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Medicine delivery system for regulating tumor microenvironment and active targeting and use thereof

A tumor microenvironment and delivery system technology, applied in the field of pharmaceutical preparations, can solve the problems of limiting the penetration of chemotherapy drugs, poor prognosis, and inability to effectively reach tumor cells, so as to increase penetration and accumulation, inhibit activation, and improve targeting efficiency Effect

Inactive Publication Date: 2019-04-09
FUDAN UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] Studies have shown that the limited chemotherapy effect of pancreatic cancer is closely related to its unique and complex tumor microenvironment; more than 90% of the cells in its tumor microenvironment are not tumor cells but mesenchymal cells, including tumor-associated fibroblasts (CAFs) , endothelial cells, pericytes, macrophages, etc., among which CAF has the most content and is an important support cell for tumors. It not only serves as a physical barrier for chemotherapy drugs to penetrate into tumor cells, but also plays an important role in tumor growth, drug resistance, and metastasis. support and promotion; the fibroblasts in it can secrete a large number of cytokines after being activated, and these factors can interact with tumor cells to promote the proliferation and metastasis of pancreatic cancer cells; at the same time, CAF can also secrete matrix metalloproteinases (MMPs), which It is also closely related to tumor metastasis; CAF can synthesize and secrete a large amount of extracellular matrix, and the massive generation and irregular deposition of these extracellular matrix is ​​the main cause of interstitial high pressure in pancreatic cancer, which limits the penetration ability of chemotherapy drugs. make it ineffective to reach tumor cells
Traditional chemotherapy methods can also non-specifically kill CAF while partially killing tumor cells, but the removal of CAF will cause depletion of tumor stroma and cause autoimmune suppression; in addition, it can also activate tumor cells that promote tumor cell proliferation, drug resistance, and metastasis. Wnt16b signaling pathway, leading to poorer prognosis

Method used

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  • Medicine delivery system for regulating tumor microenvironment and active targeting and use thereof
  • Medicine delivery system for regulating tumor microenvironment and active targeting and use thereof
  • Medicine delivery system for regulating tumor microenvironment and active targeting and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Example 1: Preparation and Characterization of Nano Delivery System

[0038]The nano drug delivery system was prepared by emulsified solvent evaporation method. Dissolve 22.5 mg of mPEG-PLA and 2.5 mg of mal-PEG-PLA in 1 mL of dichloromethane, add an appropriate amount of α-mangostin to make the concentration 0.75 mg / mL, and then add 2 mL of 1% cholic acid Sodium solution, under the condition of ice bath, ultrasonic 2.4min, ultrasonic condition is power 240W, interval time 2S. Then disperse with 8mL of 0.5% sodium cholate solution for 10min, remove residual methylene chloride by rotary evaporation, centrifuge at 15000rpm / min for 1h at 4°C, and suck off the supernatant to obtain drug-loaded nanoparticles (α-M NP). The nano drug delivery system with targeting function is based on the drug-loaded nanoparticles, through the reaction between the maleimide group on the surface of the nanoparticles and the sulfhydryl group of the polypeptide, according to the molar ratio of ...

Embodiment 2

[0040] Example 2: NIH3T3 cell uptake of the delivery system

[0041] In order to verify whether the nano-drug delivery system can target activated tumor-associated fibroblasts in the tumor microenvironment, the uptake of coumarin-6-loaded NPs and CREKA-NPs in activated and non-activated fibroblasts was investigated Behavior: First, a nano-delivery system loaded with coumarin-6 was prepared. The preparation method of nanoparticles was the same as in Example 1, except that α-mangostin was replaced by cou-6, so that the concentration of cou-6 was 2 μg / mL. NIH3T3 cells were seeded on a 96-well plate (n=3) at a density of 3000 cells per well, and the NIH3T3 cells in the activation group were pre-incubated in DMEM complete medium containing TGF-β (10 ng / mL) for 24 hours. Dilute the coumarin-loaded nanoparticles (NP and CREKA-NP) to 100 ng / mL with DMEM complete medium, add 100 μL of nanoparticle solution to each well of a 96-well plate, at 37 ° C, 5% carbon dioxide After incubating ...

Embodiment 3

[0043] Example 3: Investigation of the inhibitory effect of the drug-loaded nano-delivery system on activated NIH3T3 cells

[0044] In order to verify whether α-mangostin has an inhibitory effect on activated NIH3T3 cells and whether it can inhibit the secretion of Fibronectin, the expression of Fibronectin, α-SMA and FAP was investigated by Western Blotting and fluorescent quantitative PCR; The concentration of 20,000 cells was uniformly inoculated in 6-well plates. The NIH3T3 cells in the experimental group were pre-incubated with DMEM complete medium containing TGF-β (10ng / mL) for 24h, after which the medium was sucked off, and then given with 10μM and 20μM NP(α-M) was incubated in complete DMEM medium for 24 hours, and the negative control group was activated without adding TGF-β. After the administration period, the supernatant was aspirated, and the cells used in the Western Blotting group were washed 3 times with PBS, the 6-well plate was placed on ice, and 200 μL of RI...

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Abstract

The invention belongs to the field of pharmaceutical preparations, relates to a novel medicine delivery system, and particularly relates to a medicine delivery system for regulating tumor microenvironment and active targeting and use thereof. The medicine delivery system adopts an FDA-approved biodegradable polymer polylactic acid material; a natural drug monomer alpha-mangostin (alpha-M) is physically occluded by an emulsion solvent evaporation method to prepare a medicine-loaded nano-delivery system (alpha-M NP); functional polypeptides are further modified on a surface of the alpha-M NP bycovalent binding; tumor-associated fibroblasts abnormally activated in the tumor microenvironment can be actively targeted so as to prepare a nano medicine delivery system with functions of active targeting and regulating the tumor microenvironment. In-vitro and in-vivo experiments show that the delivery system can inhibit excessive activation of the tumor-associated fibroblasts, effectively improves the tumor microenvironment, increases accumulation of medicines in tumor locations, and has greater clinical application prospects.

Description

technical field [0001] The invention belongs to the field of pharmaceutical preparations and relates to a drug delivery system, in particular to a drug delivery system for regulating tumor microenvironment and active targeting and its application. In the delivery system of the present invention, hydrophobic natural drug monomers with a short half-life are encapsulated in biodegradable polylactic acid nanoparticles, and at the same time, polypeptides with targeting functions are modified on the surface by chemical bonding, so as to achieve specific delivery of preparations to in the tumor microenvironment. Background technique [0002] According to statistics, pancreatic cancer is a highly aggressive malignant tumor of the digestive tract, and its 5-year survival rate is less than 6%. Surgical treatment is the most effective method for the treatment of pancreatic cancer, but due to the hidden onset and rapid progression of the disease, only about 10% of patients can be surgi...

Claims

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Application Information

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IPC IPC(8): A61K47/69A61K47/64A61K31/352A61P35/00
CPCA61K31/352
Inventor 陈钧冯静娴胥敏俊朱倩倩
Owner FUDAN UNIV
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