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Tumor-targeted polypeptide-anthracycline derivative

A technology of tumor targeting and derivatives, applied in the direction of antineoplastic drugs, drug combinations, organic active ingredients, etc., can solve the problem of lack of tumor selectivity of anthracyclines, improve curative effect, increase drug concentration, reduce toxicity side effects

Inactive Publication Date: 2017-03-15
SUZHOU INSTITUE OF WUHAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Can solve the problem of lack of tumor selectivity of anthracyclines

Method used

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  • Tumor-targeted polypeptide-anthracycline derivative
  • Tumor-targeted polypeptide-anthracycline derivative
  • Tumor-targeted polypeptide-anthracycline derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] Example 1: Synthesis of N-methacryloylglycylglycine-EBP (Ma-GG-EBP)

[0023] Dissolve 90 mg of glycine (G)-glycine (G) dipeptide into 4 mL of water, add 400 mg of NaOH, add 70 μL of methacryloyl chloride dropwise while stirring at 0°C, adjust the pH to 2.0 with hydrochloric acid after reacting for 1 h, then add 2 mL of N, N-Dimethylformamide (DMF), add 126 mg of dicyclohexylcarbodiimide (DCC) at -15°C, stir for 3 hours, overnight at 4°C, centrifuge, filter to remove dicyclohexylurea crystals, and dry in vacuo To obtain methacryloylglycylglycine p-nitrophenyl ester (Ma-GG-ONp). Another 120 mg of EBP was dissolved in 4 mL of DMF, 30 mg of Ma-GG-ONp and pyridine were added, reacted at room temperature for 22 h, the reaction was terminated with 0.1 N NaOH, dialyzed with deionized water, and freeze-dried to obtain the product methacryloylglycyl Glycyl-EBP (Ma-GG-EBP).

Embodiment 2

[0024] Embodiment 2: the synthesis of DOX-HPMA-EBP

[0025] Dissolve 200 mg of glycine (G)-phenylalanine (F)-leucine (L)-glycine (G) tetrapeptide into 10 mL of dichloromethane, add 5 mg of 4-(1,1,3,3-tetramethyl butyl) catechol and 32mg sodium carbonate, add 110μL methacryloyl chloride dropwise while stirring at 0°C, add 98mg hydrazine hydrate to react for 7h, elute with isopropane three times to remove unreacted hydrazine hydrate, add di Chloromethane / ethyl acetate crystallization to obtain methacryloylglycylphenylalanylleucylglycyl hydrazide (Ma-GFLG-NHNH 2), then add 8 mL of methanol to dissolve at room temperature, add 157 mg of doxorubicin (DOX) in the dark, add 420 μ L of acetic acid dropwise while stirring, react for 30 h, and purify by gel permeation chromatography to obtain the product methacryloylglycyl Phenylalanylleucylglycine doxorubicin (Ma-GFLG-DOX). Take another 148mg of HPMA, 42mg of Ma-GFLG-DOX, 30mg of Ma-GG-EBP and 1mg of azobisisobutyronitrile, add 2mL o...

Embodiment 3

[0026] Embodiment 3: the synthesis of EPI-HPMA-EBP

[0027] Dissolve 200 mg of glycine (G)-phenylalanine (F)-leucine (L)-glycine (G) tetrapeptide into 10 mL of dichloromethane, add 5 mg of 4-(1,1,3,3-tetramethyl butyl) catechol and 32mg sodium carbonate, add 110μL methacryloyl chloride dropwise while stirring at 0°C, add 98mg hydrazine hydrate to react for 7h, elute with isopropane three times to remove unreacted hydrazine hydrate, add di Chloromethane / ethyl acetate crystallization to obtain methacryloylglycylphenylalanylleucylglycyl hydrazide (Ma-GFLG-NHNH 2 ), then add 8 mL of methanol to dissolve at room temperature, add 157 mg of epirubicin (EPI) in the dark, add 420 μL of acetic acid dropwise while stirring, react for 30 h, and purify by gel permeation chromatography to obtain the product methacryloylglycine Acylphenylalanylleucylglycine epirubicin (Ma-GFLG-EPI). Take another 148mg of HPMA, 42mg of Ma-GFLG-EPI, 30mg of Ma-GG-EBP and 1mg of azobisisobutyronitrile, add 2m...

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Abstract

The invention relates to polypeptide-anthracycline drugs with tumor-targeted vectors. A polypeptide-anthracycline derivative is characterized by comprising a targeted vector part, an N-(2-hydroxyl propyl)-methacrylamide polymer and an anthracycline anti-tumor drug part, wherein the anthracycline anti-tumor drug part and the targeted vector part are in covalent bond coupling through the N-(2-hydroxyl propyl)-methacrylamide polymer; the general formula of the derivative is shown as AN-HPMA-EBP, wherein AN refers to the anthracycline anti-tumor drug, HPMA refers to the N-(2-hydroxyl propyl)-methacrylamide polymer, and EBP refers to EGFR combined peptide. The tumor-targeted polypeptide-anthracycline derivative can be combined with a cell EGFR and selectively convey the anthracycline anti-tumor drug to target tissue expressed highly or excessively by the in-vivo cell EGFR to increase the local drug concentration on a focus, improve the treatment effect, reduce toxic and side effects and achieve the purpose of targeted therapy.

Description

technical field [0001] The invention belongs to the technical field of biology and medicine. More specifically, it relates to a coupled compound formed by covalently linking poly-N-(2-hydroxypropyl)methacrylamide with tumor-targeting carrier polypeptide and anthracycline drugs and a preparation method thereof. These covalently coupled compounds can be actively targeted to various tumors with positive expression of epidermal growth factor receptor. Background technique [0002] Doxorubicin (DOX), epirubicin (EPI), pirarubicin (THP), idarubicin (IDA) and mitoxantrone (mitoxantrone, DHAQ) and other anthracycline antineoplastic drugs exert pharmacological effects by inhibiting the synthesis of cellular DNA and RNA. It has become the core drug in various cancer chemotherapy regimens and is widely used all over the world. However, due to the lack of selectivity of anthracyclines to tumors, they often cause non-specific damage to normal tissues, causing toxic side effects such a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/64A61K47/58A61K31/704A61K31/136A61P35/00
CPCA61K31/704A61K31/136
Inventor 艾时斌
Owner SUZHOU INSTITUE OF WUHAN UNIV
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