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Preparation and application of hyaluronic acid-modified amphipathic chitosan derivative carrier with tumor microenvironment specificity drug release effect

A chitosan derivative, hyaluronic acid modification technology, applied in the direction of antitumor drugs, drug combination, drug delivery, etc., to achieve the effects of high drug loading, increased stability and biocompatibility, and high encapsulation efficiency

Inactive Publication Date: 2017-04-26
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Amphiphilic chitosan derivatives modified by hyaluronic acid modified by targeted modification of hyaluronic acid and introduction of hydrophobic groups into the tumor microenvironment have not yet been reported in literature and patents.

Method used

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  • Preparation and application of hyaluronic acid-modified amphipathic chitosan derivative carrier with tumor microenvironment specificity drug release effect
  • Preparation and application of hyaluronic acid-modified amphipathic chitosan derivative carrier with tumor microenvironment specificity drug release effect
  • Preparation and application of hyaluronic acid-modified amphipathic chitosan derivative carrier with tumor microenvironment specificity drug release effect

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0085] Embodiment 1: Preparation of hyaluronic acid modified hydroxyethyl chitosan-n-octylamine reduction sensitive copolymer

[0086] Dissolve 1.000g chitosan in 2% acetic acid aqueous solution, add 50% NaOH solution in batches, alkalinize at 40°C for 12h, add appropriate amount of ethylene oxide in batches under ice bath conditions, react at 0°C for 2-4h, Raise the temperature to 35-50° C. to continue the reaction for 24 hours, adjust the pH value to 6-8 with concentrated hydrochloric acid, dialyze (MWCO=14000) for 48-72 hours, and freeze-dry to obtain hydroxyethyl chitosan.

[0087] Dissolve 0.300g hydroxyethyl chitosan in a mixed solution of water and methanol (v / v=1:1), dissolve 0.600g 3,3'-dithiodipropionic acid in methanol solution, add 0.547 g 1-ethyl-(3-dimethylaminopropyl) carbodiimide (EDC) and 0.328g hydroxysuccinimide (NHS), after activation for 0.5-1h, slowly drop into aqueous solution of hydroxyethyl chitosan , react at room temperature for 24 hours, remove met...

Embodiment 2

[0090] Embodiment 2: Preparation of carboxymethyl chitosan-n-octanoic acid reduction-sensitive copolymer modified by hyaluronic acid

[0091] Dissolve 1.000g chitosan in isopropanol solution, add 50% NaOH solution in batches, alkalinize at 40°C for 12h, add 6.000g chloroacetic acid, react at 40°C for 24h, pour off the supernatant, add appropriate amount of water, Make it a clear and transparent yellow solution. Concentrated hydrochloric acid was used to adjust the pH value to 6-8, dispersed in methanol, suction filtered, the filter cake was redissolved in water, dialyzed (MWCO=14000) for 48-72 hours, and freeze-dried to obtain carboxymethyl chitosan.

[0092] Dissolve 0.300g carboxymethyl chitosan in water, dissolve 0.500g 3-[(2-aminoethyl)dithio]propionic acid in methanol solution, add 0.547g 1-ethyl-(3-di Methylaminopropyl) carbodiimide (EDC) and 0.328g hydroxysuccinimide (NHS), after activation for 0.5-1h, slowly drop into hydroxyethyl chitosan aqueous solution, react at r...

Embodiment 3

[0095] Embodiment 3: Preparation of hydroxyethyl chitosan-cholic acid reduction-sensitive copolymer modified by hyaluronic acid

[0096] Dissolve 1.000g of chitosan in 2% acetic acid aqueous solution, add an appropriate amount of 50% NaOH solution, alkalinize at 40°C for 12 hours, add appropriate amount of ethylene oxide in batches under ice bath conditions, react at 0°C for 2-4 hours, and heat up Continue the reaction at 35-50°C for 24 hours, adjust the pH value to 6-8 with concentrated hydrochloric acid, dialyze (MWCO=14000) for 48-72 hours, and freeze-dry to obtain hydroxyethyl chitosan.

[0097] Dissolve 0.300g of hydroxyethyl chitosan in a mixed solution of water and methanol (v / v=1:1), and dissolve 0.500g of 3-[(2-aminoethyl)dithio]propionic acid in methanol Add 0.547g of 1-ethyl-(3-dimethylaminopropyl) carbodiimide (EDC) and 0.328g of hydroxysuccinimide (NHS) into the solution, activate it for 0.5-1h, then slowly drop in hydroxyethyl Chitosan-based aqueous solution, re...

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Abstract

The invention relates to a hyaluronic acid-modified amphipathic chitosan derivative carrier with tumor microenvironment specificity drug release effect. The hyaluronic acid-modified amphipathic chitosan derivative carrier is characterized in that firstly, a hydrophilic group is introduced into a chitosan skeleton; then, a hydrophobic group is introduced into a specifically degradable link arm containing disulfide bonds, so as to realize the amphipathic function; the amphipathic derivative is assembled into nanomicelle by self in a waterborne medium, and is further modified by a charge adsorbing principle to target the molecular hyaluronic acid; the nanomicelle can effectively load an anti-tumor drug, and the hyaluronic acid is targeted to the tumor microstructure and then is degraded by hyaluronic acid enzyme in focus cells, so that the drug can be quickly released from the nanomicelle to act on the focal part, thereby obviously improving the concentration, therapy effect and biological utilization degree of free drug on the focal part. The hyaluronic acid-modified amphipathic chitosan derivative carrier has the advantages that the carrier which carries pharmaceutical activity or pharmacological activity molecules can be applied to internal injection of blood vessels or muscles or oral administration, so as to obviously improve the anti-tumor activity of drug; the preparation method is simple, the technology is matured, and the preparation method is suitable for large-scale production.

Description

technical field [0001] The invention belongs to the field of pharmaceutical preparations, and relates to an amphiphilic chitosan derivative modified by hyaluronic acid for specific drug release in the tumor microenvironment as an antitumor drug carrier, and also relates to a preparation method and application of the carrier. Background technique [0002] Cancer has been a major disease that threatens human life and health since its discovery. Currently, the clinical treatment of cancer mainly relies on medicinal chemistry. At present, people's research on the mechanism of tumors is deepening, and various basic processes such as signal transduction, cell cycle regulation, apoptosis, angiogenesis, cell metastasis, and infiltration in tumor cells are being gradually elucidated, and many anti-tumor drugs have been developed accordingly. In addition to direct killing by inhibiting proliferation or inducing apoptosis, these drugs also act on tumor cells through indirect regulation...

Claims

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Application Information

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IPC IPC(8): A61K47/36A61K47/61A61K9/107A61K45/00A61P35/00C08G81/00C08B37/08
CPCA61K47/36A61K9/0019A61K9/0053A61K9/1075A61K45/00C08B37/003C08G81/00
Inventor 周建平霍美蓉董丽慧
Owner CHINA PHARM UNIV
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