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Acid-sensitive liposome drug delivery system with internalization effect, and preparation method and applications thereof

A drug delivery system and liposome technology, applied in the field of medicine, can solve the problems of small critical micelle concentration, failure to consider and improve the hydration layer hindrance of PEG, low modification rate of acid-sensitive conjugates, etc., to achieve easy large-scale Effects of production quality control, strong selectivity, strong acid sensitivity

Inactive Publication Date: 2015-07-22
谢辉 +1
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although this acid-sensitive drug delivery system improves the selectivity of CPP for tumors to a certain extent, it still does not consider and improve the hindering effect of the hydration layer of PEG, and does not fully exert the effect of CPP.
In addition, the PE used in the long-cycle acid-sensitive part mPEG2000-HZ-PE is a phospholipid molecule with two long-chain organic acids, which has a small critical micelle concentration. It is easier to form micelles and difficult to insert into the surface of liposomes, and there is a problem of low modification rate of acid-sensitive conjugates in the preparation

Method used

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  • Acid-sensitive liposome drug delivery system with internalization effect, and preparation method and applications thereof
  • Acid-sensitive liposome drug delivery system with internalization effect, and preparation method and applications thereof
  • Acid-sensitive liposome drug delivery system with internalization effect, and preparation method and applications thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0077] Synthesis and purification of embodiment 1 acid sensitive poly Z glycol-hydrazone bond-stearic acid conjugate

[0078] The synthetic route is shown in Figure 1. mPEG 2000 -CHO was dissolved in a chloroform solution containing a slight excess of PDPH, reacted at room temperature for 48 hours, and stirred under argon protection to synthesize mPEG 2000 -HZ-PDP. STR-SH was dissolved in anhydrous chloroform containing excess mPEG 2000 -HZ-PDP, add triethylamine, stir overnight at room temperature under the protection of argon. Chloroform was removed under reduced pressure, the conjugate was purified with Sepharose CL-4B, and freeze-dried to obtain a white powder. The Agilent HP1100 / ELSD method determines that the purity of the conjugate is 99% ( figure 2 ). 1NNMR spectrum ( image 3 ) proves the structure of the conjugate.

Embodiment 2

[0079] Example 2 Preparation of acid-sensitive liposome loaded fat-soluble drug coumarin with internalization

[0080] Soybean lecithin, cholesterol, stearic acid, and coumarin were dissolved in chloroform at a molar ratio of 2:1:0.08:0.02, and a thin film was formed on the wall of the bottle by rotary evaporation under reduced pressure. The drug-containing common liposome (CL) was formed after PBS hydration. Under magnetic stirring, EDCl was added, and S-NHS was added after about 1 min. The molar ratio of stearic acid, EDCl and S-NHS in the reaction was 1:40:100. After activation at room temperature for 15 minutes, adjust the pH to 12, add CPP equivalent to STP, stir at room temperature for 12 hours, then add 8% STR-HZ-PEG2000 and incubate for 12 hours. 10000g ultrafiltration (MW cut off=30000) for 20min to remove unreacted EDCl, S-NHS and CPP. See the preparation process Figure 4 The obtained acid-sensitive liposome loaded with coumarin has a particle diameter of 100-150...

Embodiment 3

[0082] Example 3 Preparation of acid-sensitive liposome loaded with doxorubicin with internalization

[0083]Film method: soybean lecithin, cholesterol and stearic acid are dissolved in chloroform at a molar ratio of 2:1:0.08, and a thin film is formed on the wall of the bottle by rotary evaporation under reduced pressure at 40°C. The aqueous solution (pH 4-5) containing citric acid is hydrated to form blank ordinary liposomes. Adjust the pH of the external aqueous phase to 7.5-8.0 with sodium carbonate buffer, add adriamycin hydrochloric acid aqueous solution, and incubate overnight in a water bath at 50° C. to obtain ordinary liposomes of adriamycin. Under magnetic stirring, EDCl was added, and S-NHS was added after about 1 min. The molar ratio of stearic acid, EDCl and S-NHS in the reaction was 1:40:100. After activation at room temperature for 15 minutes, adjust the pH to 12, add CPP equivalent to STR, stir at room temperature for 12 hours, then add 8% STR-HZ-PEG2000 and ...

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Abstract

The invention belongs to the field of pharmaceutic preparation of medical technology, and discloses an acid-sensitive liposome drug delivery system with internalization effect, and a preparation method and applications thereof. The preparation method comprises following steps: direct coupling of a cell penetrating peptide rich in arginine residues with a liposome surface long chain organic acid is realized so as to obtain an acid-sensitive polyethylene glycol-hydrazone bond-long chain organic acid coupling compound; and the tumour targeted liposome loaded with lipid-soluble drugs and water-soluble anthraquinone alkalescent drugs is prepared via filming-rehydration; wherein the cell penetrating peptide is a poly arginine short peptide which is GGRRRRRRRRR preferably; molecular weight of polyethylene glycol ranges from 500 to 5000Da, and preferably 2000Da; optimized cell penetrating peptide density accounts for 2 to 8% of that of phosphatide, and preferably 4%; and density of the polyethylene glycol-hydrazone bond-long chain organic acid coupling compound accounts for 5 to 20% of that of phosphatide, and preferably 8%. The acid-sensitive liposome drug delivery system is capable of solving a problem that liposome cell internalization is difficult, and providing possibility for development of antitumor drug targeted subcellular organelle. The acid-sensitive liposome drug delivery system is nontoxic basically; preparation technology is simple; and the acid-sensitive liposome drug delivery system is convenient for industrialized application.

Description

technical field [0001] The invention relates to a liposome drug delivery system, in particular to a tumor targeting liposome drug delivery system and a preparation method thereof, belonging to the technical field of medicine. Background technique [0002] Liposomes have become a widely used nanocarrier system because of their biocompatibility, biodegradability, drug loading diversity, and ability to improve drug stability [1]. In 1995, the first anti-tumor drug liposome preparation, doxorubicin liposome, was approved by the FDA for the first time and entered clinical practice [2], which significantly improved the cardiotoxicity of doxorubicin, but its efficacy did not significantly improve. In order to increase the accumulation of drugs in the target area and further improve the drug efficacy, pH-sensitive liposomes with physical targeting [3, 4], heat-sensitive liposomes [5], and magnetic-sensitive liposomes have successively appeared in the field of liposome research. Pla...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/127A61K9/19A61K47/42A61K47/34A61K45/00A61P35/00C08G65/48
Inventor 谢辉陈建华
Owner 谢辉
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