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Low-toxicity bionic nano system capable of simultaneously regulating tumor microenvironment and killing tumor cells in targeted manner and construction method of low-toxicity bionic nano system

A tumor microenvironment and tumor cell technology, applied in the field of traditional Chinese medicine pharmacy, can solve the problems of poor solubility of natural products, affect tumor vascular structure, and high lethality, achieve high clinical application prospects and transformation value, prolong circulation time, and have less toxic and side effects. Effect

Inactive Publication Date: 2021-03-30
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0002] The prior art discloses that pancreatic cancer, as a malignant tumor of the digestive tract, has a high mortality rate, the five-year survival rate of patients is less than 6%, and the prognosis is extremely poor; its resistance to treatment is mainly related to the immunosuppressive tumor microenvironment
In addition, immunosuppressive M2 macrophages also secrete some immunosuppressive molecules, which affect tumor vascular structure and permeability and hinder drug delivery.
Clinical practice shows that the current combination of chemotherapy regimens can improve the efficacy of anti-pancreatic cancer, but the tumor response rate is still low and the prognosis is poor. Therefore, for pancreatic cancer, a tumor with an immunosuppressive tumor microenvironment, toxic Smaller drugs regulate the tumor microenvironment, inhibit the abnormal activation of CAFs, reduce the deposition of tumor extracellular matrix, and inhibit the polarization of macrophages to the M2 type. Combined with chemotherapy drugs to improve the anticancer effect, it has a high clinical application prospect and conversion value
[0003] Studies have reported that natural product monomers extracted from natural plants can improve the tumor microenvironment, increase the penetration and accumulation of chemotherapy drugs; and, the natural product itself has poor solubility, short half-life in vivo circulation, and faster clearance. Cannot accumulate in tumor site

Method used

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  • Low-toxicity bionic nano system capable of simultaneously regulating tumor microenvironment and killing tumor cells in targeted manner and construction method of low-toxicity bionic nano system
  • Low-toxicity bionic nano system capable of simultaneously regulating tumor microenvironment and killing tumor cells in targeted manner and construction method of low-toxicity bionic nano system
  • Low-toxicity bionic nano system capable of simultaneously regulating tumor microenvironment and killing tumor cells in targeted manner and construction method of low-toxicity bionic nano system

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] Example 1: Characterization of biomimetic nanosystems with low toxicity

[0055] To prepare a low-toxic biomimetic nanosystem, stir 14mL cyclohexane and 6mL nonylphenol polyoxyethylene ether as the oil phase, and 600μL 2.5 M CaCl 2 solution, stirred and added to the oil phase as the calcium phase, after mixing 180 μL 60 mM GEM and 100 μL 40 mM CBD, add 12.5 mM NaH 2 PO 4 (final concentration) solution to a volume of 600 μL, added to the oil phase as the phosphorus phase. After the two phases were evenly dispersed, the calcium phase was added to the phosphorus phase and stirred for 5 min, then DOPA was added to react for 1 h. The above system was demulsified by adding absolute ethanol for 30 minutes, and the supernatant was discarded by centrifugation to wash away the oil phase. The centrifugation parameters were 12500g, 20min, 4°C. Under the same conditions, the precipitate was washed twice with absolute ethanol to obtain a white solid that was evaporated to dryness ...

Embodiment 2

[0057] Example 2: The uptake and uptake mechanism of pancreatic cancer cells to the biomimetic nano-delivery system

[0058] Choose Kras G12D The uptake of CBD-GEM-HDL (LCP-4F) and CBD-GEM-LNC (LCP) in mutant KPC cells was investigated. The biomimetic nanoparticles are fluorescently labeled with a cell membrane red fluorescent probe (DiI). 24 hours after the KPC cells were seeded in a 96-well plate, the medium was sucked out, and nanoparticles were added according to the pre-set concentration gradient table. The nanoparticles were sucked out after 2 hours of ingestion by the cells, washed with phosphate buffered saline (PBS), fixed with 4% paraformaldehyde for 15 minutes and After staining the nuclei with nuclear dye (Hoechst reagent) in the dark for 8 minutes, the qualitative and quantitative results of cell uptake were investigated with a high-content analysis system. In addition, KPC cells were cultured in culture flasks, and LCP-4F or LCP with a DMPC concentration of 25 ...

Embodiment 3

[0061] Example 3: Investigation of cannabidiol on the M2 typing of macrophages and the expression of cellular proteins in CAFs

[0062] In order to verify whether cannabidiol in the bionic delivery system can affect tumor-associated macrophages in the tumor microenvironment, the changes in the proportion of macrophages in the M2 type after administration were investigated. Unactivated RAW 264.7 cells were used as the negative control group, and RAW264.7 cells activated with 10ng / ml IL-13 were used as the M2 type positive control group, comparing free drug and nano preparations containing 10 μM cannabidiol on macrophage M2 types inhibitory effect. Specifically, in a 6-well plate of RAW264.7 cells, except for the negative control group, 10 ng / ml of the stimulating factor IL-13 was added to each well, and after being placed in the incubator for 24 hours, CBD-Free and Cannabidiol with a concentration of 10 μM were given respectively. CBD-NP and an equal volume of phosphate buffer...

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Abstract

The invention belongs to the technical field of traditional Chinese medicine pharmacy, and relates to screening of effective components of traditional Chinese medicine and a preparation thereof, in particular to a low-toxicity bionic nano system capable of simultaneously adjusting a tumor microenvironment and killing pancreatic cancer cells in a targeted manner and a construction method. The bionic nano system LCP-4F has the particle size of about 15nm, is uniform and stable, can be efficiently taken in by pancreatic cancer cells in vitro, and regulates cytokines secreted by CAFs, such as fibronectin, fibroblast actin and the like. An in-vivo pharmacodynamic experiment shows that the bionic nano system can be targeted and accumulated at a tumor part, and has good microenvironment regulation and cancer cell killing effects; and the bionic nano system has broad prospects in the aspects of regulating the tumor microenvironment excessively activated by tumor-associated fibroblasts and killing cancer cells.

Description

technical field [0001] The invention belongs to the technical field of traditional Chinese medicine pharmacy, and relates to the screening of active ingredients of traditional Chinese medicine and its preparation, in particular to a low-toxicity biomimetic nano system and a construction method for simultaneously regulating the tumor microenvironment and targeting and killing tumor cells; the tumor cells are especially Pancreatic cancer cells. Background technique [0002] The prior art discloses that pancreatic cancer, as a malignant tumor of the digestive tract, has a high fatality rate, the five-year survival rate of patients is less than 6% and the prognosis is extremely poor; its resistance to treatment is mainly related to the immunosuppressive tumor microenvironment. Studies have shown that in the tumor microenvironment, mesenchymal cells account for the vast majority, including tumor-associated fibroblasts (CAFs), endothelial cells, pericytes, tumor-associated macroph...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/127A61K47/42A61K47/24A61K47/02A61K31/05A61K31/7068A61P35/00
CPCA61K9/1271A61K31/05A61K31/7068A61K47/02A61K47/24A61K47/42A61P35/00A61K2300/00
Inventor 陈钧陈梁
Owner FUDAN UNIV
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