Compositions for treatment of drug-resistant tumors and methods of use thereof

A therapeutic and compositional technology, applied in the field of composition and its application in the treatment of drug-resistant tumors, can solve the problem that the root cause is not very clear

Inactive Publication Date: 2020-01-21
UNIV OF MISSOURI BOARD OF CURATORS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the root c

Method used

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  • Compositions for treatment of drug-resistant tumors and methods of use thereof
  • Compositions for treatment of drug-resistant tumors and methods of use thereof
  • Compositions for treatment of drug-resistant tumors and methods of use thereof

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Embodiment 1

[0155] method

[0156] siRNA and crRNA reagents

[0157] To inhibit protein expression of certain pathways, siRNAs were used to target and downregulate AXL, FN14, and KRAS mRNAs. For this purpose, AXL siRNA (sense strand: 5'GGAACUGCAUGCUGAAUGAUU 3') (SEQ ID NO:2), FN14 siRNA (sense strand: 5'CUCAGAUGUCCUGAAAUUCCAUU 3') (SEQ ID NO:3) and G12S mutated KRAS siRNA were used (Sense strand: 5'CAGCUAAUUCAGAAUCAUUUU 3') (SEQ ID NO:4).

[0158] A disulfide group was introduced at the 5' position of the oligonucleotide sequence for conjugation purposes. This dithio group is deprotected or reduced to -SH for further conjugation. An example of a disulfide structure such as "S-S-oligonucleotide" is:

[0159]

[0160] For prediction of conjugated siRNA and in vitro fluorescence imaging, Cy5 was conjugated to the 3' end of the antisense strand of AXL siRNA.

[0161] AXL crRNA was designed to target TTCAGTGGTCCGACGACTGT (SEQ ID NO:5) and PAM:hg38|-chr19:41243678-41243700AGG at genomic...

Embodiment 2

[0200] In vitro targeting of AXL-FN14 using nanoparticles

[0201] Based on the results of siRNA+drug toxicity studies, the down-regulation of the AXL-FN14 axis in H820 cells by treatment with siRNA-conjugated nanoconstructs was investigated. For this study, the toxicity of gelatin nanoparticles in H820 and HCC827 cells was initially tested. The results indicated that the particles after glutaraldehyde quenching were non-toxic (Figure 45). The study also demonstrated the ability of gelatin nanoparticles to deliver drugs by encapsulation in HCC827 drug-sensitive cells (Figure 45).

[0202] Cytotoxicity assays also confirmed that the synthetic siRNA conjugates were non-toxic (Figure 46). In the next step, drug resensitization using the dual siRNA AXL-FN14 construct was investigated in H820 cells. Similar results to siRNA-based treatments were obtained (Figure 47). The results demonstrate that nanoparticles can be used to target these pathways and may be an important step in ...

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Abstract

Provided herein are methods and compositions for sensitizing a cancer cell to a cancer treatment, for example to an anticancer drug by the inhibition of at least two cancer biomarkers. Further provided are methods of treating and/or preventing a cancer including reducing the size of a tumor. Also provided are compositions comprising nanoparticles associated with inhibitory molecules, such as siRNA, and/or anticancer drugs.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of US Provisional Patent Application Serial No. 62 / 479931, filed March 31, 2017, which is hereby incorporated by reference in its entirety. [0003] Incorporation of Sequence Listings [0004] The contents of the Sequence Listing (Name: Sequence Listing_52553-173956.txt; Size: 20638 bytes; and Date Created: March 30, 2018 ) filed electronically with this application as an ASCII text file are incorporated by reference in their entirety into this article. [0005] Background of the invention [0006] In recent years, great strides have been made in understanding the efficacy of drugs following treatment in cancer patients. Uramoto et al., Lung Cancer 2011;73:361-365. This heightened interest is largely due to acquired drug resistance in patients. Brown et al., Nature Reviews Cancer 2014;14:747-753. The reason for these resistant cases is related to poor understanding of post-treatmen...

Claims

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Application Information

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IPC IPC(8): A61K31/138A61K31/15A61K31/277A61K31/352A61K31/353A61K31/423A61K33/243
CPCA61K45/06A61K31/506A61K31/517A61K31/5377A61K31/713A61K9/0019A61K9/5169A61K47/6849A61K47/6857A61K47/6935A61P35/00A61K33/243A61K33/24A61K2300/00A61P35/04A61K9/19B82Y5/00
Inventor 拉古拉曼·坎南达纳杰·苏雷什苏马沃·穆克尔吉阿吉特·P·赞布雷阿南迪·厄本德兰
Owner UNIV OF MISSOURI BOARD OF CURATORS
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