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Tumor targeted cell-penetrating cyclodextrin derivative as well as preparation method and application thereof

A tumor targeting and cyclodextrin technology, which is applied in the directions of antitumor drugs, medical preparations with inactive ingredients, and medical preparations containing active ingredients, etc., can solve the problems of lack of targeted tumor cells, etc. Simple and feasible, good specificity, good killing effect

Pending Publication Date: 2020-11-03
NANJING NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] At present, most cyclodextrin nanoparticles are designed by using the drug-loading ability of its hydrophobic cavity, which lacks the ability to target tumor cells and enter the tumor through membrane-penetrating peptides.

Method used

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  • Tumor targeted cell-penetrating cyclodextrin derivative as well as preparation method and application thereof
  • Tumor targeted cell-penetrating cyclodextrin derivative as well as preparation method and application thereof
  • Tumor targeted cell-penetrating cyclodextrin derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Step 1. Weigh 100 mg of CM-β-CD (0.065 mol, molecular weight 1541) with free carboxyl groups, dissolve it in 12 mL of DMF and mix thoroughly, inject the suspension into a 50 mL eggplant-shaped bottle, add 500 μL of hydrochloric acid to adjust the pH to 4.5 Add a rubber stopper and stir in a water bath at 30°C for 1 hour at a medium speed. Then keep the temperature in the water bath constant, weigh 20.7 mg of EDCI (0.108 mol, molecular weight 191.7) and 12.4 mg of NHS (0.108 mol, molecular weight 115) and dissolve them in 3 mL of DMF, mix well and inject them into In an eggplant-shaped bottle, the whole system was reacted for 3 hours. Weigh 27.75 mg of R6RGD (0.0216 mol, molecular weight 1283) into an eggplant-shaped bottle, adjust the pH to 8.5 with 1.4 mL of triethylamine, and then stir at a medium speed for 4 h.

[0034] Step 2: inject the reaction solution into a dialysis bag with a molecular weight of 2000, dialyze with distilled water for 24 hours, and change the ...

Embodiment 2

[0040] Step 1. Weigh 100 mg of CM-β-CD (0.065 mol, molecular weight 1541) with free carboxyl groups, dissolve it in 12 mL of DMF and mix well, inject the suspension into a 50 mL eggplant-shaped bottle, add 600 μL of hydrochloric acid to adjust the pH to 4. Add a rubber stopper and stir in a water bath at 35°C for 2 hours at a medium speed. Then keep the temperature in the water bath constant, weigh 20.7 mg of EDCI (0.108 mol, molecular weight 191.7) and 12.4 mg of NHS (0.108 mol, molecular weight 115) and dissolve them in 4 mL of DMF, mix well and inject them into In an eggplant-shaped bottle, the whole system was reacted for 4 hours. Weigh 83.40 mg of R6RGD (0.065 mol, molecular weight 1283) into an eggplant-shaped bottle, adjust the pH to 9 with 1.6 mL of triethylamine, and then stir at a medium speed for 6 h.

[0041] Step 2. Inject the reaction solution into a dialysis bag with a molecular weight of 2000, dialyze with distilled water for 36 hours, and change the dialysis ...

Embodiment 3

[0044] Step 1. Weigh 100 mg of CM-β-CD (0.065 mol, molecular weight 1541) with free carboxyl groups, dissolve it in 12 mL of DMF and mix thoroughly, inject the suspension into a 50 mL eggplant-shaped bottle, add 450 μL of hydrochloric acid to adjust the pH to 5. Add a rubber stopper and stir in a water bath at 35°C for 1 hour at a medium speed. Then keep the temperature in the water bath constant, weigh 20.7 mg of EDCI (0.108 mol, molecular weight 191.7) and 12.4 mg of NHS (0.108 mol, molecular weight 115) and dissolve them in 3 mL of DMF, mix well and inject them into In an eggplant-shaped bottle, the whole system was reacted for 3 hours. Weigh 16.68 mg of R6RGD (0.013 mol, molecular weight 1283) into an eggplant-shaped bottle, adjust the pH to 8 with 1.2 mL of triethylamine, and then stir at a medium speed for 4 h.

[0045] Step 2: inject the reaction solution into a dialysis bag with a molecular weight of 2000, dialyze with distilled water for 24 hours, and change the dial...

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Abstract

The invention discloses a tumor targeted cell-penetrating cyclodextrin derivative as well as a preparation method and application thereof. The cyclodextrin derivative comprises a targeting cell-penetrating peptide R6RGD and a carrier material carboxymethyl-beta-cyclodextrin, and the carboxymethyl-beta-cyclodextrin is beta-cyclodextrin which is modified by cyclodextrin, has strong hydrophilicity and contains a carboxyl terminal. The targeting cell-penetrating peptide R6RGD is a polypeptide fragment which has a cell-penetrating capability and is specifically targeted to tumor cells and is formedby combining a hexaarginine (R6) cell-penetrating peptide having a cell-penetrating capability with a tripeptide of RGD (arginine-glycine-aspartic acid) with a tumor cell targeting function. The targeting cell-penetrating peptide R6RGD is bonded with carboxymethyl-beta-cyclodextrin amido bonds with outer hydrophilicity and inner hydrophobicity to form a stable nano inclusion material. The sustained release preparation of the tumor targeted cell-penetrating cyclodextrin derivative has good biocompatibility and stability, has the advantages of low in-vivo toxic and side effects, strong membranepenetrating capability, good tumor targeting and the like, and is simple in preparation method, convenient to operate and high in yield.

Description

technical field [0001] The invention belongs to the field of targeted delivery of pharmaceutical antitumor drugs, and in particular relates to a cyclodextrin derivative for tumor-targeted transmembrane penetration effectively and specifically targeted, and a preparation method and application thereof. Background technique [0002] The tripeptide of RGD (arginine-glycine-aspartic acid) is an integrin ligand specifically recognized by integrin αvβ3. Integrin αvβ3 exists in the lowest amount in normal blood vessels and remains quiescent, but is significantly upregulated in human cancer neovascularization, and the upregulation of these integrins makes cancer cells more motile, invasive, and resistant to anticancer drugs. RGD has high affinity and recognition ability to integrin αvβ3, and it is used in combination with anticancer drugs. At the same time, RGD can also target on the apical surface of human M cells, and β1 integrin has been proved to be overexpressed in the apical ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/69A61K47/64C08B37/16A61K45/00A61P35/00B82Y5/00B82Y30/00B82Y40/00
CPCA61K47/6951A61K47/64A61K45/00B82Y5/00B82Y30/00B82Y40/00A61P35/00C08B37/0012
Inventor 张列峰华莹莹马晨君魏恬恬
Owner NANJING NORMAL UNIVERSITY
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