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Random copolymer based on polyphosphoester as well as preparation method and application thereof

A technology of random copolymers and polyphosphates, which can be used in medical preparations of non-active ingredients, drug combinations, pharmaceutical formulations, etc., and can solve problems such as no reports of phosphate ester copolymers

Inactive Publication Date: 2013-12-18
SUZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In the prior art, there is no report on phosphate copolymers modified with galactose groups targeting liver cells

Method used

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  • Random copolymer based on polyphosphoester as well as preparation method and application thereof
  • Random copolymer based on polyphosphoester as well as preparation method and application thereof
  • Random copolymer based on polyphosphoester as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Example 1: Random copolymer Poly(CL) with side groups having carbon-carbon double bonds 26 - co -OPEA 6 )Synthesis

[0051] Initiation of the monomer ε-caprolactone (ε-CL) and the phosphate monomer 2-acrylate ethyloxy-2-oxo-1,3,2-dioxaphospholane (OPEA) with benzyl alcohol Ring-opening copolymerization to prepare a random copolymer Poly(CL 26 - co -OPEA 6 ).

[0052] Dry the branched round-bottomed flask with a stirring bar in an oven at 120 °C for at least 24 hours, plug it with a glass stopper, connect it with an oil pump through a latex tube, and pump it to room temperature, then introduce high-purity argon gas, and then evacuate it. After repeating three times, it was filled with argon.

[0053] Benzyl alcohol (0.10 g, 0.93 mmol), ε-caprolactone (ε-CL) (4.51 g, 39.43 mmol), OPEA (2.24 g, 10.08 mmol), toluene (10 mL ) and stannous octoate [Sn(Oct) 2 ] (12 mg). After the reaction flask was filled with argon, the reaction was stirred in an oil bath at 90°C fo...

Embodiment 2

[0054] Example 2: Random copolymer Poly[CL with carboxyl groups in side groups 26 - co -(OPEA -COOH ) 6 ]Synthesis

[0055] The Poly(CL of embodiment one preparation 26 - co -OPEA 6 ) and mercaptopropionic acid, a mercapto reagent, were subjected to a mercapto-ene addition reaction under the irradiation of 365 nm ultraviolet light to obtain a random copolymer Poly[CL 26 - co -(OPEA -COOH ) 6 ].

[0056] Add Poly(CL 26 - co -OPEA 6 ) (0.52 g, 0.12 mmol), added chloroform to dissolve, then added mercaptopropionic acid (0.12 g, 1.08 mmol) and photoinitiator benzoin dimethyl ether (DMPA) (1 mg) in sequence, placed in a 365 nm ultraviolet lamp The reaction was carried out for 30 minutes. Shake the reaction dish gently every 5 minutes during the reaction to complete the reaction. After the reaction was finished, the reaction mixture was precipitated with 100 mL of ice anhydrous ether, and the ether was poured off to obtain a colorless viscous substance. The crude pro...

Embodiment 3

[0057] Example 3: Random copolymer Poly[CL with galactose groups in side groups 26 - co -(OPEA -Gal ) 6 ]Synthesis

[0058] Using galactosamine hydrochloride as the amino reagent, in 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC·HCl) and N-hydroxysuccinimide (NHS ) in the presence of Poly[CL 26 - co -(OPEA -COOH ) 6 ] carboxyl group to undergo amidation reaction to obtain a random copolymer Poly[CL with liver cell targeting and biodegradability 26 - co -(OPEA -Gal ) 6 ].

[0059] In a 25 mL dry three-necked flask, add Poly[CL 26 - co -(OPEA-COOH) 6 ] (0.23 g, 0.05 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC·HCl) (0.16 g, 0.83 mmol) and N-hydroxysuccinyl Imine (NHS) (0.08 g, 0.69 mmol), dissolved in 10 mL of dry dimethylsulfoxide (DMSO), was activated for 12 hours. Triethylamine (0.07 g, 0.69 mmol) and galactosamine hydrochloride (0.11 g, 0.51 mmol) were dissolved in 5 mL of DMSO, and added dropwise to the reaction flas...

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Abstract

The invention discloses a random copolymer based on polyphosphoester as well as a preparation method and an application thereof. The preparation method comprises the following steps of: firstly carrying out ring-opening polymerization by using an annular phosphate ester monomer and an aliphatic cyclic ester monomer so as to obtain the random copolymer, the side groups of which have carbon-carbon double bonds; then carrying out sulfydryl-alkene addition reaction on the product by using mercaptopropionic acid as a sulfydryl reagent so as to obtain the random copolymer, the side groups of which have carboxyl groups; and finally carrying out amidation reaction on the carboxyl groups through galactosamine hydrochlorides so as to obtain the galactose modified random copolymer. The random copolymer has the advantages that galactose groups on hydrophilic chain segments of the random copolymer can be peculiarly recognized by asialoglycoprotein receptors on liver cell membranes, so that medicines have targeting on liver cells; and meanwhile, a polyphosphoester structural unit can be rapidly degraded under a weak acidic condition, so that a micelle dissociates, and when a carrier reaches tumors or lesion tissues, the medicines loaded in a micelle nucleus can be rapidly released in an intracellular acid environment, and therefore, the random copolymer has good application prospect.

Description

technical field [0001] The invention belongs to the field of biomedical polymer materials, and in particular relates to a random copolymer based on polyphosphate, its preparation method and its application as a liver cell targeting drug carrier. Background technique [0002] Chemotherapy, which is currently clinically used in cancer treatment, is to inject anticancer drugs into the whole body through intravenous injection. Although this method can inhibit cancer cells, it has great damage to normal cells. The development of nanotechnology provides a new method for the effective delivery of anticancer drugs to tumors. Integrating drug molecules into nanocarriers through encapsulation, covalent bonding or adsorption can achieve drug solubilization, protect drug activity, and reduce drug side effects. At the same time, targeting ligand molecules can be used to enhance target cells. The ability to take drugs. [0003] Targeting drug delivery system (TDDS) refers to a delivery ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08G79/04C08G63/692C08G63/08A61K47/34A61P35/00
Inventor 倪沛红陶云锋何金林张明祖
Owner SUZHOU UNIV
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