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Adriamycin-carrying lipid nanoscale ultrasound contrast agent targeting tumor-related fibroblasts and preparation method of adriamycin-carrying lipid nanoscale ultrasound contrast agent

A technology of fibroblasts and ultrasound contrast agents, applied in echo/ultrasound imaging agents, medical preparations containing active ingredients, anti-tumor drugs, etc., to achieve high biological safety, excellent imaging capabilities, and enhanced imaging capabilities Effect

Active Publication Date: 2019-06-21
青岛孚嘉康达智能科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Aiming at the problem that there is currently no relevant research on CAF-targeted ultrasound contrast agents, the present invention provides a lipid nanoscale ultrasound contrast agent targeting tumor-associated fibroblasts (CAF) and carrying doxorubicin and a preparation method thereof

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] Example 1: Synthesis and identification of targeting material DSPE-PEG-FH

[0059] Synthesis of targeting material DSPE-PEG-FH:

[0060] The targeting material DSPE-PEG-FH was prepared by condensation reaction of amino group and carboxyl group. Mix DSPE-PEG-NHS, FH short peptide, and HBTU with anhydrous DMF according to a certain ratio (molar ratio 3:1:3), and add triethylamine to adjust the pH to 8-9. Gentle stirring reaction at room temperature for 2h. After mixing water, 1,2-ethanedithiol, triisopropylsilane, and trifluoroacetic acid (1:2:2:95, v / v / v / v), add the above reaction according to the volume ratio of 1:5 solution, used to remove the protective group of the short peptide, separated DSPE-PEG-FH with ether, and dialyzed the separated product for 48 hours, with a molecular weight cut-off value of 3500Da. Finally, the final product DSPE-PEG-FH was lyophilized and stored at -20°C.

[0061] Identification of targeting material DSPE-PEG-FH:

[0062] The final p...

Embodiment 2

[0063] Example 2: Preparation of lipid nanoscale ultrasound contrast agent targeting CAF and carrying DOX

[0064] (1) Weigh 0.1ml of propylene glycol and 0.1ml of glycerin and place them in a 1.5ml EP tube, add 5mgDPPC, 2mg of DSPE-PEG-NH2, 0.5mg of DSPE-PEG-FITC, and 0.5mg of DSPE-PEG-FH prepared in Example 1 , PBS to a volume of 1ml; the PBS is a phosphate buffer saline, and its components are: Na 2 HPO 4 8mM, KH 2 PO 4 2mM, pH 7.2;

[0065] (2) Pass perfluoropropane into the mixture in step (1) to replace the air, place the centrifuge tube in a constant temperature water bath at 60°C and heat until the lipid is completely dissolved;

[0066] (3) Add DOX (0.5, 1.0, 1.5, 2.0 mg / ml) to the mixture in step (2), shake it mechanically for 90 seconds, take it out, centrifuge at 300 rpm for 5 minutes, and take out the lower layer of liquid, which is the prepared nano-scale ultrasound contrast agent.

[0067] figure 2 A shows the schematic diagram of nano-scale ultrasound ...

Embodiment 3

[0071] Example 3: Experiment for Determination of In Vitro Developing Ability of Nanoscale Ultrasound Contrast Agent

[0072] The nano-scale ultrasound contrast agent prepared in Example 2 was placed in the round hole made of agar gel, and the contrast mode of the GE logiqE9 ultrasonic diagnostic instrument was used, the frequency was 9.0MHz, the mechanical index (MI) was 0.12, and the two-dimensional and ultrasound contrast modes were used. Simultaneously observe, adjust parameter settings, store image data with the internal workstation of the ultrasonic instrument, and use PBS as the control group. image 3 The results showed that enhanced imaging appeared in the nanoscale ultrasound contrast agent group, but no enhanced imaging occurred in the control PBS group.

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Abstract

The invention provides an adriamycin-carrying lipid nanoscale ultrasound contrast agent targeting tumor-related fibroblasts and a preparation method of the adriamycin-carrying lipid nanoscale ultrasound contrast agent. The surface of the contrast agent is modified by a high affinity ligand (FH short peptide) for specifically expressing a TNC protein by the tumor-related fibroblasts, the FH short peptide is used as a targeting ligand, lipid is used as a shell membrane material, and adriamycin and gaseous fluorocarbon are wrapped inside the shell membrane. The targeted ultrasound contrast agentis in nanoscale, has ultrasound imaging capability, can be used for targeted delivery of drugs into the tumor-related fibroblasts, and specifically kills the tumor-related fibroblasts, and a tumor treatment effect is achieved through intervention on a tumor microenvironment.

Description

technical field [0001] The invention relates to a nanoscale ultrasonic contrast agent, in particular to a lipid nanoscale ultrasonic contrast agent targeting tumor-associated fibroblasts and carrying doxorubicin, its preparation method and application, and belongs to the technical field of ultrasonic molecular imaging . Background technique [0002] Drug delivery system (drug delivery system, DDS) allows drugs to selectively accumulate in tumor tissues, avoiding the systemic toxicity and low bioavailability of traditional drug therapy. Although many DDS can significantly inhibit tumor cells in vitro experiments, but The curative effect is not obvious in in vivo experiments or preclinical experiments. Studies have shown that the existence of the tumor microenvironment is an important reason that hinders the efficacy of these DDS. [0003] The tumor microenvironment includes extracellular matrix, fibroblasts, and immune cells, among which cancer-associated fibroblasts (CAF) ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K49/22A61K31/704A61K47/42A61P35/00
Inventor 李杰郭鲁孟冬时丹丹商蒙蒙孙霄
Owner 青岛孚嘉康达智能科技有限公司
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