Tumor targeting nano-micelle based on hyaluronic acid as well as preparation and application of tumor targeting nano-micelle

A hyaluronic acid, tumor targeting technology, applied in the field of medicine, can solve the problems of few nanomaterials and nano dosage forms, lack of good targeting, safe nano-delivery technology platform, single function, etc., to enhance the anti-tumor effect. Effect

Pending Publication Date: 2021-07-27
TIANJIN UNIVERSITY OF SCIENCE AND TECHNOLOGY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Nano-preparation as a carrier of chemotherapy drugs has been more and more developed, but there are few types of nano-materials and nano-dosages for clinical...

Method used

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  • Tumor targeting nano-micelle based on hyaluronic acid as well as preparation and application of tumor targeting nano-micelle
  • Tumor targeting nano-micelle based on hyaluronic acid as well as preparation and application of tumor targeting nano-micelle
  • Tumor targeting nano-micelle based on hyaluronic acid as well as preparation and application of tumor targeting nano-micelle

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Embodiment 1: the synthesis of docetaxel intermediate DTX-SS

[0047] The synthetic route is as follows:

[0048]

[0049] Dissolve 500mg of docetaxel, 160mg of 3-(pyridin-2-yldisulfanyl)propionic acid, and 23mg of 4-dimethylaminopyridine in 24mL of anhydrous dichloromethane. After fully dissolving, add 134μL of N,N - Diisopropylcarbodiimide, reacted in an oil bath at 25°C for 3 hours. Then dilute the reaction system with 50mL of dichloromethane, with 150mL of NH4 Cl aqueous solution extracted the diluted system twice, collected the organic phase, then extracted the organic phase with saturated NaCl aqueous solution, collected the organic phase, and finally used anhydrous NaCl 2 SO 4 The organic phase was dried, spin-dried, and then the product was purified by column chromatography to finally obtain 294 mg of the docetaxel intermediate. The prepared docetaxel intermediate 1 H-NMR spectrum such as figure 1 shown.

Embodiment 2

[0050] Embodiment 2: the synthesis of paclitaxel intermediate PTX-SS

[0051] The synthetic route is as follows:

[0052]

[0053] Dissolve 100mg of paclitaxel, 30mg of 3-(pyridin-2-yldisulfanyl)propionic acid, and a catalytic amount of 4-dimethylaminopyridine in 5mL of anhydrous dichloromethane, and add dropwise 30μL of N,N' after fully dissolving -Diisopropylcarbodiimide, react at room temperature for 3h. The system was diluted with dichloromethane, extracted twice with saturated ammonium chloride, washed once with saturated NaCl, then dried with anhydrous sodium sulfate, spin-dried the solvent under reduced pressure, and used dichloromethane / methanol=90 / 1, 200-300 mesh silica gel Purified by column chromatography to obtain 100 mg of paclitaxel intermediate. Paclitaxel intermediates prepared 1 H-NMR spectrum such as figure 2 shown

Embodiment 3

[0054] Embodiment 3: the synthesis of podophyllotoxin intermediate PODO-SS

[0055] The synthetic route is as follows:

[0056]

[0057] Dissolve 200mg of podophyllotoxin, 160mg of 3-(pyridin-2-yldisulfanyl)propionic acid, and 70mg of 4-dimethylaminopyridine in 5mL of anhydrous dichloromethane, and dropwise add 150μL of N,N'- Diisopropylcarbodiimide, react at room temperature for 50min. The system was diluted with dichloromethane, extracted twice with saturated ammonium chloride, washed once with saturated NaCl, dried with anhydrous sodium sulfate, spin-dried the solvent under reduced pressure, and used petroleum ether / ethyl acetate=4 / 1, 200-300 mesh Silica gel was purified by column chromatography to obtain 230 mg of a podophyllotoxin intermediate. The prepared podophyllotoxin intermediate 1 H-NMR spectrum such as image 3 shown.

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Abstract

The invention provides a tumor targeting nano-micelle based on hyaluronic acid as well as a preparation method and application of the tumor targeting nano-micelle. An E selectin peptide ligand is connected with chemotherapeutic drugs such as taxanes, camptothecin and podophyllotoxin through disulfide bonds, then the conjugate is connected to carboxyl of hyaluronic acid, and a formed amphiphilic polymer can be self-assembled in an aqueous solution to form primary nano-targeting micelles. Other functional molecules such as chemotherapeutic drugs and/or photosensitizer indocyanine green can be further loaded to form a multifunctional nano-micelle, and the micelle respectively has an active targeting tumor effect mediated by hyaluronic acid and tumor targeting peptide and a passive targeting effect of the nano-micelle EPR effect, and has the characteristic of photothermal photodynamic and chemotherapy synergetic effect; and E-selectin-mediated adhesion between vascular endothelial cells and tumor cells can be competitively inhibited, so that the potential of inhibiting tumor cell metastasis is achieved. The multifunctional nano-micelle is simple and easy to prepare and wide in application range, and has important application value.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to a tumor-targeting nano-micelle and a preparation method and application thereof. Background technique [0002] Chemotherapeutic drugs are still an important means of treating tumors, but traditional chemotherapeutic drugs have obvious defects, such as strong systemic toxicity, lack of targeting, and easy drug resistance. Nano-preparation as a carrier of chemotherapy drugs has been more and more developed, but there are few types of nano-materials and nano-dosages for clinical application and single functions, lack of nano-materials with good targeting, safety and synergistic effects through multiple modes. delivery technology platform. [0003] Hyaluronic acid (HA) is a glycosaminoglycan widely present in human body. It is the main component of the extracellular matrix and plays an important physiological role in the human body. Hyaluronic acid has excellent biocompatibility an...

Claims

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Application Information

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IPC IPC(8): A61K9/107A61K47/61A61K47/64A61K41/00A61K45/06A61P35/00A61P35/04B82Y5/00B82Y40/00
CPCA61K47/64A61K47/61A61K9/1075B82Y5/00B82Y40/00A61P35/00A61P35/04A61K41/0052A61K41/0057A61K45/06
Inventor 郭娜罗艳霞杨尧郁彭李九远
Owner TIANJIN UNIVERSITY OF SCIENCE AND TECHNOLOGY
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