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Tumor-targeting pH-sensitive polymeric micelle composition resisting tumor drug resistance

An anti-tumor drug and polymer glue technology is applied in the field of anti-tumor drug-resistant pH-sensitive targeted polymer micelle compositions, which can solve problems such as insufficient drug accumulation and drug resistance.

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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  • Tumor-targeting pH-sensitive polymeric micelle composition resisting tumor drug resistance
  • Tumor-targeting pH-sensitive polymeric micelle composition resisting tumor drug resistance
  • Tumor-targeting pH-sensitive polymeric micelle composition resisting tumor drug resistance

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Example 1 Synthesis of poly(2-ethyl-2-oxazoline)-polylactic acid (PEOz5700-PLA2000)

[0045] In a three-necked flask equipped with a stirrer, 2-ethyl-2-oxazoline (10g, 150mmol), acetonitrile (40mL), methyl p-toluenesulfonate (0.47g) were added, and at an oil bath temperature of 80°C Under a nitrogen atmosphere, the reaction was stirred for 30 h. After cooling, after adding KOH in methanol solution, the reaction was continued for 4h. The solvent was removed, the residue was dissolved in THF, passed through a silica gel column, the effluent was poured into excess cold ether for precipitation, suction filtered, and vacuum-dried for 12 hours. The lactide was recrystallized three times with ethyl acetate, dried under vacuum at room temperature, and its melting point was determined to be 127°C. Put the obtained PEOz-OH powder into a 100mL round-bottomed flask, add about 70ml of toluene, use a water separator to azeotropically remove water, and stop heating after the volatil...

Embodiment 2

[0046] Example 2 Synthesis of poly(2-ethyl-2-oxazoline)-polylactic acid-poly(2-ethyl-2-oxazoline) (PEOz5000-PLA3000-PEOz5000)

[0047] In a three-necked flask equipped with a stirrer, 2-ethyl-2-oxazoline (10g, 150mmol), acetonitrile (40mL), methyl p-toluenesulfonate (0.47g) were added, and at an oil bath temperature of 80°C Under a nitrogen atmosphere, the reaction was stirred for 30 h. After cooling, after adding KOH in methanol solution, the reaction was continued for 4h. The solvent was removed, the residue was dissolved in THF, passed through a silica gel column, the effluent was poured into excess cold ether for precipitation, suction filtered, and vacuum-dried 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 a nitrogen atmosphere, and reacted at 140°C for 24h. The reaction solution was poured into excess diethyl ether for precipitation, filtered, and vacuum-dried at r...

Embodiment 3

[0048] Example 3 Synthesis of polylactic acid-poly(2-ethyl-2-oxazoline)-polylactic acid (PLA2000-PEOz8000-PLA2000)

[0049] 2-Ethyl-2-oxazoline (9.9g) and 1,4-dibromo-2-butene (420mg) were dissolved in acetone (40mL), stirred and refluxed at 100°C for 20h under nitrogen atmosphere. After cooling to room temperature, 0.1 mol / L KOH in methanol solution (40 mL) was added to the reaction flask, and the reaction was continued for 4 h. After passing through a silica gel column, the effluent was poured into excess cold diethyl ether for precipitation, suction filtered, and vacuum-dried for 24 hours. Dissolve the obtained HO-PEOz-OH powder (2g) in chlorobenzene (20mL), add D,L-lactide (0.58g) and stannous octoate (30mg) under a nitrogen atmosphere, and react at 140°C for 24h . The reaction solution was poured into excess diethyl ether to precipitate, filtered, and vacuum-dried at room temperature for 12 hours to obtain the triblock copolymer PLA2000-PEOz8000-PLA2000 of the present i...

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Abstract

The invention belongs to the field of medicinal preparations, relates to a tumor-targeting pH-sensitive polymeric micelle composition resisting tumor drug resistance, and especially relates to a tumor-targeting pH-sensitive polymeric micelle composition resisting tumor drug resistance and encapsulating a poorly-soluble anti-tumor medicine. The tumor-targeting pH-sensitive polymeric micelle composition resisting tumor drug resistance is constructed by employing a biologically-compatible pH-sensitive amphiphilic, an amphiphilic polymer connected with a targeting ligand or an antibody and D-alpha-tocopherol polyethyleneglycol succinate (TPGS) 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 a tumor-targeting anti-tumor drug-resistant pH-sensitive polymer micelle composition, especially an anti-tumor drug-resistant pH-sensitive targeting polymer micelle composition loaded with insoluble anti-tumor drugs thing. Background technique [0002] At present, most of the commonly used chemotherapeutic drugs for clinical treatment of tumors are hydrophobic drugs. Their solubility in water is very low, and it is difficult to prepare suitable preparations. Various methods are often used to increase their solubility, such as making them into salts, adding co-solvents and Solubilization by low-molecular-weight surfactants, etc. Due to the easy availability of surfactants, solubilization with low-molecular surfactants is often the first choice for clinical use. However, the blood stability of this dosage form is very poor, and the toxic and side effects of auxiliary mate...

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 刘艳赵勇李馨儒周艳霞
Owner PEKING UNIV
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