Pegylated oxaliplatin prodrug as well as preparation method and application thereof

A technology of PEGylation and oxaliplatin, which is applied in the field of medicine and chemical industry, can solve the problems of limited clinical application, easy aggregation and leakage, and poor stability of liposome formulations.

Active Publication Date: 2016-11-09
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the poor stability of liposome formulations, aggregation and leakage are prone to occur, and oxaliplatin is easily degraded, which limits its clinical application

Method used

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  • Pegylated oxaliplatin prodrug as well as preparation method and application thereof
  • Pegylated oxaliplatin prodrug as well as preparation method and application thereof
  • Pegylated oxaliplatin prodrug as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] Embodiment 1: the preparation of lysinated polyethylene glycol

[0053] Take mPEG5k 1.0g, N2, N6-bis-tert-butoxycarboxy-L-lysine 277mg, carbodiimide hydrochloride 153mg, hydroxybenzotriazole 108mg, dissolve in 10ml of anhydrous acetonitrile, add 55 μl of triethylamine was stirred in the dark for 48 hours, and the organic solvent was spun dry, dissolved in 10 ml of water, transferred to a 3500 Da dialysis bag, dialyzed with deionized water for 48 hours, and the liquid in the bag was lyophilized.

[0054] Take 500mg of the above-mentioned product, add 5ml of dichloromethane to dissolve, slowly add 5ml of trifluoroacetic acid dropwise, avoid light and stir for 24 hours, spin to dry the organic solvent, add 10ml of water to dissolve, transfer to a 3500D dialysis bag, lyophilize after 48 hours of dialysis That is, lysinated polyethylene glycol. The resulting material was characterized by proton nuclear magnetic resonance spectroscopy, and the results were as follows: figur...

Embodiment 2

[0055] Embodiment 2: the preparation of single carboxylation and alkylation oxaliplatin

[0056] Weigh 500 mg of oxaliplatin, suspend it in 10 ml of deionized water, add 3 ml of 30% hydrogen peroxide, place it in a 50 ml round bottom flask, stir and react in the dark at 30 degrees Celsius for 12 hours, remove the solvent by rotary evaporation, add methanol to dissolve the resulting substance, Precipitate with ether and dry in vacuum to obtain oxaliplatin oxide.

[0057] Take 215 mg of oxidized oxaliplatin, dissolve it in 5 ml of anhydrous dimethyl sulfoxide, add 50 mg of succinic anhydride, react at 25 °C for 12 hours, and precipitate with ether, dissolve the obtained substance in methanol, and then remove the methanol by rotary evaporation. Washing and drying in vacuum to obtain monocarboxylated oxaliplatin.

[0058] Take 60 mg of monocarboxylated oxidized oxaliplatin, dissolve it in 3 ml of anhydrous N,N-dimethylformamide, add 45.33 mg of hexadecyl isocyanate, place it at 2...

Embodiment 3

[0059] Embodiment 3: Preparation of pegylated oxaliplatin prodrug

[0060] 1. Preparation of PEGylated mono-oxaliplatin prodrug

[0061] Take the monocarboxylated and alkylated oxaliplatin 200mg prepared in Example 2, mPEG2k1.0g, carbodiimide hydrochloride 95.5mg, hydroxybenzotriazole 67.5mg, dissolve in 15ml of anhydrous acetonitrile , add 104 μl of triethylamine, stir for 48 hours in the dark, spin to dry the organic solvent, add 10ml of water to dissolve, select an ultrafiltration tube with a molecular weight cut-off of 30kDa to wash 5 times with water, and take the supernatant to freeze-dry to obtain PEGylation Oxaliplatin Prodrug. The resulting material was characterized by proton nuclear magnetic resonance spectroscopy, and the results were as follows: image 3 shown.

[0062] 2. Preparation of pegylated bisoxaliplatin prodrug

[0063] Take 500 mg of monocarboxylated and alkylated oxaliplatin prepared in Example 2, 1065.5 mg of lysinated polyethylene glycol in Exampl...

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Abstract

The invention discloses a pegylated oxaliplatin prodrug as well as a preparation method and application thereof. The pegylated oxaliplatin prodrug has a structure as shown in the formula 1 or 2, wherein the linkage unit L is as shown in the description. The pegylated oxaliplatin prodrug is mainly used for preparing medicaments for cancer treatment and can be independently self-assembled into micelles in water. In addition, the invention also discloses pegylated oshari. The formulae 1 and 2 are as shown in the description.

Description

technical field [0001] The invention belongs to the technical field of medicine and chemical industry, and specifically relates to a pegylated oxaliplatin prodrug, its preparation method and application. Background technique [0002] Chemotherapy is one of the main means of cancer treatment, among which (divalent) platinum drugs have the characteristics of good anticancer effect and wide indications, etc. Oxaliplatin is the third generation of platinum anticancer drugs after cisplatin and carboplatin. Cancer drug, and so far the only platinum-based drug with significant activity against colorectal cancer. Compared with the previous two generations of platinum drugs, oxaliplatin has better anti-tumor effects in vivo and in vitro, and is safe to use. It has obvious inhibitory effect on solid tumors such as colorectal cancer, non-small cell lung cancer and ovarian cancer. However, in the course of clinical use, it accumulates less in tumor tissue after injection into the body...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/107A61K47/48A61K31/282A61P35/00C08G65/337C08G65/333C08G65/48
CPCA61K9/1075A61K33/24C08G65/33396C08G65/337C08G65/48
Inventor 于海军李亚平付元磊冯兵周方圆王当歌王亭亭
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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