Antitumor medicine conjugate with folic acid receptor-mediated and photoresponsive functions, and preparation method thereof

An anti-tumor drug and folic acid receptor technology, which is applied in anti-tumor drugs, drug combinations, pharmaceutical formulations, etc., can solve the problems that have not been reported in the literature of photocleavage receptor-targeted anti-tumor drug conjugates, and achieve Toxicity reduction, enhanced effect, extended circulation time effect

Inactive Publication Date: 2014-05-07
YANCHENG INST OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] So far, there have been no literature reports on this kind of photocleavage receptor-targeted anti-tumor drug conjugates

Method used

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  • Antitumor medicine conjugate with folic acid receptor-mediated and photoresponsive functions, and preparation method thereof
  • Antitumor medicine conjugate with folic acid receptor-mediated and photoresponsive functions, and preparation method thereof
  • Antitumor medicine conjugate with folic acid receptor-mediated and photoresponsive functions, and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Preparation of embodiment 1 folic acid-polyethylene glycol-doxorubicin conjugate

[0030] (1) Synthesis of folic acid-polyethylene glycol-photosensitive coupling agent

[0031] 1) Folate-functionalized polyethylene glycol synthesis

[0032] Weigh double-terminal amino polyethylene glycol (NH 2 -PEG-NH 2 ,M w =3200Da) 640 mg was dissolved in 10 mL of anhydrous DMSO, 2 mL of DMSO solution dissolved with folic acid FA and NHS was added, and then DCC and TEA were added in turn (the molar amount of each substance NH 2 -PEG-NH 2 : FA: NHS: DCC: TEA = 1: 1: 1.5: 1.5: 5), under the protection of nitrogen, stirred at room temperature, protected from light for 12 hours, diluted the reaction mixture with 20 mL of deionized water, and centrifuged at 500 rpm to remove the by-products. The product dicyclohexyl urea, then add 10mL acetone to remove unreacted folic acid, put the supernatant into a dialysis tube with a molecular weight cut-off of 3000Da, dialyze with deionized wate...

Embodiment 2

[0039] Preparation of embodiment 2 folic acid-polyethylene glycol-5-FU conjugate

[0040] (1) According to the step of embodiment 1, the photosensitive group hydroxyl-activated carbonate containing folic acid functionalization is synthesized;

[0041] (2) Preparation of folic acid-polyethylene glycol-5-FU conjugate

[0042] Weigh 150 mg folic acid-functionalized photosensitive group hydroxyl-activated carbonate and dissolve it in 20 mL DMF, add 15 μL TEA dropwise, then add 5 mL DMF solution containing 50 mg 5-FU, stir at room temperature for 12 h, dialyze with DMF for 10 h, and then After dialysis with deionized water for 48 hours, freeze-dried for use.

Embodiment 3

[0043]Example 3 Preparation of Folic Acid-Polyethylene Glycol-Methotrexate Conjugate

[0044] (1) according to the step of embodiment 1 synthetic photosensitive group hydroxyl activated carbonate of folic acid functionalization;

[0045] (2) Preparation of folic acid-polyethylene glycol-methotrexate conjugate

[0046] Weigh 200 mg folic acid-functionalized photosensitive group hydroxyl-activated carbonate and dissolve it in 25 mL DMF, add 20 μL TEA dropwise, then add 5 mL DMF solution in which 50 mg methotrexate is dissolved, stir at room temperature for 12 h, then dialyze with DMF for 10 h, Then it was dialyzed with deionized water for 48 hours, and then freeze-dried for later use.

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Abstract

The invention belongs to the technical field of high-molecular medicine, and particularly relates to an antitumor medicine conjugate with folic acid receptor-mediated and photoresponsive functions and a preparation method thereof. The preparation method comprises the following steps: firstly, performing amidation reaction on folic acid and amino polyethyleneglycol; then performing amidation reaction on a product obtained in the former step and 7-ethyloic-4-hydroxymethyl coumarin to obtain a polyethyleneglycol flexible chain with a folic acid receptor targeting function and a photoresponse group; finally enabling the polyethyleneglycol flexible chain to be coupled with an antitumor medicine containing amino with an ester activation method to obtain the antitumor medicine conjugate with the folic acid receptor-mediated and photoresponsive functions. The conjugate prepared by the invention can target a tumor cell through a folic acid receptor-mediated function, and enters the cell via the endocytosis to accelerate the accumulation speed of the medicine in the tumor cell; when being irradiated by ultraviolet light with a specific wavelength or near-infrared light, the conjugate is photolyzed to release original medicine, and the medicine quickly reaches the effective concentration, so that controllable 'time / space' treatment is realized; in addition, the method provides a simple and effective manner for preparing target-controllable photoresponsive high-molecular medicine conjugates.

Description

technical field [0001] The invention belongs to the technical field of macromolecule drugs, and in particular relates to a folic acid receptor-mediated, light-responsive antitumor drug conjugate and a preparation method thereof. Background technique [0002] In recent years, the design and synthesis of stimuli-responsive polymer drug conjugates has brought new ideas to achieve the goal of tumor-targeted therapy. Its core content is to couple cytotoxic small molecule drugs with polymers containing special groups to form temporarily inactive drug conjugates. In the body, it is delivered to the lesion site in an inactive form, and then the active parent drug is released by using the physiological environment of the lesion area or external specific stimuli. The structure of many anti-tumor small molecule drugs contains amino groups that can undergo acylation reactions, and these amino groups often affect the chemical and biological properties of the drug. Once modified by other...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/48A61K41/00A61P35/00
Inventor 张怀红孙柏旺孙玉仓辉蔡照胜
Owner YANCHENG INST OF TECH
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