate amount of α-tocopheryl succinate was dissolved in dichloromethane, and functional HO-PEG-OH, dimethylaminopyridine, N-(3-dimethylaminopropyl)-N'-ethylcarbodiethylene were added in sequence Amino acid salt was stirred and reacted at room temperature for 16h. The product was separated and purified by silica gel column. Glycyrrhetinic acid is chemically reacted with PEGylated-tocopherol succinate to be connected through an ester bond. 1H-NMR (CDCl3) characterizes the synthesis of the product, δ5.69 and 5.6 are the chemical shifts of the hydrogen atoms of the glycyrrhetinic acid olefinic bond (-(C=O)-CH=C-), and δ3.52~3.76 are the chemical shifts of the PEG molecule Chemical shift, δ2.58~2.66 is the chemical shift of the succinic acid linking group, δ0.63 and 0.83~1.31 are the chemical shift of the ...

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Abstract

The invention belongs to the field of pharmaceutic preparations, and relates to a targeted ligand-PEG (polyethylene glycol)-cholesterol / tocopherol derivative, and a preparation method and an application of the derivative, in particular to an application of the derivative in a composite mechanism mediate tumor targeted drug delivery system. According to the derivative, the preparation method and the application, a drug delivery system consisting of the targeted ligand-PEG-cholesterol / tocopherol derivative with a targeting function, a long circulating function and a pH (power of hydrogen) sensitive function as a functional material, a cation liposome and a drug can simultaneously carry anticancer polypeptide and gene / chemotherapy drugs. According to the system, different drugs are jointly entrapped into the lipid nano drug delivery system and delivered into a targeted cell by utilizing a physicochemical property difference between components or by in-vivo specific targeted recognition, signal conduction blocking and pH triggering PEG chain breaking charge reversion methods, so that a targeted tumor therapeutic effect is improved. According to the derivative, the preparation method and the application, the advantages of the system in directional delivery, co-delivery and the like are proved by in-vivo and in-vitro activity evaluation, the anticancer activity is improved significantly, and definite synergic therapeutic and immunity effects are provided.

Description

technical field [0001] The invention belongs to the field of pharmaceutical preparations, and relates to a targeting ligand-PEG-cholesterol / tocopherol derivative and its preparation method and application, in particular to targeting ligand-PEG-cholesterol / tocopherol derivatives in a drug delivery system Application in simultaneously carrying anti-cancer polypeptides and genes / chemotherapy drugs. Background technique [0002] Malignant tumors are diseases that seriously threaten human health. Cancer treatment is a worldwide problem. As an important means of clinical treatment of cancer, chemotherapy has become one of the most direct and effective methods for clinical treatment of malignant tumors. However, due to the high toxicity of chemotherapy drugs and repeated use, tumor cells can easily induce multidrug resistance (MDR) to chemotherapy drugs, which seriously affects the clinical chemotherapy effect, and more than 90% of patients with tumor death are related to differe...

Claims

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Application Information

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IPC IPC(8): A61K47/34A61K45/00A61K48/00A61P35/00
Inventor 赵秀丽臧新龙陈大为
Owner SHENYANG PHARMA UNIVERSITY
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