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Preparation method and application of multi-stage liver-targeted intelligent nano drug delivery system

A nano-drug delivery system and technology of active targeting groups, which can be used in pharmaceutical formulations, preparations for in vivo tests, and medical preparations with inactive ingredients, etc. problems such as poor liver targeting, to achieve the effect of promoting selective recognition into cells, good biocompatibility, and reducing side effects

Inactive Publication Date: 2017-02-15
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The main reason why this stubborn fortress has not been conquered is that besides the unsatisfactory pharmacological effect of the therapeutic drug itself, the drug is not effectively delivered to the lesion of the liver, that is, the liver targeting of the drug is poor.

Method used

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  • Preparation method and application of multi-stage liver-targeted intelligent nano drug delivery system
  • Preparation method and application of multi-stage liver-targeted intelligent nano drug delivery system
  • Preparation method and application of multi-stage liver-targeted intelligent nano drug delivery system

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] Example 1: Preparation of a multi-stage liver-targeted reduction-sensitive nano-drug delivery system

[0062] In this example, the multi-stage liver-targeted reduction-sensitive nano-drug delivery system is prepared through the following steps.

[0063] Propargylamine (1g), Boc-L-Lys(Boc)-OH (6.92g), HBTU (3.82g) and HOBT (2.70g) were added to the reaction flask and dissolved in 52mL of redistilled dichloromethane, under nitrogen Under the protection, 12mL of DIEA was added and reacted at room temperature for 48h, rotary-evaporated, diluted by adding chloroform, and then sequentially washed with saturated NaHCO 3 solution, washed with HCl (1M) and saturated NaCl solution, anhydrous MgSO 4 After drying overnight, compound a was separated by means of a column.

[0064] Under nitrogen protection, compound a (4.5 g, 24.5 mmol) was dissolved in 18 mL of CH 2 Cl 2 Then, 18 mL of TFA was added, reacted at room temperature for 5 h, and then rotary-evaporated, ether was prec...

Embodiment 2

[0074] Example 2: Preparation of a multi-stage liver-targeted pH-sensitive nano-drug delivery system

[0075] In this example, the multi-stage liver-targeted pH-sensitive nano-drug delivery system is prepared through the following steps.

[0076] H-Lys-OMe·2HCl (2.5g), Boc-L-Lys(Boc)-OH (12.81g), HBTU7.0g) and HOBT (5.0g) were added to the reaction flask with 80mL of redistilled dichloride. Methane was dissolved, under nitrogen protection, 10.2 mL of DIEA was added, reacted at room temperature for 48 h, rotary-evaporated, diluted by adding chloroform, and then saturated NaHCO was successively added. 3 solution, washed with HCl (1M) and saturated NaCl solution, anhydrous MgSO 4 After drying overnight, it was purified by column separation to give compound 1.

[0077] Under nitrogen protection, the above product compound 1 (1.82 g, 2 mmol) was dissolved in 6 mL of CH 2 Cl 2 , and then 7 mL of trifluoroacetic acid (TFA) was added, and after reacting at room temperature for 7 h...

Embodiment 3

[0090] Example 3: Preparation of a multi-stage liver-targeting MMP enzyme-sensitive nano-drug delivery system

[0091] In this example, the multi-stage liver-targeting MMP enzyme-sensitive nano-drug delivery system is prepared through the following steps.

[0092] H-Lys-OMe·2HCl (2.5g), Boc-L-Lys(Boc)-OH (12.81g), HBTU (7.0g) and HOBT (5.0g) were added to the reaction flask and 80mL of redistilled Chloromethane was dissolved, and under nitrogen protection, 10.2 mL of DIPEA was added, and the reaction was carried out at room temperature for 48 h, rotary-evaporated, diluted by adding chloroform, and then sequentially washed with saturated NaHCO 3 solution, washed with HCl (1M) and saturated NaCl solution, anhydrous MgSO 4 After drying overnight, it was purified by column separation to give compound 1.

[0093] Under nitrogen protection, the above product compound 1 (1.82 g, 2 mmol) was dissolved in 6 mL of CH 2 Cl 2 , and then 7 mL of trifluoroacetic acid (TFA) was added, an...

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Abstract

The invention discloses a multi-stage liver-targeted intelligent nano drug delivery system, and belongs to the field of biological materials. The nano drug delivery system comprises hydrophobic dendrimers, hydrophilic natural macromolecular polysaccharides, active targeting groups and hydrophobic drug molecules. According to the nano drug delivery system provided by the invention, the hydrophobic dendrimers are linked to the hydrophilic natural macromolecular polysaccharides by virtue of environment-responsive chemical bonds, so that amphipathic molecules are formed; then, hydrophobic drugs are encapsulated in hydrophobic cavities of nanoparticles formed by the amphipathic molecules under hydrophilic and hydrophobic actions as well as a [pi]-[pi] stacking action; and the active targeting groups, which have a tumor specific recognition function, are linked to the natural macromolecular polysaccharides by virtue of stable covalent bonds. According to the drug delivery system, intelligent nanoparticles having an environment-responsive performance can be formed through self-assembling; the drug delivery system is good in biocompatibility and biodegradability, multi-stage liver targeting can be achieved, and the drug delivery system is applicable to delivery of such hydrophobic molecules as antineoplastic drugs, fluorescent molecules, photosensitizers and the like.

Description

technical field [0001] The invention belongs to the field of biological materials, and in particular relates to a preparation method and application of a multi-stage liver targeting intelligent nano drug delivery system. [0002] technical background [0003] Cancer is a major cause of death in the world today. According to the World Health Organization, about 840 million people died of cancer between 2005 and 2015. The three main treatments for cancer include chemotherapy, radiotherapy, and surgery. Among them, chemotherapy has led to the failure of cancer treatment due to poor water solubility of therapeutic drugs, narrow therapeutic window and toxic side effects on normal tissues. Our nano-delivery system has unique conditions to solve the above problems, but how to realize the specific recognition of tumor tissue by the delivery system and the accurate release of drugs in tumor cells, and reduce the toxic and side effects to normal tissues, still needs to be solve. ...

Claims

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Application Information

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IPC IPC(8): A61K9/51A61K47/36A61K47/12A61K47/42A61K49/00A61P35/00C08B37/00A61K31/704
CPCA61K9/5161A61K31/704A61K49/0054A61K49/0093C08B37/0018
Inventor 顾忠伟何一燕周洁马胜男姜倩岳冬
Owner SICHUAN UNIV
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