Folic acid-targeted acid sensitive core-crosslinked drug-loaded micelles based on polyphosphoester

A polyphosphate, folic acid targeting technology, used in antitumor drugs, drug combinations, pharmaceutical formulations, etc., to achieve the effect of prolonging the circulation time in the body

Active Publication Date: 2016-08-10
SUZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although great progress has been made in the research of drug carriers, the development of drug carriers still faces great challenges.

Method used

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  • Folic acid-targeted acid sensitive core-crosslinked drug-loaded micelles based on polyphosphoester
  • Folic acid-targeted acid sensitive core-crosslinked drug-loaded micelles based on polyphosphoester
  • Folic acid-targeted acid sensitive core-crosslinked drug-loaded micelles based on polyphosphoester

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] Example 1: Preparation of polyphosphate block copolymer (PBYP-b-PEOP-OH)

[0064] Dry the ampoule with a stirrer in an oven at 120°C for at least 24 hours, take it out, connect the ampoule to the double-row tube, pump it with an oil pump, and cool it to room temperature, repeat the pumping and inflation three times, and finally fill it with nitrogen. Next, add 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.2738 g, 0.18 mmol), dichloromethane (CH 2 Cl 2, 1.5 mL), isopropanol (IPA, 0.1121 g, 0.12 mmol) and the monomer 2-ynbutyl-2-oxo-1, 3, 2-dioxaphospholane (BYP, 0.8453 g, 4.8 mmol), put the reaction vial into an oil bath set at 25°C, and react under stirring for 30 minutes. After the reaction, the monomer 2-ethyl-2-oxo-1, 3, 2-dioxaphospholane (EOP, 0.73 g, 4.8 mmol) was added, and the reaction was continued in an oil bath at 25°C for 30 minute.

[0065] After the ring-opening reaction, the product was concentrated, and then the concentrated solution was dropped into me...

Embodiment 2

[0066] Example 2: Preparation of folic acid-modified polyphosphate block copolymer (PBYP-b-PEOP-FA)

[0067] After treating the branched vial and the ground glass stopper equipped with a stirring bar according to the method of Example 1, it was filled with nitrogen, and under the condition of nitrogen, folic acid (FA, 0.0159 g, 0.036 mmol), dimethyl sulfoxide (DMSO, 10 mL), dicyclohexylcarbodiimide (DCC, 0.0096 g, 0.0468 mmol), N-hydroxysuccinimide (NHS, 0.0054 g, 0.0468 mmol) and 4-dimethylaminopyridine (DMAP, 0.0057 g, 0.0468 mmol). The reaction bottle was filled with nitrogen, and the reaction was stirred at 25°C for 12 hours. After the reaction, weigh the PBYP 43 -b-PEOP 41 -OH (0.4161 g, 0.0300 mmol) was added to the reaction liquid, and the reaction was continued for 24 hours.

[0068] After the reaction, the product was transferred to a molecular weight cut-off of 3500 g·mol -1 In a dialysis bag, dialyze in deionized water for 24 hours, freeze-dry to obtain a light...

Embodiment 3

[0069] Example Three: Acid-sensitive Tetraethylene Glycol (N 3 -a-TEG-a-N 3 ) preparation

[0070] Weigh tetraethylene glycol (TEG, 0.97 g, 5 mmol) and pyridinium 4-methylbenzenesulfonate (PPTS, 0.2513 g, 1 mmol) into a 100 mL vial equipped with a magnetic stirring bar, add toluene ( 20 mL), azeotropically remove water twice, and then dissolve the azeotropic mixture in anhydrous dichloromethane (30 mL), slowly add 2-chloroethyl vinyl ether (CEVE, 2.5 mL , 25 mmol) and anhydrous dichloromethane (10 mL) into a branched vial, after the dropwise addition, the reaction was stirred in an ice-water bath for 0.5 hours.

[0071] After the reaction was completed, 5% sodium carbonate aqueous solution was added to terminate the reaction, diluted with dichloromethane (30 mL), and then saturated sodium chloride phosphate buffer solution (pH 10.0, 10 mL) was added. The lower organic phase was removed, and the aqueous phase was extracted with dichloromethane (20 mL). The organic phases wer...

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Abstract

The invention discloses folic acid-targeted acid sensitive core-crosslinked drug-loaded micelles based on polyphosphoester. An amphiphilic polyphosphoester segmented copolymer is prepared in an open loop mode through a one-pot method at first; the terminal hydroxyl of the copolymer is modified, and a folic acid-modified segmented copolymer is obtained; hydroxyl on tetraglycol is modified to be a molecule with the terminal containing an aldehyde acetal group and an azide group; finally, CuAAC click reaction is adopted for obtaining the acid sensitive core-crosslinked drug-loaded micelles. The prepared core-crosslinked drug-loaded micelles can wrap hydrophobic anti-cancer drug through self-assembly; under the acid condition, due to fracture of the aldehyde acetal group, the structure of the micelles is damaged, the wrapped medicine can be released, and the micelles can be used as a carrier for releasing medicine controllably. The core-crosslinked drug-loaded micelles can be used as the carrier for releasing medicine efficiently and controllably, and has the good application value in the fields of biological materials and biological medicine.

Description

[0001] This application is a divisional application of the Chinese invention patent application with application number 2014103660130. The filing date of the original application is: July 29, 2014, the application number is: 2014103660130, and the invention name is: folic acid targeting acid based on polyphosphate Sensitive core-crosslinked drug-loaded micelles and preparation methods thereof. technical field [0002] The invention belongs to the field of biomedical polymer materials, in particular to a folic acid-targeted acid-sensitive biodegradable core-crosslinked drug-loaded micelle based on polyphosphate. Background technique [0003] Amphiphilic copolymers are generally composed of hydrophilic and hydrophobic segments. Since they can self-assemble into nanoparticles of various shapes in aqueous solution, such as micelles, vesicles, nanorods, and flakes, they are widely used in biomedicine, supramolecular and Nanotechnology and other fields have broad application prosp...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/107A61K47/34A61K47/22A61K45/00A61K31/337A61K31/4164A61K31/704A61P35/00
CPCA61K9/1075A61K31/337A61K31/4164A61K31/704A61K45/00A61K47/22A61K47/34
Inventor 倪沛红胡健何金林张明祖
Owner SUZHOU UNIV
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