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Liver target anticancer nano prodrug system based on tree shaped polymer, preparation and use

A polymer and liver-targeted technology, applied in the fields of biomedical technology and nanomedicine, can solve the problems of low selectivity of chemical drugs and radiopharmaceuticals, fast metabolism of small molecule drugs, cytotoxic side effects, etc., to improve clinical efficacy and Bioavailability, overcoming the unsatisfactory clinical treatment effect, enhancing the effect of phagocytosis

Inactive Publication Date: 2008-09-10
EAST CHINA NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Usually, the selectivity of chemical drugs and radiopharmaceuticals is not high, and there are obvious toxic side effects in the treatment
Clinically used antineoplastic drugs are generally small molecule drugs, which are characterized by not only killing cancer cells, but also having relatively large toxic and side effects on normal cells
In addition, small molecule drugs have disadvantages such as fast metabolism and short half-life.

Method used

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  • Liver target anticancer nano prodrug system based on tree shaped polymer, preparation and use
  • Liver target anticancer nano prodrug system based on tree shaped polymer, preparation and use
  • Liver target anticancer nano prodrug system based on tree shaped polymer, preparation and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] 1. Synthesis of HO-PEG-PAMAM:

[0043] 0.1732g (0.0507mmol) of monosubstituted polyethylene glycol amine (HO-PEG-NH 2 ) was dissolved in anhydrous methanol, 0.913ml (10.1mmol) methyl acrylate (MA) was added, reacted in the dark at 25°C for 72 hours, most of the solvent was evaporated by rotary evaporation, and then dissolved in a small amount of methanol, and dissolved in a large amount of anhydrous ether Re-precipitated, centrifuged to separate the precipitate and vacuum-dried to obtain half generation 0.5 generation (G 0.5 ); then G 0.5 Dissolve in anhydrous methanol, add 1.352ml (20.2mmol) ethylenediamine (EDA), react at 25°C for 72 hours, evaporate most of the solvent by rotary evaporation, then dissolve in a small amount of methanol, and reprecipitate in a large amount of anhydrous ether, The precipitate was separated by centrifugation and vacuum-dried to obtain generation 1.0 (G 1.0 ); then the G 1.0 Dissolve in anhydrous methanol, add 3.651ml (40.4mmol) MA, r...

Embodiment 2

[0048] Example 2: NH 2 -PEG-NH 2 Synthesis

[0049] PEG→Cl-PEG-Cl

[0050] Take PEG-1000 (10.3g, 10.3mmol) and dissolve it in toluene (250mL), and use an oil-water separator to azeotropically remove water. Add freshly distilled pyridine (0.83mL, 10.3mmol) and thionyl chloride (7.3mL, 103mmol), and reflux at 75°C for 12h. Cool to room temperature, remove most of the solvent by rotary evaporation, redissolve in dichloromethane, and use Dry the water with potassium carbonate for 12 hours, filter, and then absorb the filtrate with neutral aluminum oxide (20g, activated for 2 hours at 120°C), filter, concentrate the filtrate, precipitate it with ether, dissolve it in dichloromethane, and reprecipitate once with ether , centrifuged, and vacuum-dried.

[0051] Cl-PEG-Cl→N 3 -PEG-N 3

[0052] Dissolve Cl-PEG-Cl (7g, 6.8mmol) in DMF (20mL), add sodium azide (7.7g, 118mmol), and stir at reflux at 70°C for 24h. The reaction solution was cooled to room temperature and then filtere...

Embodiment 3

[0057] Example 3: T-PEG-NH 2 Galactosyl polyethylene glycol amine Gal-PEG-NH whose T targeting group is galactosyl 2 Synthesis

[0058] 1. Mono Boc protected polyethylene glycol diamine (Boc-PEG-NH 2 )Synthesis

[0059] Take 2.0922g (2.0922mmol) NH 2 -PEG-NH 2 Dissolve in 50mL CH 2 Cl 2 , then 0.4812mL (2.0922mmol) di-tert-butyl dicarbonate (Boc anhydride) and 0.6956mL (4.8121mL) triethylamine (Et 3 N) dissolved in 50mL CH 2 Cl 2 Add the above NH dropwise under nitrogen protection at 30°C 2 -PEG-NH 2 Solution, after 48 hours of reaction, rotary evaporation removed most of the solvent, and then dissolved in a small amount of CH 2 Cl 2 and reprecipitated in ether, centrifuged and vacuum-dried the solid, and then separated and purified by silica gel column chromatography, the eluent was CHCl 3 / CH 3 OH, the ratio is 16 / 1. The product was dried in vacuo after most of the solvent was removed by rotary evaporation.

[0060] 2 Galactosyl polyethylene glycol amine (Gal...

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Abstract

The invention relates to a liver targeting anticancer nanometer prodrug system basing on dendritic polymer, provides a method for preparing the prodrug system and the uses thereof and belongs to the technical field of biological medicine as well as the technical field of nano medicine. With the polyethylene glycol modified PAMAM treelike polymer of distal liver targeting group (T) as a carrier (T-PEG-PAMAM) and Doxorubicin (DOX) as treatment drug, the invention obtains the prodrug (T-PEG-PAMAM-DOX) through the covalent bond connection with degradable lysosome between the carrier and the Doxorubicin. The invention further provides the application of the liver targeting anticancer nanometer prodrug system basing on the dendritic polymer in the preparation of drugs for treating solid tumors. With the long-acting cycle in blood, the liver targeting anticancer nanometer prodrug system basing on the dendritic polymer can enhance the phagocytosis of hepatoma cells on polymers nano-micelles, realize the active and passive targeting on liver tumor tissues, improve the clinical efficacy and the bioavailability of present liver cancer therapeutic drugs and lower toxic and side effects.

Description

technical field [0001] The invention relates to a liver-targeting anti-cancer nanometer prodrug system based on a tree polymer, provides a preparation method and application of the prodrug system, and belongs to the technical fields of biomedicine technology and nanometer medicine. Background technique [0002] Tumor is one of the most serious diseases that affect human health and even life after cardiovascular disease. The mortality rate of patients with malignant tumors has always been high, especially liver cancer. Drug therapy is currently one of the main treatments for cancer patients. Usually, the selectivity of chemical drugs and radiopharmaceuticals is not high, and there are obvious toxic side effects in the treatment. Clinically used antineoplastic drugs are generally small molecule drugs, which are characterized by not only killing cancer cells, but also having relatively large toxic and side effects on normal cells. In addition, small molecule drugs have disadv...

Claims

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Application Information

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IPC IPC(8): A61K47/48A61K31/704A61P1/16A61P35/00A61K47/59
Inventor 余家会高峰刘顺英罗淑芳黄进
Owner EAST CHINA NORMAL UNIV
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