Fully dissociable polyethylene glycol-poly(l-glutamic acid-γ-benzyl ester)-polyethyleneimine copolymer and its synthesis method and application

A polyethyleneimine copolymer and polyethyleneimine technology are applied in the field of completely dissociable polyethylene glycol-poly-polyethyleneimine copolymer and its synthesis, which can solve the problem of repeated medication and inability to combine , patient trouble and other problems, to achieve the effect of increasing the effective concentration of the drug, reducing the toxic and side effects, and promoting escape

Inactive Publication Date: 2016-11-23
XI AN JIAOTONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, these imine bonds cannot guarantee the stability of the gene carrier, and may have been dissociated before reaching the tumor tissue and entering the cells, making it difficult to guarantee the transfection effect
[0004] Sequential combination therapy is often used in clinical malignant tumors to overcome the unsatisfactory therapeutic effect of single agents
However, this combination therapy cannot achieve combination at the microscopic level, and requires repeated medications, which brings unnecessary troubles to patients.
At the same time, this combined treatment method is difficult to ensure the combined drug at the same site, the effect of synergistic anti-tumor treatment is not easy to reflect, and the clinical efficacy is not satisfactory.

Method used

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  • Fully dissociable polyethylene glycol-poly(l-glutamic acid-γ-benzyl ester)-polyethyleneimine copolymer and its synthesis method and application
  • Fully dissociable polyethylene glycol-poly(l-glutamic acid-γ-benzyl ester)-polyethyleneimine copolymer and its synthesis method and application
  • Fully dissociable polyethylene glycol-poly(l-glutamic acid-γ-benzyl ester)-polyethyleneimine copolymer and its synthesis method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] 1) Synthesis of cystaminated methoxypolyethylene glycol (mPEG):

[0047] 1.1) Dissolve dry methoxy-terminated polyethylene glycol with a molecular weight of 4000Da, dibutyltin dilaurate and 2,2'-dithiodiethylisocyanate in anhydrous toluene, and store at 85°C under a nitrogen atmosphere. After reacting for 48 hours, the resulting reaction system was precipitated three times in anhydrous n-hexane, and the precipitate was collected and dried in vacuo to obtain mPEG modified with 2,2'-dithiodiethylisocyanate; The molar ratio of polyethylene glycol, dibutyltin dilaurate and 2,2'-dithiodiethylisocyanate is 1:0.06:8; dissolve 5g of methoxy-terminated polyethylene glycol per 100ml of anhydrous toluene alcohol;

[0048] 1.2) Dissolve 2,2'-dithiodiethylisocyanate-modified mPEG in distilled water and react at 60°C for 6 hours. The reaction system is dialyzed in distilled water and freeze-dried to obtain white powder cystaminated endoform Oxypolyethylene glycol; Dissolve 5g of 2,...

Embodiment 2

[0064] 1) Synthesis of cystaminated methoxypolyethylene glycol:

[0065] 1.1) Dissolve dry methoxy-terminated polyethylene glycol with a molecular weight of 1200Da, dibutyltin dilaurate and 2,2'-dithiodiethylisocyanate in anhydrous toluene, and react at 85°C under a nitrogen atmosphere After 48 hours, the resulting reaction system was precipitated three times in anhydrous n-hexane, and the precipitate was collected and dried in vacuo to obtain 2,2'-dithiodiethylisocyanate-modified mPEG; wherein, the methoxy-terminated poly The molar ratio of ethylene glycol, dibutyltin dilaurate and 2,2'-dithiodiethylisocyanate is 1:0.04:5, and 25g of methoxy-terminated polyethylene glycol is dissolved in 100ml of anhydrous toluene ;

[0066] 1.2) Dissolve 2,2'-dithiodiethylisocyanate-modified mPEG in distilled water and react at 60°C for 6 hours. The reaction system is dialyzed in distilled water and freeze-dried to obtain white powder cystaminated endoform Oxy-polyethylene glycol; wherein,...

Embodiment 3

[0076] 1) Synthesis of cystaminated methoxypolyethylene glycol:

[0077] 1.1) Dissolve dry methoxy-terminated polyethylene glycol with a molecular weight of 2000Da, dibutyltin dilaurate and 2,2'-dithiodiethylisocyanate in anhydrous toluene, and react at 85°C under a nitrogen atmosphere After 48 hours, the resulting reaction system was precipitated three times in anhydrous n-hexane, and the precipitate was collected and dried in vacuo to obtain 2,2'-dithiodiethylisocyanate-modified mPEG; wherein, the methoxy-terminated poly The molar ratio of ethylene glycol, dibutyltin dilaurate and 2,2'-dithiodiethylisocyanate is 1:0.02:3, and 10g of methoxy-terminated polyethylene glycol is dissolved in 100ml of anhydrous toluene ;

[0078] 1.2) Dissolve 2,2'-dithiodiethylisocyanate-modified mPEG in distilled water and react at 60°C for 6 hours. The reaction system is dialyzed in distilled water and freeze-dried to obtain white powder cystaminated endoform Oxy-polyethylene glycol; wherein,...

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Abstract

Fully dissociable polyethylene glycol-poly(L-glutamic acid-γ-benzyl ester)-polyethyleneimine copolymer and its synthesis method and application, first carry out cystamine to end-methoxy polyethylene glycol modification, using its terminal amino group to initiate the ring-opening polymerization of γ-benzyl ester-L-glutamic acid-N-carboxyl anhydride, and then use 2,2'-dithiodiethylisocyanate to add The product obtained by the ring-opening polymerization reaction is linked with polyethyleneimine to obtain the target product. The copolymer synthesized by the method of the present invention has amphiphilicity and can be self-assembled to form nanoparticles; the copolymer can be used as a drug carrier to simultaneously load chemotherapeutic drugs and gene drugs; and can be completely dissociated in response to reducing substances such as glutathione The collapse is not only conducive to the escape of the carrier from the endosome to the cytoplasm, but also can quickly release the drug and improve the therapeutic effect. The method of the invention can control the molecular weight and length of each segment in the block copolymer, has mild reaction conditions and is suitable for many kinds of drugs.

Description

technical field [0001] The invention belongs to the field of biomedical materials, and in particular relates to a completely dissociable polyethylene glycol-poly(L-glutamic acid-γ-benzyl ester)-polyethyleneimine copolymer and its synthesis method and application. Background technique [0002] Malignant tumor is one of the main threats to human health, and its treatment is a worldwide problem. Chemotherapy, like surgery and radiotherapy, is currently the mainstay of cancer treatment. Chemotherapy is a method that uses cytotoxic drugs to kill tumor cells for therapeutic purposes. However, cytotoxic drugs, such as doxorubicin, paclitaxel, epirubicin, and docetaxel, are usually poorly water-soluble and non-selective, with low bioavailability, which can cause serious side effects. Moreover, tumor cells are prone to multidrug resistance during chemotherapy, and the curative effect is not ideal. According to the American Cancer Society estimates, more than 90% of cancer patients...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C08G81/00C08G69/48C08G69/40C08G65/48A61K47/48A61K48/00A61P35/00A61K31/704A61K31/337A61K31/4745A61K47/34A61K47/59
Inventor 钱军民徐明辉胥伟军刘茸茸王红洁
Owner XI AN JIAOTONG UNIV
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