Polyphosphoester-based folate-targeted acid-sensitive core-crosslinked drug-loaded micelle and preparation method thereof

A targeted technology of polyphosphate and folic acid, which is applied in the direction of pharmaceutical formulations, medical preparations with non-active ingredients, medical preparations containing active ingredients, etc., to prolong the circulation time in the body, good biocompatibility and biodegradability sexual effect

Active Publication Date: 2014-12-03
SUZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Although great progress has been made in the research of drug carri

Method used

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  • Polyphosphoester-based folate-targeted acid-sensitive core-crosslinked drug-loaded micelle and preparation method thereof
  • Polyphosphoester-based folate-targeted acid-sensitive core-crosslinked drug-loaded micelle and preparation method thereof
  • Polyphosphoester-based folate-targeted acid-sensitive core-crosslinked drug-loaded micelle and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] Example 1: Polyphosphate block copolymer (PBYP- b -PEOP-OH) Preparation

[0063] 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.

[0064] After the ring-opening reaction, the product was concentrated, and then the concentrated solution was dropped into me...

Embodiment 2

[0065] Embodiment two: the polyphosphate block copolymer (PBYP- b -PEOP-FA) Preparation

[0066] 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.

[0067] 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 yellow...

Embodiment 3

[0068] Example Three: Acid-sensitive Tetraethylene Glycol (N 3 - a -TEG- a -N 3 ) preparation

[0069] 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.

[0070] 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 phas...

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Abstract

The invention discloses a polyphosphoester-based folate-targeted acid-sensitive core-crosslinked drug-loaded micelle and a preparation method thereof. The preparation method comprises the following steps: firstly, preparing an amphiphilic polyphosphoester segmented copolymer in a ring opening manner by adopting a one-pot method; modifying the terminal hydroxyl of the segmented copolymer to obtain a folate-modified segmented copolymer; then, modifying the hydroxyl on tetraglycol into a molecule of which the terminal contains aldehyde acetal group and azide group; and finally, preparing the acid sensitive core-crosslinked drug-loaded micelle by adopting a 'CuAAC' click reaction. The core-crosslinked micelle prepared by the method is capable of entrapping hydrophobic anticancer drugs by means of self-assembly and releasing the entrapped drugs because the broken aldehyde acetal group causes damage of the micelle structure under an acid condition, and can be used as a controlled drug release carrier. The core-crosslinked micelle disclosed by the invention can be used as an effective controlled release drug carrier, and has an excellent application value in the field of biomaterials and biomedicine.

Description

technical field [0001] 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 and a preparation method thereof. Background technique [0002] 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 prospects. As we all know, most anticancer drugs have strong hydrophobicity, and the core-shell structure micelles formed by self-assembly of amphiphilic copolymers have a hydrophobic inner core, which can be used to load hydrophobic anticancer drugs, while hydrophilic The water-based shell can stabilize the micelles, increase the water solubility of the drug, and gre...

Claims

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Application Information

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IPC IPC(8): A61K9/10A61K47/34A61K45/00C08G79/04A61P35/00
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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