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Preparation method of cholesterol derivative-based organic-inorganic composite nano vesicle

A cholesterol derivative, inorganic compound technology, applied in the directions of non-active ingredients medical preparations, liposome delivery, pharmaceutical formulations, etc., can solve the limitation of clinical application and industrial production of liposome preparations, in vivo stability and storage stability problems such as poor biocompatibility and improved stability, achieving good application prospects, overcoming poor biocompatibility and improving stability

Inactive Publication Date: 2011-06-15
HARBIN INST OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the shortcomings of poor in vivo stability and storage stability, the clinical application and industrial production of liposome preparations are limited.
Therefore, poor stability is an urgent problem to be solved in the process of liposome commercialization
[0004] In recent years, researchers have developed highly stable inorganic / organic composite liposomes with a liposome-like structure, called "ceramic bodies", which maintain the essential characteristics of liposomes , but the stability is significantly improved compared with traditional liposomes

Method used

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  • Preparation method of cholesterol derivative-based organic-inorganic composite nano vesicle
  • Preparation method of cholesterol derivative-based organic-inorganic composite nano vesicle
  • Preparation method of cholesterol derivative-based organic-inorganic composite nano vesicle

Examples

Experimental program
Comparison scheme
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Embodiment 1

[0037] Synthesis of Cholesterol Succinate Monoester: Cholesterol (1eq.), succinic anhydride (3eq.) and DMAP (0.1eq.) were dissolved in dichloromethane and refluxed at 55°C for 3 days. Solvent was removed under vacuum. The residue was dissolved in ethanol and poured into cold 15% NaCl solution. The resulting suspension was adjusted to pH 2 with 1M HCl. Filter and wash with neutral water. The dried solid was recrystallized from ethanol / ethyl acetate (10:1, v / v) in nearly 100% yield.

[0038] Synthesis of organic-inorganic composite cholesterol derivatives (1): as figure 1 As shown, EDC (1.2eq.) and cholesterol succinic acid monoester (1.2eq.) were mixed and dissolved in dry dichloromethane. After 30min, APTES (1.2eq.) was added and stirred at room temperature for 4h. The solvent was removed in vacuo, and the crude product was separated with a silica gel column using ethyl acetate / dichloromethane (1:3 v / v) as the developing solvent to obtain a white solid with a yield of abou...

Embodiment 2

[0040] Synthesis of Organic-Inorganic Complex Cholesterol Derivatives (2): Such as figure 2Cholesterol (0.5mmol) was dissolved in 20mL of dry dichloromethane as shown, and then added isocyanatopropyltriethoxysilane (IPTES, 0.5mmol) and dibutyltin dilaurate (0.1mmol ), the reaction mixture was stirred at 50° C. for 24 h under nitrogen protection, and the progress of the reaction was monitored by TLC. After the reaction was completed, the solvent was removed under vacuum, and the crude product was separated with a silica gel column using ethyl acetate / n-hexane (1:5 v / v) as the developing solvent to obtain a white solid with a yield of about 75%. The melting point measured by the melting point instrument is 81-82°C; the NMR results are as follows: 1 H NMR (CDCl 3 , 400MHz) δ: 0.63 (t, J=8.0Hz, 2H, NHCH 2 CH 2 CH 2 Si), 0.67(s, 3H, CH 3 ), 0.85~0.87 (m, 6H, CH 3 ), 0.90~0.92 (m, 3H, CH 3 ), 1.00 (s, 3H, CH 3 ), 1.02~1.21(m, 6H), 1.22~1.35(m, 9H), 1.35~1.47(m, 3H), 1.48~1...

Embodiment 3

[0042] The synthesized organic-inorganic composite cholesterol derivative (1) was dissolved in ethanol, and then injected into the aqueous solution under ultrasonic conditions to allow self-assembly to prepare vesicles with a liposome-like structure. DLS results showed that its The particle size is about 100-200nm, which is consistent with the results of TEM and SEM. EDX results showed that the surface contained C, O, and Si elements, indicating that the surface of the vesicle had a Si-O-Si structure ( image 3 ), demonstrating the formation of a silica shell on its surface.

[0043] The stability of CSS vesicles was measured by measuring the size change of CSS vesicles by adding Triton X-100. the result shows( Figure 4 ), when TritonX-100 was added to the DPPC and CHS liposome suspension, it would initially cause the particle size of the vesicles to increase and then suddenly decrease, which indicated that the vesicles had been destroyed. In contrast, the particle size of...

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Abstract

The invention discloses a preparation method of a cholesterol derivative-based organic-inorganic composite nano vesicle. The preparation method is characterized in that: the structure of an organic-inorganic composite cholesterol derivative is Si-L-Ch, wherein the Si is a silicane head group; the L is an aliphatic chain linking group; carbon number in the L is between 2 and 18; and the Ch is a cholesterol group or a cholesterol derivative group. The method comprises the following steps of: performing derivation on a hydroxy group of a cholesterol molecule to form a carboxyl; reacting the carboxyl and an amino of garma-aminopropyltriethoxysilane (APTES) under the condition of dehydration by using EDC as a dehydrating agent; and synthesizing the novel silicane head group-containing cholesterol derivative through covalent connection of an amido bond or by directly reacting the carboxyl on the cholesterol molecule and isocyanatopropyltriethoxysilane (IPTES). The cholesterol derivative-based organic-inorganic composite nano vesicle has excellent biocompatibility. The organic-inorganic composite cholesterol derivative can perform self assembly to form a highly dispersed system similar to a liposome and is applied to embedding, transferring and sustained release of various medicaments, such as hydrophilic medicaments, oleophylic medicaments, amphiphilic medicaments and the like. The method has a simple operation process and high repeatability, can be relatively widely applied to the synthesis of a plurality of organic-inorganic composite cholesterol derivatives and has a wide application prospect.

Description

technical field [0001] The invention relates to a method for preparing organic-inorganic composite nanovesicles based on cholesterol derivatives. Background technique [0002] Malignant tumor is one of the diseases that seriously endanger human health. At present, chemical drug therapy is still the most commonly used treatment method. The ideal drug therapy should only have an effect on the specific cells of the host, but not on the normal cells of the host, or cause very little toxic side effects, but the anticancer drugs currently used also have a killing effect on normal cells. In order to increase the anti-cancer effect and reduce toxic side effects, researchers are racing to research and develop the latest nano-drug carrier materials and technologies, so as to fundamentally change the current status of cancer diagnosis, treatment and prevention. [0003] As a kind of drug carrier, liposome is composed of bilayer. Because of its cell-like structure, liposome becomes an ...

Claims

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Application Information

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IPC IPC(8): A61K9/127A61K47/28A61K47/24
Inventor 戴志飞马艳查正宝梁晓龙岳秀丽
Owner HARBIN INST OF TECH
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