Bio-click-triggered high-efficiency targeting conjugate and bio-click-triggered high-efficiency targeting multi-component composition as well as preparation methods and application thereof

A technology of conjugates and compositions, which is applied in the field of high-efficiency targeting conjugates and their multi-component compositions, and can solve the problems of different types and numbers of receptors, inability to be used as therapeutic targets, and limited targeting capabilities , to achieve the effects of reducing the frequency of administration, enhancing sensitivity and intake, and reducing toxic and side effects

Active Publication Date: 2019-04-26
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the traditional active targeting is limited by the number of binding receptors, which will cause saturation and limit its targeting ability.
In addition, the heterogeneity of tumor cells makes the types and numbers of receptors expressed by various subpopulations of tumor cells different, or some target cells may not express this specific receptor due to mutations and other reasons, so they cannot be used as therapeutic targets

Method used

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  • Bio-click-triggered high-efficiency targeting conjugate and bio-click-triggered high-efficiency targeting multi-component composition as well as preparation methods and application thereof
  • Bio-click-triggered high-efficiency targeting conjugate and bio-click-triggered high-efficiency targeting multi-component composition as well as preparation methods and application thereof
  • Bio-click-triggered high-efficiency targeting conjugate and bio-click-triggered high-efficiency targeting multi-component composition as well as preparation methods and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Example 1: Preparation of 5,6-dihydrodibenzo[b,f]azocyne-low molecular weight heparin-quercetin conjugate

[0044] Weigh 1 mmol of low molecular weight heparin and dissolve it in 10 mL of formamide, add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide under ice-bath condition, activate Low molecular weight heparin carboxyl. After activation in ice bath for 0.5 h, add 5 mL of quercetin solution dissolved in formamide (low molecular weight heparin: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride: N-hydroxy Succinimide: the molar ratio of quercetin is successively 1: 4: 4: 2), slowly added dropwise in the low molecular weight heparin solution, after reacting for 24h, adding 5 times the volume of ice methanol for precipitation, suction filtration to obtain the precipitate, Reconstitute with an appropriate amount of distilled water, centrifuge at 3000 rpm for 10 min, ultrafilter, and freeze-dry to obtain a low molecular weight...

Embodiment 2

[0045] Example 2: Preparation of bicyclo[6.1.0]nonyne-unfractionated heparin-chrysin conjugate

[0046]Weigh 1 mmol of unfractionated heparin and dissolve it in 10 mL of N,N-dimethylformamide, and add N,N'-carbonyldiimidazole under ice-cooling conditions to activate the carboxyl group of unfractionated heparin. After activation in ice bath for 1 h, add 5 mL of chrysin solution dissolved in N,N-dimethylformamide (the molar ratio of unfractionated heparin:N,N'-carbonyldiimidazole:chrysin is 1:8:3) , slowly added dropwise to the unfractionated heparin solution, reacted for 48 hours, added 5 times the volume of glacial ether to precipitate, centrifuged to obtain the precipitate, redissolved with an appropriate amount of distilled water, centrifuged at 3000rpm for 10min, dialyzed in distilled water, and dried in vacuum to obtain the unfractionated Heparin-Chrysin Conjugate. Weigh an appropriate amount of unfractionated heparin-chrysin conjugate powder and dissolve it in 10 mL of f...

Embodiment 3

[0047] Example 3: Preparation of bicyclo[6.1.0]nonyne-desulfated heparin-curcumin conjugate

[0048] Weigh 1 mmol of desulfated heparin and dissolve it in 10 mL of N,N-dimethylacetamide, add N,N'-dicyclohexylcarboimide and 4-dimethylaminopyridine under ice-cooling conditions to activate the carboxyl group of desulfated heparin. After activation in ice bath for 2 h, add 5 mL of curcumin solution dissolved in a mixed solvent of formamide and N,N-dimethylacetamide (v:v=1:1) (desulfated heparin: N,N'- Hexylcarbimide: 4-dimethylaminopyridine: the molar ratio of curcumin is 1: 10: 10: 3), slowly added dropwise to the desulfated heparin solution, and after 36 hours of dark reaction, add 5 times the volume of Precipitate with ice methanol, filter with suction to get the precipitate, redissolve with appropriate amount of distilled water, centrifuge at 3000rpm for 10min, ultrafilter, and spray dry to obtain the desulfated heparin-curcumin conjugate. Weigh an appropriate amount of desul...

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Abstract

The invention discloses a bio-click-triggered high-efficiency targeting conjugate and a bio-click-triggered high-efficiency targeting multi-component composition as well as preparation methods and application thereof. The multi-component composition is formed by assembling an anti-angiogenic therapeutic agent, a chemotherapeutic drug and a photosensitizer in the same nano-system; furthermore, thetargeting conjugate (a cycloalkyne-heparin polysaccharide-natural active hydrophobic medicine) is modified with a small molecular target with a cycloalkyne structure, so that in-vivo click targeting is efficiently realized. After nanoparticles are formed in water by means of self-assembly, a chemotherapeutic medicine and a thermotherapy photosensitizer are simultaneously encapsulated in hydrophobic cores of the nanoparticles by using a physical method; therefore, the toxic and side effects on the normal tissues are greatly reduced while the combined administration is realized; the conjugate and the multi-component composition have the characteristics of being intelligent, efficient and low in toxicity, having targeting property, reversing tumor MDR, having a synergistic anti-tumor effect,and the like; a brand-new combined chemotherapy model is created.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical preparations, and relates to a targeted pharmaceutical composition of polymer materials, in particular to a biological click-triggered high-efficiency targeting conjugate and its multi-component composition, preparation method and application. Background technique [0002] Malignant tumors have become one of the thorny diseases that cause human death, and its morbidity and mortality are increasing year by year. Therefore, the treatment of cancer has become a problem that is generally faced and needs to be solved urgently in the world. Currently, tumor treatment methods include surgical resection, chemotherapy and radiotherapy. However, surgical treatment has limitations and trauma; the side effects of radiotherapy will bring great pain to patients; chemotherapy is currently the most commonly used treatment for cancer, but its selectivity is poor, and it is easy to produce multidrug resistan...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/61A61K45/00A61K31/727A61K41/00A61P35/00
CPCA61K41/0071A61K45/00A61K47/61A61P35/00A61K31/727A61K2300/00
Inventor 姚静田烽椿乔佳男
Owner CHINA PHARM UNIV
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