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A kind of tumor targeting thermosensitive prodrug and its preparation method and application

A tumor-targeted, anti-tumor drug technology, applied in the field of biomedicine, can solve problems such as intractability and stability, and achieve the effects of reducing toxic side effects, increasing concentration, and overcoming insoluble in water

Active Publication Date: 2019-08-23
NAT INST OF ADVANCED MEDICAL DEVICES SHENZHEN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Many chemotherapeutic drugs widely used at present have the disadvantages of being insoluble in water and having poor stability in water, and while the chemotherapeutic drugs inhibit and kill tumor cells, they also have a killing effect on normal cells, especially normal cells that proliferate rapidly. , such as bone marrow hematopoietic cells and gastrointestinal mucosal epithelial cells, etc.

Method used

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  • A kind of tumor targeting thermosensitive prodrug and its preparation method and application
  • A kind of tumor targeting thermosensitive prodrug and its preparation method and application
  • A kind of tumor targeting thermosensitive prodrug and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] (1) Accurately weigh 0.00028g (0.001mmol) 4,4'-azobis(4-cyanovaleric acid), dissolve it in 0.1mL dimethyl sulfoxide, then add 0.00012g (0.001mmol) NHS React with 0.00019g (0.001mmol) EDC and 1μL pyridine at room temperature for 0.5h under nitrogen protection.

[0056] (2) Add 0.00054 g (0.001 mmol) of doxorubicin hydrochloride to the above reaction solution, and react for 0.5 h at room temperature under nitrogen protection (the carboxyl group at one end of 4,4'-azobis(4-cyanovaleric acid) and Amino reaction of doxorubicin hydrochloride).

[0057] (3) The product was purified by silica gel column chromatography and dried in vacuum.

[0058] (4) Dissolve the dried product in step (3) in 0.1 mL dimethyl sulfoxide, then add 0.00012 g (0.001 mmol) NHS, 0.00019 g (0.001 mmol) EDC and 1 μL pyridine, and react at room temperature for 0.5 h under nitrogen protection get a mixed solution.

[0059] (5) Dissolve 0.0067g of human serum albumin in 1mL of PBS, add the above mixed s...

Embodiment 2

[0062] (1) Accurately weigh 2.8g (10mmol) 4,4'-azobis(4-cyanovaleric acid), dissolve it in 100mL dimethyl sulfoxide, then add 1.2g (10mmol) NHS and 1.9g (10 mmol) EDC and 200 μL pyridine, reacted at room temperature for 48 h under nitrogen protection.

[0063] (2) Add 5.4g (10mmol) doxorubicin hydrochloride to the above reaction solution, and react for 48h at room temperature under the protection of nitrogen (4,4'- azobis(4-cyanovaleric acid) at one end of the carboxyl group and doxorubicin hydrochloride aminomycin reaction).

[0064] (3) The product was purified by silica gel column chromatography and dried in vacuum.

[0065] (4) Dissolve the dried product in step (3) in 100 mL of dimethyl sulfoxide, then add 1.2 g (10 mmol) of NHS, 1.9 g (10 mmol) of EDC and 200 μL of pyridine, and react at room temperature for 48 h under nitrogen protection to obtain a mixed solution.

[0066] (5) Dissolve 0.67g of human serum albumin in 1000mL of PBS, add the above mixed solution to it,...

Embodiment 3

[0069] (1) Accurately weigh 0.28g (1mmol) 4,4'-azobis(4-cyanovaleric acid), dissolve it in 100mL dimethyl sulfoxide, then add 0.24g (2mmol) NHS and 0.19g (1 mmol) EDC and 20 μL pyridine were reacted at room temperature for 24 h under nitrogen protection.

[0070] (2) Add 0.54g (1mmol) doxorubicin hydrochloride to the appealing reaction solution, and react for 24 hours at room temperature under the protection of nitrogen (4,4'-azobis(4-cyanovaleric acid) at one end of the carboxyl group and doxorubicin hydrochloride aminomycin reaction).

[0071] (3) The product was purified by silica gel column chromatography and dried in vacuum.

[0072] (4) Dissolve the product in 100 mL dimethyl sulfoxide, add 0.12 g (1 mmol) NHS, 0.19 g (1 mmol) EDC and 20 μL pyridine, and react at room temperature for 24 h under nitrogen protection to obtain a mixed solution.

[0073] (5) 6.7g of human serum albumin was dissolved in 100mL of PBS, and the above mixed solution was added thereto, and the r...

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Abstract

The invention provides a tumor targeting thermosensitive prodrug, and a preparation method and an application thereof. The prodrug is expressed by the formula X-(Y-Z)n, wherein X is albumin; Z is amino-containing antitumor drug; Y is biodegradable albumin-drug spacer containing two or more than two carboxyls; Y contains an azo group; amino in X is bonded with carboxyl in Y through an amido bond; amino in Y is bonded with another carboxyl in Y through the amido bond; n is the number between 0.05 to 15. The prodrug is applied to the field of thermo-chemotherapy; the prodrug is a thermal response prodrug; the albumin-drug bonded compound can be released at a fixed point of the tumor part through the thermal response mechanism; the concentration of cytoplasm and cell nucleus on the drug acting part can be greatly increased; the drug-fast property of the tumor can be overcome; the toxic and side effects of the chemotherapy can be reduced.

Description

technical field [0001] The invention relates to a tumor-targeting heat-sensitive prodrug and its preparation method and application, belonging to the technical field of biomedicine. Background technique [0002] Cancer seriously endangers human life and health, and is considered to be the main cause of death after cardiovascular and cerebrovascular diseases (China Cancer, 2009, 18, 88-89). In China, cancer has become the number one cause of death, and the morbidity and mortality are still rising. Cancer has become a very important public health problem. Due to the difficulty of early detection, its treatment has always been a difficult point in the medical field. Many chemotherapeutic drugs widely used at present have the disadvantages of being insoluble in water and having poor stability in water, and while the chemotherapeutic drugs inhibit and kill tumor cells, they also have a killing effect on normal cells, especially normal cells that proliferate rapidly. , such as b...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K47/64A61K31/704A61P35/00
CPCA61K31/704
Inventor 郑海荣胡德红盛宗海
Owner NAT INST OF ADVANCED MEDICAL DEVICES SHENZHEN