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Enzymatic type cleavable PEGylation ( polyethylene glycol) lipid material

A lipid material and enzymatic technology, applied in the direction of liposome delivery, genetic material components, non-active components of polymer compounds, etc.

Active Publication Date: 2013-09-04
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] One of purpose of the present invention provides a kind of novel PEGylated lipid material, to solve the problem that PEG runs into when modifying liposome

Method used

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  • Enzymatic type cleavable PEGylation ( polyethylene glycol) lipid material
  • Enzymatic type cleavable PEGylation ( polyethylene glycol) lipid material
  • Enzymatic type cleavable PEGylation ( polyethylene glycol) lipid material

Examples

Experimental program
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Effect test

Embodiment 1

[0051] Synthesis of Cholesterol Bromoacetyl Ester (1)

[0052] 0.5 mmol of cholesterol (193 mg) was dissolved in 5 ml of anhydrous THF, and 3 mmol of bromoacetyl chloride (250 μl) was added dropwise. The reaction mixture was heated, stirred and refluxed for about 4h, and detected by TLC (petroleum ether: CH 2 Cl 2 =4:1) The reaction is complete. The organic solvent was evaporated by rotary evaporation to obtain a yellow crude product, which was then purified by a silica gel column (eluent was sherwood oil: CH 2 Cl 2 =5:1). Finally, a white sample is obtained, that is, Chol-CO-CH 2 Br.

[0053] 1H NMR (CDCl3, 400 MHz): δ0.6 —2.25ppm(m, 43H, cholesterol protons), 3.8ppm(s, 2H, CH2Br), 4.6ppm(m, 1H, 3-CH-cholesterol), 5.4ppm (d, 1H, 6-CH-cholesterol).

Embodiment 2

[0055] Synthesis of Cholesterol Bromoacetyl Ester (2)

[0056] Dissolve 100 mg cholesterol and 40 mg bromoacetic acid in 10 ml anhydrous CH 2 Cl 2 , and then added 44 μl of N,N'-diisopropylcarbimide and 1.5 mg of 4-dimethylaminopyridine. Stir at room temperature for 48h. The organic solvent was evaporated by rotary evaporation to obtain a yellow crude product, which was then purified by a silica gel column (eluent was sherwood oil: CH 2 Cl 2 =5:1). Finally, a white solid is obtained, namely Chol-CO-CH 2 Br.

[0057] 1 H NMR (CDCl 3 , 400 MHz): δ0.6 —2.25ppm(m, 43H, cholesterol protons), 3.8ppm(s, 2H, CH2Br), 4.6ppm(m, 1H, 3-CH-cholesterol), 5.4ppm(d, 1H , 6-CH-cholesterol).

Embodiment 3

[0059] Synthesis of PEG-peptide-SH (Ⅰ)

[0060] mPEG2000-NHS (purchased from Sigma, USA) and short peptide (GPLGIAGQC)-SH (synthesized by Shanghai Chueptide Biotechnology Co., Ltd.) were mixed at a molar ratio of 1.2:1, stirred in carbonic acid buffer (pH 8.5) at 4°C overnight. After dialysis (dialysis bag molecular weight cut-off 1000) and freeze-drying, a white solid, PEG2000-peptide(GPLGIAGQC)-SH (I), was obtained. ( figure 2 PEG-MMP substrate peptide 1 H NMR spectrum)

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Abstract

The invention provides an enzymatic type cleavable PEG (polyethylene glycol) modified cholesterol lipid material and provides a synthesis method of the material. Phagocytosis of immune system can be avoided by using liposome prepared by the enzymatic type cleavable PEGylation lipid material, while PEG can be removed off under the action of matrix metalloproteinase secreted by tumor cells. Therefore, the purpose of tumor targeting can be achieved, and the mutual action between drugs and tumor cells cannot be inhibited. The material is suitable for preparing some carriers of anti-cancer drugs or genes.

Description

technical field [0001] The invention relates to a novel PEGylated lipid material for preparing liposomes, in particular to enzymatically breaking the PEGylated lipid material. Background technique [0002] After years of research and development, liposomes have been widely used as carriers of anticancer drugs. The U.S. FDA has approved liposome preparations for the clinical treatment of malignant tumors at present, such as: Adriamycin liposome, daunorubicin liposome etc. (Davis, M. E., Chen, Z. G, Shin, D. M., Nanoparticle therapeutics: An emerging treatment modality for cancer. Nat. Rev. Drug Discov. 2008, 7 , 771-782.). In addition, with the development of gene therapy, liposomes also play an important carrier role in the field of tumor gene therapy. [0003] However, common liposomes have the following problems in the application process of tumor therapy: traditional liposomes are easily cleared by the reticuloendothelial system (RES) in the body, and the circulation ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K9/127A61K47/42A61K48/00A61P35/00
Inventor 孙逊万瑜张志荣龚涛
Owner SICHUAN UNIV