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ph-sensitive polymeric micelle composition resisting tumor drug resistance

An anti-tumor drug and polymer glue technology, which is applied in the field of anti-tumor drug-resistant pH-sensitive polymer micelle composition, can solve problems such as drug resistance and insufficient drug accumulation, and achieve the effect of achieving effectiveness and safety

Inactive Publication Date: 2014-10-29
PEKING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The purpose of the present invention is to overcome the problems of drug resistance of tumor cells, premature drug release of conventional polymer micelles, and insufficient drug concentration or drug accumulation at the tumor site

Method used

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  • ph-sensitive polymeric micelle composition resisting tumor drug resistance
  • ph-sensitive polymeric micelle composition resisting tumor drug resistance
  • ph-sensitive polymeric micelle composition resisting tumor drug resistance

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Example 1 Synthesis of PEOz2000-VES

[0029] Methyl p-toluenesulfonate (150 mg) and 2-ethyl-2-oxazoline (5 g) were dissolved in acetonitrile (80 mL), and heated and stirred at reflux for 12 h under a nitrogen atmosphere. After cooling to room temperature, use NH 3 As a terminator, cold ether is precipitated and refined and dried in vacuum to prepare PEOz (PEOz-NH) with amino end groups and a molecular weight of 2000 2 ). Take appropriate amount of VES, EDC and NHS, and react in dichloromethane for 2 hours to obtain the active ester of VES (VES-NHS). Then add PEOz-NH in an appropriate molar ratio 2 , Using TEA as a catalyst, after 4 hours of reaction, precipitation and purification with cold ether, and vacuum drying to obtain the PEOz2000-VES of the present invention.

Embodiment 2

[0030] Example 2 Synthesis of poly(2-ethyl-2-oxazoline)-polylactic acid-poly(2-ethyl-2-oxazoline) (PEOz5000-PLA3000-PEOz5000)

[0031] In a three-necked flask equipped with a stirrer, add 2-ethyl-2-oxazoline (10g, 150mmol), acetonitrile (40mL), and methyl p-toluenesulfonate (0.47g) at an oil bath temperature of 80°C. Under nitrogen atmosphere, the reaction was stirred for 30h. After cooling, the methanol solution of KOH was added, and the reaction was continued for 4 hours. The solvent was removed, the residue was dissolved in THF, passed through a silica gel column, and the effluent was poured into excess cold ether for precipitation, suction filtration, and vacuum drying for 12 hours. The obtained PEOz-OH powder (4g) was dissolved in chlorobenzene (80mL), D,L-lactide (6.3g) and stannous octoate (0.63g) were added under nitrogen atmosphere, and reacted at 140°C for 24h. The reaction solution was poured into excess ether for precipitation, filtered, and vacuum dried at room tem...

Embodiment 3

[0032] Example 3 Synthesis of polylactic acid-poly(2-ethyl-2-oxazoline)-polylactic acid (PLA2000-PEOz8000-PLA2000)

[0033] 2-Ethyl-2-oxazoline (9.9 g) and 1,4-dibromo-2-butene (420 mg) were dissolved in acetone (40 mL), and stirred and refluxed at 100° C. for 20 h under a nitrogen atmosphere. After cooling to room temperature, 0.1 mol / L KOH methanol solution (40 mL) was added to the reaction flask, and the reaction was continued for 4 hours. After passing through a silica gel column, the effluent is poured into excess cold ether for precipitation, suction filtration, and vacuum drying for 24 hours. The obtained HO-PEOz-OH powder (2g) was dissolved in chlorobenzene (20mL), D, L-lactide (0.58g) and stannous octoate (30mg) were added under nitrogen atmosphere, and reacted at 140℃ for 24h . The reaction solution was poured into excess ether for precipitation, filtered, and vacuum dried at room temperature for 12 hours to obtain the triblock copolymer PLA2000-PEOz8000-PLA2000 of th...

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Abstract

The invention belongs to the field of medicinal preparations, relates to a pH-sensitive polymeric micelle composition resisting tumor drug resistance, and especially relates to a pH-sensitive polymeric micelle composition resisting tumor drug resistance and encapsulating a poorly-soluble anti-tumor medicine. The pH-sensitive polymeric micelle composition resisting tumor drug resistance is constructed by employing two kinds of biologically-compactable pH-sensitive amphiphilic block polymer and an amphiphilic polymer D-alpha-tocopherol polyethyleneglycol succinate (TPGS) as a P-gp inhibitor in a certain ratio, and encapsulates a poorly-soluble anti-tumor medicine. Experiments prove that the polymeric micelle composition has pH-dependent release characteristic, is accumulated in tumor tissue in a high concentration, has specifically targeting inhibiting effect on growth of tumor cells generating drug resistance because of over expression of P-glycoprotein, and provides a novel carrier and preparation strategy for poorly-soluble anti-tumor medicines and reversing of drug resistance of tumor cells.

Description

Technical field [0001] The invention belongs to the field of pharmaceutical preparations, and relates to an anti-tumor drug-resistant pH-sensitive polymer micelle composition, especially an anti-tumor drug-resistant pH-sensitive polymer micelle composition containing poorly soluble anti-tumor drugs. Background technique [0002] At present, most commonly used chemotherapeutics for the treatment of tumors are hydrophobic drugs, and their solubility in water is very low. It is difficult to prepare suitable preparations. Various methods are often used to increase their solubility, such as making them into salts, adding cosolvents and Solubilization by low-molecular-weight surfactants. Because surfactants are readily available, low-molecular-weight surfactants are often the first choice for clinical use. However, the blood stability of this dosage form is very poor, the toxic and side effects of auxiliary materials such as low-molecular surfactants are also great, and the release be...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/107A61K45/00A61K47/34A61P35/00
Inventor 刘艳张超李馨儒周艳霞
Owner PEKING UNIV
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