Amphiphilic polysaccharide-anti-tumor medicament conjugate capable of releasing medicines specifically at lesion site of living body, as well as preparation method and application of medicinal composition of amphiphilic polysaccharide-anti-tumor medicament conjugate

A technology of anti-tumor drugs and amphiphilic polysaccharides, which is applied in the direction of anti-tumor drugs, drug combinations, medical preparations of non-active ingredients, etc. It can solve the problems of slow shedding of hydrophobic anti-tumor drugs, harsh synthesis conditions, and single mechanism of action. question

Inactive Publication Date: 2013-09-18
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Some polysaccharide-antineoplastic drug conjugates are currently in the research stage, but these conjugates still have obvious disadvantages: the synthesis conditions are relatively harsh; the bridging groups connecting the drug and the polymer are mostly amide bonds or ester bonds, The high stability of these two chemical bonds in the body makes the hydrophobic anti-tumor drug fall off very slowly, which leads to the inability to release the drug in time after reaching the drug effect site, resulting in insuf

Method used

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  • Amphiphilic polysaccharide-anti-tumor medicament conjugate capable of releasing medicines specifically at lesion site of living body, as well as preparation method and application of medicinal composition of amphiphilic polysaccharide-anti-tumor medicament conjugate
  • Amphiphilic polysaccharide-anti-tumor medicament conjugate capable of releasing medicines specifically at lesion site of living body, as well as preparation method and application of medicinal composition of amphiphilic polysaccharide-anti-tumor medicament conjugate
  • Amphiphilic polysaccharide-anti-tumor medicament conjugate capable of releasing medicines specifically at lesion site of living body, as well as preparation method and application of medicinal composition of amphiphilic polysaccharide-anti-tumor medicament conjugate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0112] Example 1: Preparation of hyaluronic acid-cystamine-paclitaxel conjugate

[0113] 0.1 mmol of hyaluronic acid, 1 mmol of cystamine, 0.2 mmol of EDC and 0.2 mmol of NHS were dissolved in formamide, reacted for 24 hours, precipitated with excess acetone, and filtered with suction. Add water to redissolve the precipitate, dialyze with distilled water for 3 days (MWCO=3500), and freeze-dry to obtain the hyaluronic acid intermediate with free one-terminal amino group.

[0114] Dissolve 0.4mmol paclitaxel in pyridine, add 0.4mmol succinic anhydride, and stir at room temperature for 4h. Pyridine was removed by rotary evaporation and dried in vacuo. Add an appropriate amount of double-distilled water, stir for 30 minutes, collect the precipitate by filtration, dissolve the precipitate in an appropriate amount of acetone, slowly add double-distilled water, collect the crystals, and dry in vacuum to obtain a carboxyl-containing 2'-succinyl paclitaxel derivative.

[0115] 0.025m...

Embodiment 2

[0116] Embodiment 2: preparation of chitosan-3,3'-dithiodipropionic acid-paclitaxel conjugate

[0117] Dissolve 0.1mmol chitosan in a mixed solvent of water and methanol (v / v=1:1), add 1mmol 3,3'-dithiodipropionic acid, 0.1mmol EDC and 0.1mmol HOBt, react for 8h, remove by rotary evaporation Methanol and distilled water were dialyzed for 3 days (MWCO=3500) to obtain a chitosan intermediate with a free carboxyl group at one end.

[0118] 0.025mmol paclitaxel, 0.1mmol chitosan intermediate, 0.025mmol EDC and a small amount of DMAP were dissolved in a mixed solvent of water and methanol (v / v=1:3), and reacted for 48h. Methanol was removed by rotary evaporation, dialyzed in distilled water for 3 days (MWCO=3500), and freeze-dried to obtain the chitosan-3,3'-dithiodipropionic acid-paclitaxel conjugate carrier.

Embodiment 3

[0119] Embodiment 3: Preparation of chondroitin sulfate-cystamine-gambogic acid conjugate

[0120] 0.1mmol of chondroitin sulfate, 2mmol of cystamine, 0.4mmol of EDC and 0.4mmol of NHS were dissolved in formamide, reacted for 12h, precipitated with excess acetone, and filtered with suction. Add water to redissolve the precipitate, dialyze with distilled water for 3 days (MWCO=3500), and freeze-dry to obtain the chondroitin sulfate intermediate with free one-terminal amino group.

[0121] 0.5mmol gambogic acid, 0.6mmol DCC, and 0.6mmol NHS were dissolved in N,N-dimethylformamide, reacted in ice bath for 30min, and then raised to room temperature for 48h. After the reaction, the precipitate was filtered off, and the gambogic acid-NHS activated ester was purified by silica gel column chromatography using dichloromethane and methanol (v / v=1:1) as the eluent.

[0122] Dissolve 0.4mmol gambogic acid-NHS activated ester and 0.1mmol chondroitin sulfate intermediate in formamide, and ...

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Abstract

The invention relates an amphiphilic polysaccharide-anti-tumor medicament conjugate capable of releasing medicines specifically at a lesion site of a living body, as well as a preparation method and application of a medicinal composition of the amphiphilic polysaccharide-anti-tumor medicament conjugate. In the conjugates, hydrophobic anti-tumor medicaments are introduced into a polysaccharide skeleton through a connecting arm which contains a disulfide bond, so that the polysaccharide-anti-tumor medicament conjugate has amphipathic characteristics and can be self-assembled into nano-micelles; the nano-micelles can load anti-tumor medicaments additionally and also can be directly used as conjugate pre-drug micelles. The amphiphilic polysaccharide-anti-tumor medicament conjugate is mainly characterized in that 1) after the nano-micelles reach the lesion site, the disulfide bond connecting arm of the conjugate can be specifically degraded by high-concentration reducing substances in lesion cells, so that the micelles are depolymerized and the medicament is released quickly, and therefore, the treatment effect is improved; 2) the anti-tumor medicament is chemically conjugated and physically coated to achieve a common treatment effect. The polysaccharide conjugate and the medicinal composition thereof can be used for injection, oral administration or external use administration; the anti-tumor activity can be improved remarkably; new ideas are provided for the development of anti-tumor medicaments.

Description

technical field [0001] The invention belongs to the field of pharmaceutical preparations, and relates to an amphiphilic polysaccharide-antitumor drug conjugate that releases drugs specifically at the lesion site of a biological body as a drug carrier, and also relates to a preparation method and application of the conjugate carrier. Background technique [0002] Cancer is one of the major diseases threatening human health. According to a survey report published by the World Health Organization on February 1, 2013, the number of people who died of cancer in the world in 2008 reached 7.6 million, and there were about 13 million new cancer patients every year, and the trend was increasing year by year. [0003] Antineoplastic drugs are one of the main methods of clinical treatment at present. However, most of the existing antineoplastic drugs are insoluble water-soluble small molecular compounds, which have poor oral absorption, low bioavailability, and rapid metabolism in the ...

Claims

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Application Information

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IPC IPC(8): A61K47/48A61K45/00A61K9/10A61P35/00
Inventor 周建平霍美蓉王竞张栩源王磊殷婷婕
Owner CHINA PHARM UNIV
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