Folic acid-modified O-carboxymethyl chitosan-deoxycholic acid complex and preparation method and application thereof

A technology of carboxymethyl chitosan and deoxycholic acid, which is applied in the field of pharmaceutical preparations, can solve the problems that are rarely found on the surface of normal cells, achieve good biocompatibility, good stability, and increase the effect of distribution

Inactive Publication Date: 2012-01-18
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

It is well known that the folate receptor (FR), a folate-coupling protein, is overexpressed on the cell surface of many human solid tumors (ovarian cancer, renal cancer, uterine cancer, colon cancer, lung cancer), but is rarely found on the surface of normal cells

Method used

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  • Folic acid-modified O-carboxymethyl chitosan-deoxycholic acid complex and preparation method and application thereof
  • Folic acid-modified O-carboxymethyl chitosan-deoxycholic acid complex and preparation method and application thereof
  • Folic acid-modified O-carboxymethyl chitosan-deoxycholic acid complex and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] Embodiment 1: the synthesis of folic acid modified targeting chitosan carrier material (folate modified O-carboxymethyl chitosan-deoxycholic acid complex)

[0052] (1) O-carboxymethyl chitosan-deoxycholic acid coupling:

[0053] Weigh 250mg of O-carboxymethyl chitosan and dissolve it in 25ml of distilled water, then add 75ml of methanol to dilute; dissolve 153mg of deoxycholic acid in 10ml of anhydrous dimethyl sulfoxide, add 112mg of 1-ethyl-3- 3-Dimethylaminopropylcarbodiimide hydrochloride (1-Ethyl-3-(3-Dimethylaminopropyl)carbodiiamideHydrochloride) and 68mg N-hydroxysuccinimide, reacted at room temperature for 2h; added activated deoxycholic acid In a solution of O-carboxymethyl chitosan, stir vigorously until the solution is optically clear. After the mixture was reacted at room temperature for 36 hours, it was purified and freeze-dried to obtain an amphiphilic O-carboxymethyl chitosan-deoxycholic acid conjugate, namely DOMC. The degree of substitution of deoxyc...

Embodiment 2

[0057] Example 2: Carrier material cytotoxicity detection

[0058] Breast cancer MCF-7 cells in the logarithmic growth phase were inoculated at 5000cells / well / 100μL in a 96-well plate, and 24 hours later, 0.01-1mg / mL micellar solution prepared by micellar materials DOMC and DOMC-FA were given respectively. After incubating in an incubator at 37°C for 72 hours, add 15 μl of 5 mg / ml MTT solution, continue to cultivate at 37°C for 4 hours, then replace the culture solution with 200 μl of DMSO, shake for 10 minutes, and measure the absorbance at 570 nm with a microplate reader. The tumor cells without carrier material were used as the control, and the cell inhibition rate was calculated.

[0059] The toxicity results of carrier materials DOMC-FA and DOMC to MCF-7 cells are shown in figure 2 . The results showed that in the range of 0.01-1 mg / mL, the cell survival rates of DOMC and DOMC-FA were both greater than 85%, indicating that the carrier material itself has little toxicit...

Embodiment 3

[0060] Example 3: Uptake of rhodamine B-loaded nanomicelles by MCF-7 cells cultured in vitro

[0061] Preparation of DOMC and DOMC-FA nanomicelles loaded with rhodamine B.

[0062] The breast cancer MCF-7 cells in the logarithmic growth phase were inoculated on a 6-well plate, and after culturing for 24 hours, the culture medium was removed, washed once with cold PBS, and then mixed with DOMC and DOMC-FA nanomicelle solution loaded with Rhodamine B 1ml was incubated for 0.5h, 2h, 4h (the concentration of Rhodamine B was 5 μM), the same concentration of free Rhodamine B was used as a control, and PBS was used for three times, and the uptake of Rhodamine B was observed under a fluorescence microscope. see results image 3 . image 3Fluorescence electron micrographs of MCF-7 cells incubated with rhodamine B-loaded DOMC and DOMC-FA nanomicelles for different times, A: free rhodamine B, B: rhodamine B-loaded DOMC nanomicelle solution, C : DOMC-FA nanomicelle solution loaded with...

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Abstract

The invention discloses a folic acid-modified O-carboxymethyl chitosan-deoxycholic acid complex which is an active-targeting nano-micelle carrier material prepared by using folic acid, O-carboxymethyl chitosan and deoxycholic acid as raw materials; O-carboxymethyl chitosan is used as a carrier material; deoxycholic acid is used for hydrophobicity reconstruction; folic acid is used for surface modification; and folic acid-mediated tumor tissue-targeting polymer micelle is prepared. Drug-loaded nano-micelle is prepared by a self-assembly method with paclitaxel as a model drug; experiment demonstrates that the drug-loaded nano-micelle has high drug load and encapsulation efficiency, has sustained release effect, is intaken into tumor cells through a folic acid acceptor approach, can increase the distribution of the drug in tumor tissue, thus improves curative effect, reduces toxic and side effect, and reaches the purpose of targeting treatment. The invention provides an ideal and novel drug carrier and preparation form for hard-soluble antitumor drugs.

Description

technical field [0001] The invention relates to a folic acid-modified O-carboxymethyl chitosan-deoxycholic acid complex, a preparation method thereof, and its ability to mediate targeting chitosan drug-loaded nano-micelles in the preparation of anti-tumor drug receptors The application in targeted nanomicelle preparations belongs to the field of pharmaceutical preparations. Background technique [0002] At present, tumor has become a common and frequently-occurring disease that seriously threatens human health, and its mortality rate accounts for 12% of the total number of human deaths in the world. Therefore, conquering tumors has been one of the main tasks of governments, scientific research and medical institutions of various countries for nearly half a century. Chemotherapy, as one of the three conventional treatment methods for tumors, has become an indispensable means of tumor treatment. At present, most of the commonly used anti-tumor chemotherapy drugs in clinical ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/36A61K47/28A61K47/22A61K9/00A61P35/00
Inventor 张典瑞王飞虎陈瑀璇刘悦段存贤贾乐姣刘光璞
Owner SHANDONG UNIV
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