Long-circulating target photosensitive antitumor medicine conjugate and preparation method thereof

An anti-tumor drug, long-circulation technology, applied in anti-tumor drugs, drug combinations, pharmaceutical formulations, etc., can solve the problems that have not been reported in the literature on long-circulating photocleavage receptor-targeted anti-tumor drug conjugates, etc. Achieve the effect of enhancing passive targeting of tumor tissue, prolonging circulation time, and increasing penetration depth

Inactive Publication Date: 2012-08-15
YANCHENG INST OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] So far, there have been no literature reports on long-circ

Method used

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  • Long-circulating target photosensitive antitumor medicine conjugate and preparation method thereof
  • Long-circulating target photosensitive antitumor medicine conjugate and preparation method thereof
  • Long-circulating target photosensitive antitumor medicine conjugate 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) 640mg was dissolved in 10mL of anhydrous DMSO, 2mL of DMSO solution dissolved with folic acid FA and NHS was added, then DCC, TEA (molar ratio NH 2 -PEG-NH 2 : FA: NHS: DCC: TEA = 1: 1: 1.2: 1.2: 3), under the condition of blowing nitrogen, stir at room temperature, and react in the dark for 12 hours, dilute the reaction mixture with 20 mL of deionized water, centrifuge at 500 rpm, remove By-product dicyclohexyl urea, add 10 mL of acetone to remove unreacted folic acid, put the supernatant into a dialysis tube with a molecular weight cut-off of 1000 Da, dialyze with deionized water for 48 hours, and freeze-dry to obtain FA-PEG-NH 2 .

[0033] 2) Synt...

Embodiment 2

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

[0040] (1) according to the step synthesis of embodiment 1, the polyethylene glycol maleimide carbonate containing folic acid functionalization;

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

[0042] Weigh 150 mg of polyethylene glycol maleimide carbonate containing folic acid and dissolve it in 22 mL of DMF, add 15 μL of TEA dropwise, then add 5 mL of DMF solution containing 50 mg of 5-FU, stir at room temperature for 12 hours, and then dialyze with DMF 10h, and then dialyzed with deionized water for 48h, freeze-dried for use.

Embodiment 3

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

[0044] (1) according to the step synthesis of embodiment 1, the polyethylene glycol maleimide carbonate containing folic acid functionalization;

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

[0046] Weigh 170 mg of polyethylene glycol maleimide carbonate containing folic acid and dissolve it in 25 mL of DMF, add 15 μLTEA dropwise, then add 5 mL of DMF solution containing 50 mg of methotrexate, stir at room temperature for 12 hours, and then dialyze with DMF 10h, and then dialyzed with deionized water for 48h, freeze-dried for use.

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Abstract

The invention belongs to the technical field of polymer drugs, and particularly relates to a long-circulating target photosensitive antitumor drug conjugate and a preparation method of the long-circulating target photosensitive antitumor drug conjugate. The preparation method comprises the following steps: firstly, carrying out amidation reaction to a single-end amino polyethylene glycol amino with ligand functionalization and 4-(1-ethoxy)-2- methoxy group-5-nitrobenzoic acid containing a photosensitive group; then carrying out esterification reaction with an esterifying agent; and finally coupling with the antitumor drug containing the amino to obtain the long-circulating target photosensitive antitumor drug conjugate. According to the conjugate prepared by the preparation method, the circulating time of the drug in the body can be prolonged, tumor tissues are accelerated to adsorb drug, and the conjugate has the target to quicken the enrichment speed of the antitumor drug in the tumor tissues. The conjugate is fractured by the photostimulation of specific wavelength to release original drug and quickly achieve treatment concentration, and 'time/space' controllable effective treatment is obtained. Meanwhile, the preparation method provides a simple and effective path for preparing the target controllable photosensitive biological polymer drug.

Description

technical field [0001] The invention belongs to the technical field of macromolecule drugs, and in particular relates to a long-circulation targeted, photosensitive anti-tumor 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 gro...

Claims

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Application Information

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IPC IPC(8): A61K47/48A61K41/00A61P35/00A61K47/34A61K47/22
Inventor 张怀红孙柏旺孙玉严新蔡照胜
Owner YANCHENG INST OF TECH
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