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Liposome drug delivery system targeting tumor-associated fibroblasts

A technology related to fibroblasts and tumors, which is applied in the field of new tumor-related fibroblasts targeting drug-loaded liposomes and liposome drug-loaded systems, which can solve the problems of increased interstitial pressure, poor anti-tumor efficacy, weakened Nano-preparation penetration and other issues, to reduce toxicity, improve tumor microenvironment, enhance the effect of anti-tumor drugs

Inactive Publication Date: 2018-08-17
PEKING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, tumor-associated fibroblasts can also synthesize a large amount of collagen to form dense tumor tissue, resulting in abnormally increased interstitial pressure in the tumor, providing a physical barrier for tumor cells, and further weakening the nano-preparation in the tumor. Penetration
This is also one of the main reasons for the poor anti-tumor efficacy of nano-preparations in vivo.

Method used

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  • Liposome drug delivery system targeting tumor-associated fibroblasts
  • Liposome drug delivery system targeting tumor-associated fibroblasts
  • Liposome drug delivery system targeting tumor-associated fibroblasts

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Example 1. Preparation of drug-loaded liposomes targeting tumor-associated fibroblasts

[0044] 1. Synthesis of Guided Compounds

[0045] A certain amount of NHS active esterified polyethylene glycol-modified phospholipid and polypeptide powder (molar ratio 2:1) was weighed and dissolved in anhydrous dimethylformamide respectively. After the powder is completely dissolved, the polypeptide solution is first transferred to an eggplant-shaped bottle, and the NHS active esterified polyethylene glycol-modified phospholipid solution is added dropwise to the polypeptide solution under magnetic stirring. After mixing evenly, add an appropriate amount of triethylamine to adjust the pH of the reaction solution to 8.0-9.0, and react at room temperature for 96 hours under the protection of nitrogen and light. During the reaction, the progress of the reaction was followed by thin layer chromatography. At the end of the reaction, the target compound was obtained by dialysis and fre...

Embodiment 2

[0059] Example 2. Targeting evaluation of FH polypeptide-liposome / Navitoclax on tumor-associated fibroblasts in vitro

[0060] HPLC was used to measure the uptake of free Navitoclax, liposome / Navitoclax, FH polypeptide-liposome / Navitoclax and FH polypeptide+FH polypeptide-liposome / Navitoclax by LX‐2 cells. LX‐2 cells were seeded in 24-well plates, incubated overnight until they were completely attached to the wall, discarded the original culture medium, and washed with phosphate buffer; 1ml of different Navitoclax preparations (free Navitoclax, liposome / Navitoclax, FH polypeptide‐liposome / Navitoclax and FH polypeptide+FH polypeptide‐liposome / Navitoclax), the final concentration of Navitoclax was 40 μg / ml, and incubated in a 37°C incubator for 3 hours; Phosphate buffer solution to stop cell uptake, then add 0.2ml RIPA cell lysate, lyse the cells at room temperature for 5min; transfer the cell lysate to a 1.5ml EP tube, add 0.3ml methanol to each well, and transfer to Correspo...

Embodiment 3

[0061] Establish a nude mouse model bearing Hep G2 tumor until the tumor volume is 200mm 3 , were randomly divided into 4 groups, and injected 200 μl of normal saline, free Navitoclax, liposome / Navitoclax and FH polypeptide-liposome / Navitoclax respectively into the tail vein. The dose of Navitoclax is 5 mg / kg, administered every other day, for a total of three administrations. The animals were sacrificed on the third day after the third administration, and frozen sections of tumor tissues were prepared. Tumor-associated fibroblasts were labeled by immunofluorescence: the frozen sections of the tumor were dried by cold air, fixed with 4% paraformaldehyde at room temperature for 15 minutes, washed with phosphate buffer for 3 times, each time for 5 minutes, and placed on glass after cleaning. Mark the tumor area on the back of the slice; add 0.1% TritonX‐100 (prepared in phosphate buffer), permeabilize at room temperature for 5 minutes, wash with a large amount of PBS again for ...

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Abstract

The invention belongs to the field of pharmaceutic preparation, and relates to a targeted drug-carrying liposome of a tumor associated fibroblast. The surface of the targeted drug-carrying liposome is modified with a high-affinity ligand of a specific expression protein of the tumor associated fibroblast. The targeted drug-carrying liposome is capable of realizing targeted delivering of drugs into the tumor associated fibroblast, realizing intervention on tumor microenvironment via action on the tumor associated fibroblast, and realizing tumor treatment. And in addition, the tumor associated fibroblast targeted preparation can be combined with routine tumor cell targeted nano preparations so as to improve antitumous effects of the routine tumor cell targeted nano preparations.

Description

technical field [0001] The invention relates to the field of pharmaceutical preparation technology and tumor treatment, in particular to a liposome drug-carrying system targeting tumor-associated fibroblasts. It specifically involves the modification of liposomes carrying selective or non-selective drugs for tumor-associated fibroblasts with high-affinity binding polypeptides specifically expressed by tumor-associated fibroblasts, and the preparation of new tumor-associated fibroblast-targeted drug-loaded lipids body and its medicinal uses. Background technique [0002] In anti-tumor research, the research on active targeting liposome drug delivery system has been quite mature, but in the current research, most of the targeting agents are targeting the tumor cells themselves. Although the drug delivery system targeting tumor cells can achieve direct tumor suppression, because the tumor is a complex and heterogeneous tissue, components other than the tumor cells themselves p...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K9/127A61K47/42A61K31/635A61K31/704A61K33/24A61K31/337A61P35/00A61P35/04A61K47/24A61K47/28A61K47/62A61K47/69
Inventor 张强代文兵陈斌龙王学清张华刘同舟
Owner PEKING UNIV
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