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Application of dual-target antagonistic oligonucleotides to inhibit the drug of neovascular proliferative diseases

A proliferative disease, oligonucleotide technology, applied in cardiovascular system diseases, sensory diseases, anti-tumor drugs, etc., can solve problems such as lack of treatment methods, and achieve the effect of reducing corneal angiogenesis

Active Publication Date: 2016-12-21
SIRNAOMICS BIOPHARMACEUTICALS (SUZHOU) CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

At present, there are many factors that affect the curative effect of colorectal cancer, and there is still a lack of effective treatment methods, so new treatment methods are urgently needed

Method used

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  • Application of dual-target antagonistic oligonucleotides to inhibit the drug of neovascular proliferative diseases
  • Application of dual-target antagonistic oligonucleotides to inhibit the drug of neovascular proliferative diseases
  • Application of dual-target antagonistic oligonucleotides to inhibit the drug of neovascular proliferative diseases

Examples

Experimental program
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Effect test

preparation example Construction

[0080] Preparation of ligand-targeted nanoparticles: The RGD-PEG-HKP aqueous solution and the RNA nucleotide aqueous solution are mixed in equal volumes with an N / P mass ratio of 4:1 to obtain nanoparticles, and the electrostatic interaction between the ligand HK polymer and the RNA nucleotide will promote the formation of The RGD-PEG-HKP / antagomir complex with an average distribution particle size of about 100 nm. The average particle size distribution and Zeta potential were determined with a Brookhaven Particle Size Analyzer Plus 90 (Brookhaven, NY).

[0081] Treatment of mice with antagomir-132 nanoparticles: Mice ocularly infected with HSV1 RE Tumpey were divided into two groups. The treatment of Antagomir-132 nanoparticles started on the 2nd day after infection and was administered every other day until the 13th day after infection. In another group of experiments, administration was started on the 7th day after infection, and administered every other day until the ...

specific Embodiment 1

[0091] Specific embodiment 1. siRNA or antagomir oligonucleotide is loaded into HK polymer

[0092] Antagomir-132 and scrambled oligonucleotide sequences were purchased from Ambion and used according to the supplier's guidelines. Optimized histidine-lysine polymers (HKP) have been widely used for in vitro and in vivo delivery of siRNA (15,16), and we used one of the HKPs, H3K(+H)4b, whose structure is shown in figure 1 As shown, concentrated siRNA or antagomir oligonucleotides can be encapsulated to form nanoparticles with an average diameter of approximately 150 nm. These nanoparticles, containing antagomir-132 or antagomir-132 / 155, were tested for antiangiogenic activity in vivo in an animal model of herpes simplex stromal keratitis (HSK) induced by HSV infection. The therapeutic effects of these HKP-siRNA or HKP-antagomir formulations have been tested in various vascular proliferation models and xenograft tumor models. Such as figure 1 As shown, after subconjunctiv...

specific Embodiment 2

[0093] Specific Example 2. Increased level of miR-132 in the cornea of ​​mice infected with herpes simplex virus

[0094] To detect the level of miR-132 after ocular infection with HSV, tissue samples were collected at various time points, and miRNA was extracted for QPCR analysis. Changes in miR-132 levels were observed on day 2 post-infection and peaked at days 7 and 14, whereas miR-133a levels did not change in controls ( figure 2 , A and B), while the uninfected negative control had no change in miR-132 levels at the same time points (data not shown). These data suggest that miR-132 expression levels are increased following ocular infection with HSV.

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Abstract

The invention discloses a drug for treating neovascularization diseases. The drug uses miRNA-132 and miRNA-155 as targets, and uses two specific antagonistic oligonucleotides antagomir-132 and antagomir-155 as the basic components of the drug. Knocking down the above two micronucleic acids in the lesion at the same time can inhibit the excessive proliferation of new blood vessels and achieve the therapeutic effect. In order to ensure the effective use of the drug, the present invention adopts in vivo import carriers, such as histidine-lysine polypeptide polymer HKP, and ligand-targeted import nanoparticle system RGD-PEG-HKP, to enhance drug import into blood vessel proliferation Site (ocular or tumor site) specificity and efficiency.

Description

technical field [0001] The present invention relates to a drug product using nucleic acid technology to treat angioproliferative diseases, in particular to using at least two antagonistic oligonucleotides (antagomir) and a drug delivery carrier to form a drug to specifically inhibit at least two micronucleic acid (miRNA) related to angiogenesis ), so as to achieve the treatment of angioproliferative diseases (such as fundus retinopathy, solid tumors, etc.). The antagomir specifically targets miR-132 and miR-155, two micronucleic acids involved in upregulating the pathological processes of angiogenesis, tumorigenesis and proliferation. Background technique [0002] Micronucleic acid (microRNA, miRNA) is a kind of non-coding RNA with a length of 18-24 nucleotides that exists in eukaryotes. Degradation, thereby inhibiting gene expression and realizing its gene silencing function (1,2). [0003] miRNA is a highly conserved small molecule in eukaryotes, an important functional ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K48/00A61K31/7088A61P9/00A61P35/00A61P29/00A61P27/02
Inventor 徐军陆阳路阳唐盛高
Owner SIRNAOMICS BIOPHARMACEUTICALS (SUZHOU) CO LTD
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