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PEG-decorated phospholipid derivative using octreotide as target ligand and production method thereof

A polyethylene glycol and octreotide technology, applied in the application of new materials in anti-tumor drug preparations, in the field of polyethylene glycol-modified phospholipid derivatives, can solve the problem of limited space stable immunoliposome development, poor stability, and chemical bond toxicity And other issues

Inactive Publication Date: 2009-06-17
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

② Poor stability of liposomes in vivo
Commonly used such phospholipids include Mal-PEG-DSPE, PDP-PEG-DSPE, and a system using EDC / NHS as a coupling agent. Some of these methods require the coupled molecule to have a specific site (sulfhydryl group), and some require Modification of coupling proteins in advance, and some chemical bonds formed after coupling are toxic, which limit the development of sterically stable immunoliposomes

Method used

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  • PEG-decorated phospholipid derivative using octreotide as target ligand and production method thereof
  • PEG-decorated phospholipid derivative using octreotide as target ligand and production method thereof
  • PEG-decorated phospholipid derivative using octreotide as target ligand and production method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Polyethylene glycol bis-p-nitrophenyl carbonate ((pNP) 2 -PEG) synthesis

[0040] Weigh 2 g of 4-nitrophenyl chloroformate, PEG 4000 20g. The above two substances were dissolved in 4ml and 36ml of anhydrous dichloromethane, respectively, and 1.5ml of triethylamine (TEA) was added to the solution of PEG in anhydrous dichloromethane. The PEG anhydrous dichloromethane solution containing triethylamine was slowly added to the anhydrous dichloromethane solution of 4-nitrophenyl chloroformate under stirring, and the reaction was stirred overnight at room temperature.

[0041] The precipitated triethylamine hydrochloride formed in the reaction solution was filtered off, and the solvent was evaporated to dryness under reduced pressure. The obtained crude product was precipitated with anhydrous ether, and the precipitate was recrystallized twice with ethyl acetate and ether, respectively. After two recrystallizations, the product was dissolved in dichloromethane, and 5 time...

Embodiment 2

[0044] Preparation of p-nitrophenyl carbonate-based polyethylene glycol phosphatidylethanolamine (pNP-PEG-PE)

[0045] Weigh 50mg of distearoylphosphatidylethanolamine (DSPE) and dissolve it in 2.5ml of chloroform, add 0.2ml of TEA, add the above mixture to (pNP) 2 -PEG 4000 Chloroform solution (200mg / ml) 7ml, stirred at room temperature overnight. Chloroform was evaporated to dryness under reduced pressure, 10 ml of 0.01M hydrochloric acid solution was added, and a transparent micellar solution was formed by ultrasonication.

[0046] Gained micellar solution was centrifuged at 10000r / min for 5 minutes, and the supernatant was used for molecular sieve chromatography. Sepharose4B column (2×60cm) was eluted with 0.01M hydrochloric acid (flow rate was 0.35ml / min). The eluate was collected by the partial collector, and the ultraviolet absorption of each part was measured at 270nm. Plot the elution profile. The molybdenum blue color reaction detected by TCL is the position of p...

Embodiment 3

[0049] Linkage of pNP-PEG-PE to Octreotide

[0050] pNP-PEG 4000 - Dissolve 50mg of PE in chloroform, remove chloroform under reduced pressure to form a lipid film, dissolve 10mg of octreotide in 0.01mol / l HCl 4ml, add to the lipid film, shake gently to fully disperse the lipid film. Add 20ml of 10mmol / l (pH9.0) Tris buffer to the above suspension, mix well, and react overnight at 4°C. Using water as the medium, the dialysis bag with a molecular mass of 3kD was dialyzed for 2 days, and the product was freeze-dried.

[0051] 1 H-NMR (300MHz, D 2 O): δ 0.85-0.89 (CH 3 -), δ 1.25 (-CH 2 -), δ 2.28-2.40(-OC H 2 C H 2 NH-), δ 3.60-3.73 (O-CH 2 CH 2 -O), δ 7.10-7.35 (-NHCO-).

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Abstract

The invention relates to the field of medical polymer auxiliary materials and medicines, in particular to polyethylene glycol modified phospholipids derivatives (I) which take octreotide as a targeting ligand. In the polyethylene glycol modified phospholipids derivatives (I), a polyethylene glycol long chain has the function of spatial stabilization and makes modified liposome realize long circulation; simultaneously, the octreotide is connected to the outside of a PEG hydrophilic chain, exposed to the outer layer of the liposome and not influenced by the PEG chain; and the conjugation between active targeting tumor cells and a cell membrane SSTR receptor is maintained after the liposome is effluent out of a tumor novel blood vessel, so as to improve uptake of liposome-containing medicines of tumor cells.

Description

technical field [0001] The invention relates to the field of pharmaceutical polymer excipients and medicaments. It specifically relates to a class of polyethylene glycol-modified phospholipid derivatives with octreotide as a targeting ligand, and also relates to the application of this new type of material in antitumor drug preparations. Background technique [0002] In 1965, British Bangham discovered liposomes. After more than 40 years of development, liposomes have been applied in many fields. Liposomes have a high degree of biocompatibility, and the use of liposomes to deliver drugs has sustained release and targeting, while reducing the toxicity of encapsulated drugs and improving drug stability. In addition to the above excellent properties, the application of traditional liposomes to deliver drugs also has limitations. ①Liposome is a passive targeted drug delivery system. After administration, it is mainly concentrated in organs rich in reticuloendothelial cells suc...

Claims

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Application Information

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IPC IPC(8): A61K47/48A61K9/127C08G65/48A61P35/00A61K47/42A61K47/64
Inventor 平其能王宇孙敏捷沈洁
Owner CHINA PHARM UNIV
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