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Difunctional tumor targeted liposome drug-delivery system and preparation and application thereof

A technology for targeting liposomes and drug delivery systems, applied in the field of liposome drug delivery systems, tumor-targeted liposome drug delivery systems and their preparations, can solve the problem of small critical micelle concentration, without considering and improving PEG The barrier effect of the hydration layer and the low modification rate of acid-sensitive conjugates, etc., achieve the effects of easy mass production quality control, strong selectivity, and strong acid sensitivity

Inactive Publication Date: 2015-11-04
PEKING UNIV
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  • Summary
  • 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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  • Difunctional tumor targeted liposome drug-delivery system and preparation and application thereof
  • Difunctional tumor targeted liposome drug-delivery system and preparation and application thereof
  • Difunctional tumor targeted liposome drug-delivery system and preparation and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0076] Example 1 Synthesis and purification of acid-sensitive polyethylene glycol-hydrazone bond-stearic acid conjugate

[0077] Synthetic route such as figure 1 shown. 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 determined that the purity of the conjugate was 99% ( figure 2 ). 1NNMR spectrum ( image 3 ) proves the structure of the conjugate.

Embodiment 2

[0078] Example 2 Preparation of bifunctional liposome-loaded fat-soluble drug coumarin

[0079] 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, EDCI was added, and S-NHS was added after about 1 min. The molar ratio of stearic acid, EDCI 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 EDCI, S-NHS and CPP. See the preparation process Figure 4 The obtained acid-sensitive liposome loaded with coumarin has a particle diameter of 100-150nm, an encapsulation ra...

Embodiment 3

[0081] Example 3 Preparation of bifunctional liposome-loaded doxorubicin

[0082]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, EDCI was added, and S-NHS was added after about 1 min. The molar ratio of stearic acid, EDCI 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 incubate for 12 hours. 1000...

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Abstract

The invention belongs to the field of pharmaceutic preparations in medical technology and discloses a difunctional tumor targeted liposome drug-delivery system and a preparation method and an application thereof. By directly coupling a cell-penetrating peptide rich in arginine residues and liposome surface long-chain organic acid and with the combination of a polyethylene glycol-hydrazone bond-long-chain organic acid conjugate, a tumor targeted liposome loading a fat soluble drug and a water-soluble anthraquinone slightly alkaline drug is prepared by a thin-film rehydration method, wherein the cell-penetrating peptide is polyarginine short peptide, preferably nonaarginine; molecular weight of polyethylene glycol is 500 Da-5000 Da, preferably 2000 Da; optimal cell-penetrating peptide density is 2-8% (preferably 4%) of density of phospholipid; and density of the polyethylene glycol-hydrazone bond-long-chain organic acid conjugate is 5-20% (preferably 8%) of density of phospholipid. The system provided by the invention solves the problem that existing liposome cellular internalization is difficult, and provides possibility for antitumor drug targeting subcellular organelle. The drug-delivery system basically is nontoxic, has a simple preparation technology and is easy for industrial 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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IPC IPC(8): A61K47/34C08G65/48A61P35/00A61K47/60A61K47/66A61K47/69
Inventor 谢英丁源刘畅徐海峰孙丹杨鸿鸽
Owner PEKING UNIV
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