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Modified micrornas and their use in the treatment of cancer

A cancer, pancreatic cancer technology, applied in the field of modified microRNA and their use in the treatment of cancer, can solve the problem of toxic side effects

Pending Publication Date: 2021-10-29
THE RES FOUND OF STATE UNIV OF NEW YORK
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For example, it is well known that 5-FU and gemcitabine, despite being quite effective in the treatment of many types of cancer, have significant toxicity and can cause many adverse side effects

Method used

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  • Modified micrornas and their use in the treatment of cancer
  • Modified micrornas and their use in the treatment of cancer
  • Modified micrornas and their use in the treatment of cancer

Examples

Experimental program
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Embodiment 1

[0119] Example 1. Materials and methods.

[0120] modified microRNA . All modified microRNAs were synthesized by automated oligonucleotide synthesis and purified by HPLC. The two strands are annealed to produce a mature modified 5-FU-miR and / or modified miR-194 of the disclosure having cytosine bases replaced by gemcitabine molecules. For the modified microRNA-194 containing 5-halouracil, a method called "2'-ACE RNA synthesis" was used. 2'-ACE RNA synthesis is based on a protecting group scheme using a silyl ether to protect the 5'-hydroxyl group combined with an acid-labile orthoester protecting group (2'-ACE) on the 2'-hydroxyl. This combination of protecting groups is then used with standard phosphoramidate solid phase synthesis techniques. See, eg, S.A. Scaringe, F.E. Wincott, and M.H. Caruthers, J. Am. Chem. Soc. , 120 (45), 11820-11821 (1998); International PCT Application WO / 1996 / 041809; M.D. Matteucci, M.H. Caruthers, J. Am. Chem. Soc. , 103, 3185-3191 (1981); ...

Embodiment 2

[0129] Example 2: Modified miR-194 nucleic acid has anticancer activity.

[0130] In the following experiments, all 5 cytosine bases in the guide strand of native miR-194 (SEQ ID NO:1) were replaced by gemcitabine to form the exemplary modified microRNA shown in SEQ ID NO:2 . see Figure 1C . Another modified microRNA was formed by replacing all uracil bases in the guide strand of the native miR-194 nucleic acid with a 5-FU molecule, as shown in SEQ ID NO. 4. see Figure 1B . In one experiment, all U bases in miR-194 were replaced by 5-FU, and all cytosines (C bases) were replaced by gemcitabine molecules, as in Figure 1D As shown in the provided structure and as shown in SEQ ID NO: 3.

[0131] Target specificity analysis: The results of western blot experiments in pancreatic cells confirmed that exemplary modified miR-194 polynucleotides of the present disclosure were able to retain their target specificity for SET8 and BMI1. The results are displayed in Figures 2A ...

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Abstract

The present disclosure provides modified microRNA nucleic acid compositions that have one or more cytosine and / or uracil bases replaced with gemcitabine or a 5-halouracil, respectively. More specifically, the present disclosure reveals that the replacement of cytosine nucleotides within a microRNA nucleotide sequence with a gemcitabine molecule increases the ability of the microRNA to inhibit cancer progression and tumorigenesis. In addition, the present disclosure reveals that the replacement of cytosine nucleotides within a microRNA nucleotide sequence with a gemcitabine molecule and replacement of uracil bases with 5-halouracil increases the ability of the microRNA to inhibit cancer development. As such, the present disclosure provides various modified nucleic acid (e.g., microRNA) compositions having gemcitabine molecules incorporated in their nucleic acid sequences and methods for using the same. The present disclosure further provides pharmaceutical compositions comprising the modified nucleic acid compositions, and methods for treating cancers using the same.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of priority to U.S. Provisional Application No. 62 / 818,190, filed March 14, 2019, the entire contents of which are incorporated herein by reference. [0003] governmental support [0004] This invention was made with Government support under Grant No. CA197098 awarded by the National Institutes of Health. The government has certain rights in this invention. [0005] Incorporation by reference of the sequence listing [0006] The sequence listing in the ASCII text file is incorporated herein by reference, the name of the sequence listing is 050_9017_PCT_SequenceListing.txt, the size is 3 KB bytes, and it is submitted to the United States Patent and Trademark Office (United States Patent and Trademark Office) via EFS-Web . technical field [0007] The present disclosure generally relates to nucleic acid compositions comprising 2'2'-difluoro2'deoxycytidine (gemcitabine). More specifi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K45/06A61P35/00C07H21/02A61K48/00C07H19/06
CPCC07H21/02A61P35/00A61K45/06A61K31/7115A61K31/713C12N15/111C12N2310/141C12N2310/344C12N2310/334C12N15/1135C12N2740/16043C12N2310/322C12N2310/3533A61K48/00
Inventor J·菊A·费斯勒
Owner THE RES FOUND OF STATE UNIV OF NEW YORK
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