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Gambogic acid-folic acid-HPMA high-molecular polymer as well as preparation method and application thereof

A technology of high molecular polymer and high molecular copolymer, which is applied in the field of gambogic acid-folic acid-HPMA polymer copolymer and its preparation, can solve problems such as unreported, and achieves increased solubility, extended stability and reduced damage effect

Active Publication Date: 2018-08-03
LIAONING UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] So far, there have been no reports at home and abroad about the connection of gambogic acid drugs with HPMA polymers and the targeting molecule folic acid

Method used

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  • Gambogic acid-folic acid-HPMA high-molecular polymer as well as preparation method and application thereof
  • Gambogic acid-folic acid-HPMA high-molecular polymer as well as preparation method and application thereof
  • Gambogic acid-folic acid-HPMA high-molecular polymer as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Example 1 A kind of gambogic acid-folic acid-HPMA polymer copolymer

[0029] Its structure is as follows:

[0030]

[0031] In the formula, x=10-20 mol%, y=80-90 mol%, Mn=24994, Mw / Mn=1.056.

[0032] The preparation method of the compound is as follows:

[0033] First, gambogic acid is used as a raw material to prepare gambogic acid oxamide monomer; folic acid is used as a raw material to prepare folic acid amide monomer; then gambogic acid oxamide monomer is reacted with folic acid amide monomer to prepare folic acid- Gambogic acid monomer; Finally, the folic acid-gambogic acid monomer is condensed with HPMA to form the gambogic acid-folic acid-HPMA polymer copolymer. The reaction formula is as follows:

[0034]

[0035] 1) Using gambogic acid as raw material to prepare gambogic acid oxamide monomer, the specific operation is as follows:

[0036]

[0037] Under the protection of nitrogen, dissolve gambogic acid 3.60g (5.7mmol), EDCI 2.21g (11.6mmol), DMAP 1.41g (11.6mmol) and H...

Embodiment 2

[0056] Example 2 A tissue distribution test of gambogic acid-folate-HPMA polymer copolymer

[0057] Taking the gambogic acid-folic acid-HPMA polymer copolymer prepared in Example 1 as the test sample, the targeted study as shown in the following tissue distribution test is shown.

[0058] Twenty-seven male SPF-grade Kunming mice weighing 20±2g were randomly divided into three groups, 9 mice in each group, namely GA (homemade 2% Tween 80 dissolved gambogic acid solution, 0.5 mg / mL) group, HPMA-FA-GA polymer group (HPMA-FA-GA polymer prodrug micellar solution, 3.6 mg / mL), fasted for 24 hours before the experiment, and had free drinking water. The dosage for intragastric administration is 4.0 mg / kg. Each group presets 3 time points, each time point 3 parallel. The mice were sacrificed by neck removal at 2h, 4h, and 6h after administration. The liver, spleen, lung, and kidney tissues were quickly dissected and removed. The residual blood was washed with normal saline. The surface wat...

Embodiment 3

[0065] Example 3 Pharmacokinetic test of a kind of gambogic acid-folate-HPMA polymer copolymer

[0066] Twenty-four male SPF-grade Kunming mice weighing 20±2g were randomly divided into three groups, 8 in each group, namely GA (homemade 2% Tween 80 dissolved gambogic acid solution, 0.5 mg / mL) group, HPMA-FA-GA polymer group (home-made HPMA-FA-GA polymer prodrug micellar solution, 3.6 mg / mL), fasted for 24 hours before the experiment, and had free drinking water. The dosage for intragastric administration is (in GA) 4.0 mg / kg. After intragastric administration, 0.3ml of blood was taken from the orbit at preset time points such as 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h, 12h, 24h, and the blood sample was placed in a heparinized cusp centrifuge tube Centrifuge at 5000r / min for 15min, accurately pipet 100μL of supernatant plasma into a new conical centrifuge tube, add 1.9ml methanol to precipitate the protein, sonicate for 10min, vortex for 5min, centrifuge at 4000r / min for 10min, t...

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Abstract

The invention discloses a gambogic acid-folic acid-HPMA high-molecular polymer as well as a preparation method and application thereof. The structure of the copolymer is shown as a formula (1). According to the preparation, firstly, gambogic acid is used as raw materials; gambogic acidoxalamide monomers are prepared; then, folic acid is used as raw materials for preparing folic acid monomers; next, the gambogic acid oxalamidemonomers and the folic acidmonomers take a reaction to prepare folic acid-gambogic acid monomers; finally, the folic acid-gambogic acidmonomers and HPMA perform condensation to produce the gambogic acid-folic acid-HPMA high-molecular polymer. The copolymer is applied to medicine for treating tumor diseases, has the targeted intelligent medicine release function, and has good inhibition effects on cancer such as liver cancer, lung cancer, gastric cancer and colon cancer. (The formula is shown in the description.).

Description

Technical field [0001] The invention belongs to the field of polymer anti-tumor targeted drugs, and specifically relates to gambogic acid-folic acid-HPMA polymer copolymer, and a preparation method and application thereof. Background technique [0002] Gamboge is a dry resin secreted by Garcinia hanbaryi Hook.f., one of its main active ingredients is Gambogic Acid (GA, C38H44O8, C38H4408, Mr=628.76) It is an orange-yellow amorphous powder with optical activity. It has been confirmed by in vitro cytotoxicity studies and in vivo modeling animal anti-tumor activity studies that gambogic acid has multi-target and multi-pathway cross-inhibition effects on a variety of tumors. Liver cancer, lewis lung cancer, Ehrlich ascites cancer and other animal transplantation tumors, as well as human lung cancer small cells NCI-H1993, human leukemia cells K562, gastric cancer cells, human pancreatic cancer SW1990 and human colon cancer cells HT-29 have obvious effects Inhibition. [0003] N-(2-hyd...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08F220/58C08F220/60A61K47/54A61K47/58A61K47/69A61K31/352A61P35/00
CPCA61K31/352A61K47/545A61K47/58A61K47/6907A61P35/00C08F220/58C08F220/603
Inventor 陈烨李圣男刘举王洋丁实梁瑀彤
Owner LIAONING UNIVERSITY
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