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Bone-targeted delivery system for osteogenesis treatment based on small nucleic acid medicine, and preparation method thereof

A technology for small nucleic acid drugs and delivery systems, which is applied in the field of molecular biology and can solve problems such as high transfection efficiency of polymer materials

Active Publication Date: 2012-12-19
THE CHINESE UNIVERSITY OF HONG KONG
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] In addition, because small nucleic acid drugs need to be released in the cytoplasm and interact with mRNA, it is difficult for ordinary polymer materials to ensure high transfection efficiency, so the bone-targeted delivery system for delivering small molecule drugs is not suitable for small nucleic acid drug

Method used

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  • Bone-targeted delivery system for osteogenesis treatment based on small nucleic acid medicine, and preparation method thereof
  • Bone-targeted delivery system for osteogenesis treatment based on small nucleic acid medicine, and preparation method thereof
  • Bone-targeted delivery system for osteogenesis treatment based on small nucleic acid medicine, and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0059] Embodiment 1 (DSS) 6 Ability to selectively target bone-forming surfaces

[0060] Eighteen 6-month-old female rats (Sprague-dawley) were selected and divided into FITC group (fluorescein isothiocyanate, n=6), Asp 8 Group (n=6) and (DSS) 6 Group (n=6). Asp 8 and (DSS) 6 Both were marked with FITC. Rats were subcutaneously injected 3 days in advance, and Xylenol Orange (XO, 30mg / kg) was injected to mark the surface of bone formation. After the rats were anesthetized with ketamine (75 mg / kg) and xylazine (10 mg / kg), FITC, Asp 8 -FITC and (DSS) 6 - FITC was administered by tail vein injection, 27 μM / kg / 0.2ml normal saline, respectively. After 24 hours, the rats were killed to observe the non-calcified tissue parts. Femurs and tibias were dehydrated with graded concentrations of ethanol and embedded in modified methyl methacrylate (without decalcification). Femurs were sectioned to a thickness of 15 μm using a Leica SM2500E microcrotome (Leica Microsystems). Then,...

Embodiment 2

[0062] Example 2 Preparation of bone-targeted small nucleic acid drug liposome delivery system

[0063] (1) Preparation of liposomes containing small nucleic acid drugs: get dioleoyl dimethyl ammonium propane (DODAP), dioleoyl phosphatidylethanolamine (DOPE), cholesterol (Chol), DSPE-mPEG2000 (methoxy is the terminal PEG) was dissolved in ethanol at a molar ratio of 40:10:45:5, and slowly added into citrate buffer (pH 4) of 1 mg / mL random sequence of small interfering ribonucleic acid in rapid stirring, ethanol accounted for The total volume is 35%, and the mass ratio of siRNA to lipid is 10%. After stirring at room temperature for 20 minutes, the liposome was extruded by an extruder, passed through a double-layer polycarbonate membrane with a pore size of 0.08 μm, and the particle size was controlled at 50-100 nm. The liposomes were dialyzed against pH 7.4 buffered saline solution for 3 hours at room temperature to remove ethanol and unencapsulated siRNA.

[0064] (2) Linki...

Embodiment 3

[0068] Example 3 Preparation of bone-targeted small nucleic acid drug liposome delivery system

[0069] (1) Preparation of blank liposomes: N-(1-(2,3-dioleoyloxy)propyl)-N,N,N-trimethylammonium chloride (DOTAP), dioleoyl phospholipid Ethanolamine (DOPE), cholesterol (Chol), distearoylphosphatidylethanolamine-polyethylene glycol 2000 (DSPE-mPEG2000) and distearoylphosphatidylethanolamine-polyethylene glycol 2000-maleimide ( DSPE-PEG-MAL) was dissolved in chloroform at a molar ratio of 42: 15: 38: 3: 2, and the film dispersion method was used. After the chloroform was removed by rotary evaporation, 10 mM phosphate buffer was added for hydration to form multilayered liposomes. The multilayer liposome is extruded by an extruder to obtain a large single-chamber blank liposome;

[0070] (2) Connect bone-targeting molecules and blank liposomes: take bone-targeting molecules (DSS) with sulfhydryl groups at the end 6 -SH (3:1 molar ratio relative to DSPE-PEG-MAL in blank liposomes) w...

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Abstract

The invention provides a bone-targeted delivery system for osteogenesis treatment based on small nucleic acid medicine, and a preparation method thereof. The bone-targeted delivery system comprises liposome, bone-targeted molecules and small nucleic acid medicine, wherein the bone-targeted molecules are one or more selected from bisphosphonate, eight aspartic acid polypeptide repeat sequences, six aspartic acid-serine-serine polypeptide repetitive sequences and screened out aptamer aiming at osteoblastlike cells; and the small nucleic acid medicine is one or more selected from blocking agents of small interfering ribonucleic acid, micro ribonucleic acid mimics and micro ribonucleic acid which have the function of promoting bone formation. Compared with conventional bone-targeted delivery systems, the bone-targeted delivery system has stronger specificity and high transfection efficiency for the small nucleic acid, and can reach relatively high silencing efficiency.

Description

technical field [0001] The invention belongs to the field of molecular biology, and relates to a bone-targeted delivery system based on small nucleic acid drug osteogenesis therapy and a preparation method thereof. Background technique [0002] The basic process of osteogenesis includes two aspects of bone tissue formation and bone tissue resorption. Osteoblasts and osteoclasts are responsible for bone formation and bone resorption, respectively, and the balance between the two ensures constant bone mass in adult animals and humans. [0003] At present, bone-targeted drug delivery systems are mainly used for the delivery of small molecule drugs, usually composed of bone-targeted molecules and small molecule drugs / polymer compounds. Common bone-targeting molecules include tetracyclines, bisphosphonates, and aspartic acid repeat-containing peptides. These targeting molecules can be directly covalently linked with small molecule drugs such as estradiol, ibuprofen, etc., or li...

Claims

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Application Information

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IPC IPC(8): A61K48/00A61K9/127A61K47/42A61K47/02A61K47/28A61K47/24A61K47/34A61P19/08
Inventor 张戈秦岭吴蘅熊良俭
Owner THE CHINESE UNIVERSITY OF HONG KONG
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