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High-molecular material containing cholic acid and liver-targeting drug delivery nanoparticle modified by same

A drug-loaded nanometer and amphiphilic polymer technology, applied in the field of liver-targeted drug delivery nanoparticles, can solve the problems of unstable liposome properties, affecting the bioavailability of drugs, and difficult control of modification operating conditions. Simple operation, good biocompatibility effect

Active Publication Date: 2014-01-29
TSINGHUA UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the prodrug is not easy to dissociate from the drug molecule, which may affect the bioavailability of the drug; while the liposome is unstable and the modification operation conditions are not easy to control
There are no reports on the synthesis of cholic acid-containing polymer materials for surface modification of nanoparticles and their modified nanoparticles for liver-targeted drug delivery.

Method used

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  • High-molecular material containing cholic acid and liver-targeting drug delivery nanoparticle modified by same
  • High-molecular material containing cholic acid and liver-targeting drug delivery nanoparticle modified by same
  • High-molecular material containing cholic acid and liver-targeting drug delivery nanoparticle modified by same

Examples

Experimental program
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Effect test

Embodiment 1

[0049] Embodiment 1: Amphiphilic polymer material containing cholic acid of the present invention and its synthesis

[0050] 1) Dissolve 4-vinylbenzoic acid (2.0mmol) in 10mL of dichloromethane, add SOCl 2 (2.6mmol) and 1 drop of DMF, reacted at room temperature for 4h, evaporated under reduced pressure to remove the solvent, then added 2-3mL chloroform to dissolve, sealed and stored at low temperature (in a refrigerator at -20°C). Unreacted reactants and catalysts do not need to be separated, and will be removed during the recrystallization of the product in step 2).

[0051] 2) Dissolve methyl cholate (3.0mmol) in 15mL of chloroform, add triethylamine (4.8mmol), slowly drop into 4.5mmol of 4-vinylbenzoyl chloride solution (dissolved in a very small amount of In chloroform, there is about 1 mL of chloroform in actual operation), after reacting for 2 hours, slowly warming up to room temperature and continuing to react for 24 hours, distilling off the solvent under reduced pre...

Embodiment 2

[0056] Embodiment 2: Amphiphilic polymer material containing cholic acid of the present invention and its synthesis

[0057] The synthesis of the monomer was the same as in Example 1. The polymer monomer (0.55 g) and 4.9 mg of AIBN were dissolved in 15 ml of chloroform, and the temperature was slowly raised to 68° C. under the protection of nitrogen, and the reaction was continued for 20 hours with stirring. After the reaction, the solvent was removed, and the polymer was precipitated with methanol, filtered, washed with methanol three times, and dried. The polymerization product is a white solid with a conversion rate of 80.7%, a weight average molecular weight of 15700 (n=28), and m.p.=106.5-114.9°C. 1H-NMR and Fourier transform infrared spectrograms are the same as in Example 1.

[0058] Dissolve the polymer (formula II) (0.3g, containing 0.54mmol of methyl cholate structure) in 10ml of tetrahydrofuran, add 3ml of NaOH aqueous solution (concentration: 2mol / L), heat and ref...

Embodiment 3

[0059] Embodiment 3: the hydrophilic and hydrophobic properties of the cholic acid polymer material PVBCA of the present invention

[0060] The cholic acid-containing polymer material PVBCA was prepared according to Example 1. Configure the CH of PVBCA at a concentration of 1.0 mg / mL 2 Cl 2 The solution was spread evenly on the glass slide, and the PVBCA material film was formed after the solvent volatilized, and the contact angle of the material was measured with a contact angle meter. The average contact angle was 35.8°, which indicated that the material had good hydrophilicity.

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Abstract

The invention discloses a high-molecular material containing cholic acid and a drug-loaded nanoparticle modified by the same. The material has a structural formula as represented by formula III, and n in the formula is equal to 25 to 40. Monomers of the material are obtained by reacting hydroxy groups at C3 position of cholic acid methylester with 4-vinylbenzyl chloride and are initiated by an initiator so as to obtain a polymer precursor; ester groups at C24 position of the polymer precursor are hydrolyzed and turn into carboxyl groups so as to obtain the material in the invention. The material has amphipathy and is capable of assembling and of modifying the surface of the nanoparticles in the process of preparing the nanoparticles by using the method of emulsification-solvent evaporation. The molecular structure of cholic acid in the material can specifically bind to bile acid transporters on the surface of parenchymal hepatic cells; under the mediation of the bile acid transporters, the nanoparticles are absorbed by the parenchymal hepatic cells, and therefore, a drug is targetedly delivered to the parenchymal hepatic cells. Thus, the material provided in the invention can be used as an ideal surface modification material for development of a liver-targeting nanometer drug loading system.

Description

technical field [0001] The invention relates to a macromolecule material containing cholic acid and modified liver-targeted drug delivery nanoparticles. Background technique [0002] Targeted drug delivery system can significantly improve drug utilization and reduce drug side effects. Drug-loaded nanoparticles are an important way to achieve targeted drug delivery. Nanoparticles can protect drug molecules and achieve slow and controlled release. By modifying the surface of nanoparticles with materials containing special functional groups, nanoparticles can be targeted to specific cells by virtue of the receptor-ligand interaction on the cell surface. [0003] The drug treatment effect of liver diseases such as hepatitis and liver cancer is not very satisfactory at present. The reason is not only limited by the pharmacological effect of the drug itself, but also one of the important reasons is that the drug cannot be effectively delivered to the liver lesion. The liver-targ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K47/32C08F112/32C08F8/12C07J9/00A61K47/34A61K9/19A61P1/16
Inventor 蒋国强唐世福于洋丁富新
Owner TSINGHUA UNIV
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