# US 11,110,182 B2 · Multifunctional RNA nanoparticles and methods for treating cancer and therapeutic resistant cancer

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- Number: US 11,110,182 B2
- Document ID: US11110182B2
- Status: Granted
- Kind: B2
- Application number: 16/467,690
- Filed: 2017-12-08
- Published: 2019-11-21
- Granted: 2021-09-07
- Earliest claimed: 2016-12-08
- Assignees: University of Cincinnati; Ohio State Innovation Foundation
- Applicants: University of Cincinnati
- Inventors: Xiaoting Zhang; Peixuan Guo
- Web page: https://patentgrep.com/patent/US11110182B2

## CPC

- A61K 47/549: {Sugars, nucleosides, nucleotides or nucleic acids}
- A61K 47/6929: {the form being a nanoparticle, e.g. an immuno-nanoparticle}
- A61K 31/138: Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine (atenolol A61K31/165; pindolol A61K31/404; timolol A61K31/5377)
- A61K 31/4196: 1,2,4-Triazoles
- A61K 31/566: having an oxo group in position 17, e.g. estrone
- A61K 31/713: Double-stranded nucleic acids or oligonucleotides
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 35/00: Antineoplastic agents
- C12N 15/113: Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; {Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing (when used in plants C12N15/8218)}
- C12N 15/115: Aptamers, i.e. nucleic acids binding a target molecule specifically and with high affinity without hybridising therewith {; Nucleic acids binding to non-nucleic acids, e.g. aptamers}
- C12N 2310/14: interfering nucleic acids [NA]
- C12N 2310/16: Aptamers
- C12N 2310/3519: Fusion with another nucleic acid
- C12N 2320/32: Special delivery means, e.g. tissue-specific
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

RNA nanoparticles functionalized with a HER2-targeting RNA aptamer and at least one MED1 siRNA for targeted delivery of MED1 siRNA to human cancer cells via human epidermal growth factor receptor 2 (HER2) receptors, pharmaceutical compositions of the inventive RNA nanoparticles, and methods for treating breast, HER2-implicated cancers, and in particular therapeutic-resistant cancer such as tamoxifen-resistant breast cancer, by administering pharmaceutical compositions of the inventive RNA nanoparticles.

## Claims

### Claim 1

A pRNA nanoparticle functionalized for targeted delivery of Mediator Subunit 1 (MED1) silencing RNA (siRNA) to human cancer cells via human epidermal growth factor receptor 2 (HER2) receptors, the nanoparticle comprising: a three-way junction (3-WJ) pRNA, a HER2-targeting RNA aptamer, and two different MED 1 siRNAs, wherein each of the HER-2 targeting RNA aptamer and the MED1 siRNAs is annealed to a separate extending arm of the 3-WJ pRNA, wherein the pRNA nanoparticle is selected from the group consisting of:
pRNA-HER2mini apt-MED1-siRNA (SEQ ID NO: 13),
pRNA-HER2A1 apt-MED1-siRNA (SEQ ID NO: 14),
pRNA-HER2B3 apt-MED1-siRNA (SEQ ID NO: 15),
pRNA-HER2C3 apt-MED1-siRNA (SEQ ID NO: 16),
pRNA-HER2D3 apt-MED1-siRNA (SEQ ID NO: 17), and
pRNA-HER2E1 apt-MED1-siRNA (SEQ ID NO: 18).

### Claim 2 (depends on 1)

The pRNA nanoparticle according to claim 1 comprising a 2′F-modification.

### Claim 3 (depends on 1)

The pRNA nanoparticle according to claim 1 having a diameter of about 7 nm to about 11 nm as measured by DLS scattering.

### Claim 4 (depends on 1)

The pRNA nanoparticle according to claim 1, wherein the human cancer cells comprise one or more of breast, uterine, ovarian, lung, stomach, bladder and salivary cancer cells.

### Claim 5 (depends on 1)

The pRNA nanoparticle according to claim 1, wherein the nanoparticle comprises 2′F-modified 3-WJ pRNA-HER2B3 apt-MED1-siRNA (SEQ ID NO: 15).

### Claim 6 (depends on 1)

A pharmaceutical composition formulated for local or systemic administration comprising:
the pRNA nanoparticle according to claim 1; and
a pharmaceutically acceptable vehicle, and, optionally, a pharmaceutically acceptable excipient.

### Claim 7 (depends on 6)

The pharmaceutical composition according to claim 6, further comprising at least one anti-estrogenic agent.

### Claim 8 (depends on 7)

The pharmaceutical composition according to claim 7, wherein the anti-estrogenic agent is selected from Tamoxifen, Toremifene, Fulvestrant, Raloxifene, lasofoxifene, Bazedoxifene, RAD-1901, an aromatase inhibitor (AI), and combinations thereof.

### Claim 9 (depends on 8)

The pharmaceutical composition according to claim 8, wherein the AI is selected from Letrozole, Anastrozole, and Exemestane.

### Claim 10 (depends on 6)

A method for selectively inhibiting expression of MED1 in HER2-overexpressing cells, the method comprising administering a composition according to claim 6 to the cells.

### Claim 11

A method for treating a human suffering from a cancer selected from breast, uterine, ovarian, stomach, lung, bladder, and salivary cancer, the method comprising administering to the human a pharmaceutical composition comprising at least one pRNA nanoparticle comprising a three-way junction (3-WJ) pRNA, a HER2-targeting RNA aptamer, and two different MED 1 siRNAs, wherein each of the HER-2 targeting RNA aptamer and the MED1 siRNAs is annealed to a separate extending arm of the 3-WJ pRNA.

### Claim 12 (depends on 11)

The method according to claim 11, wherein the HER2-targeting RNA aptamer is selected from MINI (SEQ ID NO: 7), Al (SEQ ID NO: 8), B3 (SEQ ID NO: 9), C3 (SEQ ID NO: 10), D3 (SEQ ID NO: 11), and E1 (SEQ ID NO: 12).

### Claim 13 (depends on 11)

The method according to claim 11, wherein the RNA aptamer is 2′F-modified and the pRNA nanoparticle is selected from pRNA-HER2mini apt-MED1-siRNA (SEQ ID NO: 13), pRNA-HER2A1 apt-MED1-siRNA (SEQ ID NO: 14), pRNA-HER2B3 apt-MED1-siRNA (SEQ ID NO: 15), pRNA-HER2C3 apt-MED1-siRNA (SEQ ID NO: 16), pRNA-HER2D3 apt-MED1-siRNA (SEQ ID NO: 17), and pRNA-HER2E1 apt-MED1-siRNA (SEQ ID NO: 18).

### Claim 14 (depends on 11)

The method according to claim 11, wherein the pRNA nanoparticle comprises 2′F-modified 3-WJ pRNA-HER2B3 apt-MED1-siRNA (SEQ ID NO: 15).

### Claim 15 (depends on 11)

The method according to claim 11, wherein the cancer comprises breast cancer.

### Claim 16 (depends on 15)

The method according to claim 15, wherein the breast cancer is resistant to treatment with anti-estrogenic agents, said resistance being primary or acquired.