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Conjugate of 10-hydroxycamptothecine-butanedioic acid and adenovirus, as well as production method and use thereof

A technology of hydroxycamptothecin and adenovirus, which is applied in the direction of medical raw materials derived from viruses/phages, drug combinations, and medical preparations containing active ingredients, etc., can solve problems such as drug resistance and affect effectiveness, and achieve reduction Dosage, improvement of killing effect, and effect of reducing toxic and side effects

Active Publication Date: 2013-11-27
ZHEJIANG SCI-TECH UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Repeated administration of camptothecin derivatives in cancer patients can lead to drug resistance, which also affects their effectiveness

Method used

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  • Conjugate of 10-hydroxycamptothecine-butanedioic acid and adenovirus, as well as production method and use thereof
  • Conjugate of 10-hydroxycamptothecine-butanedioic acid and adenovirus, as well as production method and use thereof
  • Conjugate of 10-hydroxycamptothecine-butanedioic acid and adenovirus, as well as production method and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] The synthesis of embodiment 1, 10-hydroxycamptothecin-succinic anhydride

[0043] After 10-hydroxycamptothecin (200mg, 0.247mmol) was dissolved in anhydrous pyridine (20ml), DMAP (4-dimethylaminopyridine, 123.6mg, 0.594mmol) and succinic anhydride (1180mg, 2.47mmol) were added, 60 Stir at ℃ for 72h. After the reaction product was cooled to room temperature, it was diluted with 20ml of toluene, then evaporated to dryness in a rotary vacuum (condition: 0.1Mpa, 50°C), and repeated once (ie, repeat the dilution with toluene and evaporated to dryness in a rotary vacuum). Add another 50ml of chloroform to the spinner bottle, and wash the organic phase with 20ml of 2% (mass concentration) dilute hydrochloric acid and 20ml of saturated NaCl solution, and repeat once (that is, repeatedly wash the organic phase with 20ml of 2% dilute hydrochloric acid and 20ml of saturated NaCl solution); The phase was dried with anhydrous MgSO4, filtered with suction, and concentrated to consta...

Embodiment 2

[0054] Example 2 HCPT-SA-Ad trail preparation of

[0055] HCPT-SA (15 mg, 0.027 mmol) was dissolved in DMF (N,N-dimethylformamide, 500 μL), and NHS (N-hydroxysuccinimide, 4.6 mg, 0.05 mmol) and EDAC (1-(3 -Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 4.8mg, 0.027mmol) was reacted at room temperature (10~25°C) for 4 hours. Add the reacted solution to about 2mL containing 2×10 10 Ad of pfu trail PBS (10mM, pH 7.4) solution (the molar ratio is HCPT-SA: Ad trail = 10 9 : 1 pmol), at 4 ° C, stirred dark reaction for 12 hours. After the reaction, centrifuge (5000rpm, 30min), take the supernatant, and purify the supernatant by Sephadex G-25. The specific content of the purification is: use Sephadex G-25 gel chromatography, the buffer solution is PBS (10 mM, pH 8.0), the flow rate is 1 ml / min, after equilibrating the chromatography column with 5 column volumes of PBS solution, put on After the sample, continue to add PBS, keep the flow rate at 1 ml / min, detect the ...

Embodiment 3

[0058] Example 3 HCPT and Ad trail Determination of the number of covalently bound molecules of capsid proteins

[0059] Make a standard absorption curve of HCPT monomer, and determine HCPT and Ad by calculating the recovery rate of unreacted HCPT trail The number of covalently bound molecules of amino groups on the capsid protein (n=4), and the number of unbound HCPT molecules were calculated according to the standard curve of the regression equation. In the above experiments, methanol was used as a blank. The amount of HCPT reaction is calculated based on its UV absorption value at 375nm. The standard curve regression equation established based on the UV absorption value of HCPT at 375 nm (methanol solution): Y (OD) = 112.02X (μg / mL) - 1.2959 (R 2 =0.9994), its linear range is 0.0018 ~ 15.18μg / mL, calculate the HCPT content in the eluate. Subtract the HCPT content in the purified column eluate from the amount of HCPT initially participating in the reaction to obtain HCPT...

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Abstract

The invention discloses a conjugate of 10-hydroxycamptothecine-butanedioic acid and adenovirus. The preparation method of the conjugate comprises the following steps of: catalyzing 10-hydroxycamptothecine and succinic anhydride in anhydrous pyridine by virtue of 4-dimethylamino-pyridine so that a hydroxyl on the 10-hydroxycamptothecine reacts with a carboxyl on the succinic anhydride to generate HCPT-SA; reacting the HCPT-SA with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in N,N-dimethyl formamide through N-hydroxysuccinimide, and then adding adenovirus for a dark reaction; then reacting the carboxyl on the HCPT-SA with the amino group of adenovirus capsidprotein to form the conjugate of 10-hydroxycamptothecine-butanedioic acid and adenovirus. The conjugate of 10-hydroxycamptothecine-butanedioic acid and adenovirus provided by the invention is applied to preparation of anti-tumor drugs.

Description

technical field [0001] The invention relates to a combination of 10-hydroxycamptothecin-succinic acid and adenovirus, a preparation method thereof and an antitumor application thereof. Background technique [0002] As a natural alkaloid, camptothecin was first extracted from the trunk of Camptotheca acuminata introduced from China by American chemist Wall et al. in 1966. However, the water solubility of natural camptothecin is extremely poor, so the water-soluble sodium carboxylic acid salt of camptothecin was used in early clinical practice. Unfortunately, the anticancer activity of camptothecin decreased sharply after it was made into carboxylic acid sodium salt, and the activity was only 10-20% of that of camptothecin itself. Studies have shown that the stability of the lactone ring is an important indicator for camptothecin to maintain its activity. At present, irinotecan, topotecan and belotecan have been approved for marketing for clinical treatment. These drugs mainl...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K35/76A61K31/4745A61P35/00A61K35/761
Inventor 徐涛陈文铎
Owner ZHEJIANG SCI-TECH UNIV
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