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Preparation method of heparin-folic acid conjugate with low anticoagulant activity and tumor targeting property

A tumor-targeted, heparin folic acid technology, applied in anti-tumor drugs, organic active ingredients, medical preparations with non-active ingredients, etc. In clinical treatment and other problems, to achieve the effect of low anticoagulant activity

Inactive Publication Date: 2015-04-08
JIANGNAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Although heparin has antitumor activity, its strong anticoagulant activity prevents its high-dose and long-term clinical application
In addition, due to the various biological activities of heparin in vivo, it is difficult to determine the mechanism of antitumor activity of heparin

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0011] Example 1: Preparation of N-desulfated heparin

[0012] Precisely weigh 500mg of heparin sodium and completely dissolve it in 3mL of deionized water, add 50mL of anhydrous DMSO, and then add the same volume of deionized water in a constant temperature water bath at 55°C under stirring conditions for 2 hours to complete the reaction. After the reaction, adjust the pH to 8~ with 1M NaOH 9. Precipitate heparin derivatives with cold anhydrous sodium acetate saturated absolute ethanol, precipitate overnight at 4°C, collect the precipitate by centrifugation, wash the precipitate twice with ice anhydrous sodium acetate saturated absolute ethanol, dissolve the precipitate with appropriate amount of deionized water, Using a dialysis membrane with a molecular weight cut-off of 3500, it was dialyzed in deionized water for 3 days, and then freeze-dried to obtain a white flocculent solid.

Embodiment 2

[0013] Embodiment two: the preparation of folic acid active ester

[0014] Precisely weigh 40mg of folic acid and put it into a conical flask, add 10mL of DMSO, add 20μL of EDC under stirring, keep stirring in a constant temperature water bath at 25°C for 1 hour, and carry out the reaction under dark conditions to obtain a reddish-brown DMSO solution of folic acid active ester .

Embodiment 3

[0015] Example 3: Synthesis of Heparin-Folic Acid Conjugates

[0016] Accurately weigh 100mg of N-desulfated heparin, react in a homogeneous phase, that is, suspend in 10mL DMSO, slowly add the DMSO solution of folic acid active ester into the N-desulfated heparin solution under magnetic stirring, and stir in a constant temperature water bath at 30°C 16h, the reaction was carried out under dark conditions; 100mg N-desulfated heparin was precisely weighed, and reacted in a heterogeneous phase, that is, it was completely dissolved in 10mL of acetic acid-sodium acetate buffer solution with a pH of 4.7 (or a pH of 5.6), and the folic acid The active ester solution was slowly added dropwise to the N-desulfated heparin solution, and stirred while adding, in a constant temperature water bath at 30°C for 16 hours under the stirring condition, and the reaction was carried out under the condition of avoiding light. After the reaction, use a dialysis membrane with a molecular weight cut-...

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Abstract

The invention belongs to the technical field of biological medicines and in particular relates to a preparation method of a heparin-folic acid conjugate with low anticoagulant activity and tumor targeting property. The preparation method of the heparin-folic acid conjugate comprises the following steps: preparing a heparin derivative which is N-desulfated heparin by starting from heparin, connecting amidogen of the N-desulfated heparin and folic acid by virtue of an amido bond by using a cross-inking agent EDC in heterogeneous or homogeneous reaction, and removing unreacted and dissociated folic acid and EDC by dialyzing and freeze-drying a product to obtain a solid. The detection on the biological activity of the conjugate discovers that the conjugate has low anticoagulant activity and tumor targeting property.

Description

technical field [0001] The invention belongs to the field of biomedicine, and in particular relates to a preparation method of a heparin folic acid conjugate with low anticoagulant activity and tumor targeting. Background technique [0002] In recent years, studies have demonstrated that the highly sulfated glycosaminoglycan heparin has antitumor activity. In fact, cancer patients are treated with heparin mainly for the treatment of venous thrombosis, and it has been observed through a large number of clinical trials that heparin can prolong the survival time of patients with malignant tumors. The multiple effects of heparin on malignant tumors are based on its inhibitory effect on angiogenesis factors, such as bFGF; or by inhibiting the activity of heparanase to interfere with the invasion process of tumor metastatic cells; in addition, heparin itself may hinder tumor growth or prevent cancer cells generated activity. In addition, some studies have also demonstrated that ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/48A61K31/727A61P35/00A61P7/02C08B37/10
Inventor 滕丽萍付海田王敏陈敬华
Owner JIANGNAN UNIV
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