# US 8,541,568 B2 · Compositions and methods using siRNA molecules for treatment of gliomas

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- Number: US 8,541,568 B2
- Document ID: US8541568B2
- Status: Granted
- Kind: B2
- Application number: 12/994,738
- Filed: 2009-05-26
- Published: 2011-07-07
- Granted: 2013-09-24
- Earliest claimed: 2008-05-24
- Applicants: Hai Yan; Patrick Y. Lu; Darell D. Bigner
- Inventors: Hai Yan; Patrick Y. Lu; Darell D. Bigner
- Web page: https://patentgrep.com/patent/US8541568B2

## CPC

- C12N 15/1138: {against receptors or cell surface proteins}
- A61P 35/00: Antineoplastic agents
- C12N 15/1136: {against growth factors, growth regulators, cytokines, lymphokines or hormones}
- C12N 15/1137: {against enzymes (viral enzymes C12N15/1131; receptors C12N15/1138)}
- C12N 2310/14: interfering nucleic acids [NA]
- C12N 2320/31: Combination therapy
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention provides small interfering RNA (siRNA) molecules, compositions containing the molecules, and methods of using the compositions to treat gliomas.

## Claims

### Claim 1

A composition comprising at least three isolated siRNA molecules, wherein at least one isolated siRNA molecule (sense: 5′-CUGUAGACACACCCACCCACAUACA-3′ (SEQ ID NO: 10), antisense: 5′-UGUAUGUGGGUGGGUGUGUCUACAG-3′) (SEQ ID NO: 11) binds to an mRNA molecule that encodes a human VEGF protein and binds to an mRNA molecule that encodes a mouse VEGF protein, at least one isolated siRNA molecule (sense: 5′-CCAUCGAUGUCUACAUGAUCAUGGU-3′ (SEQ ID NO: 14), antisense: 5′-ACCAUGAUCAUGUAGACAUCGAUGG-3′) (SEQ ID NO: 15) binds to an mRNA molecule that encodes a human EGFR protein and binds to an mRNA molecule that encodes a mouse EGFR protein, and at least one isolated siRNA molecule (sense: 5′-GCUGAAGGUUGUGAAAUUCGGAGAA-3′ (SEQ ID NO: 18), antisense: 5′-UUCUCCGAAUUUCACAACCUUCAGC-3′) (SEQ ID NO: 19) binds to an mRNA molecule that encodes a human MGMT protein and binds to an mRNA molecule that encodes a mouse MGMT protein.

### Claim 2 (depends on 1)

The composition of claim 1, further comprising a pharmaceutically acceptable carrier.

### Claim 3 (depends on 2)

The composition of claim 2, wherein said carrier comprises at least one of the following: a glucose solution, a polycationic binding agent, a cationic lipid, a cationic micelle, a cationic polypeptide, a hydrophilic polymer grafted polymer, a non-natural cationic polymer, a cationic polyacetal, a hydrophilic polymer grafted polyacetal, a ligand functionalized cationic polymer, a ligand functionalized-hydrophilic polymer grafted polymer, and a ligand functionalized liposome.

### Claim 4 (depends on 3)

The composition of claim 3, wherein said ligand comprises one or more of an RGD peptide, an RVG peptide, or a FROP peptide.

### Claim 5 (depends on 3)

The composition of claim 3, wherein said polymers comprise a biodegradable histidine-lysine polymer, a biodegradable polyester, a polyamidoamine (PAMAM) dendrimer, a cationic lipid, optionally DOTAP, and a PEGylated PEI.

### Claim 6 (depends on 2)

The composition of claim 2, wherein said carrier comprises a histidine-lysine copolymer that forms a nanoparticle with the siRNA molecules.

### Claim 7 (depends on 1)

The composition of claim 1, further comprising a therapeutic agent that impedes or blocks tumorigenesis, angiogenesis, or cell proliferation in the brain or spinal cord of a mammal.

### Claim 8 (depends on 7)

The composition of claim 7, wherein said therapeutic agent is selected from the group consisting of bevacizumab, sunitinib, sorafenib, temsirolimus, and temozolomide.

### Claim 9 (depends on 1)

A nanoparticle comprising the siRNA molecules of claim 1, a pharmaceutically acceptable carrier, and a targeting ligand.

### Claim 10 (depends on 9)

The nanoparticle of claim 9, wherein said pharmaceutically accepable carrier is a histidine-lysine copolymer.

### Claim 11 (depends on 9)

The nanoparticle of claim 9, wherein said targeting ligand is selected from the group consisting of EGF receptor ligands, IL13 ligand, hepatocyte growth factor ligand, single chain monoclonal antibodies, RGD peptide ligands, and RVG peptide ligands.

### Claim 12 (depends on 4)

The composition of claim 4 wherein said RGD peptide is H-ACRGDMFGCA-OH, said RVG peptide is H-YTIWMPENPRPGTPCDIFTNSRGKRASNG-OH, and said FROP peptide is H-EDYELMDLLAYL-OH.

### Claim 13 (depends on 5)

The composition of claim 5 wherein said biodegradable polyester comprises poly(lactic acid) (PLA), poly(glycolic acid) (PGA), or poly(lactic-co-glycolic acid) (PLGA).

### Claim 14 (depends on 9)

The nanoparticle of claim 9 wherein said targeting ligand is an RGD peptide ligand or an RVG peptide ligand.

### Claim 15 (depends on 14)

The nanoparticle of claim 14 wherein said RGD peptide ligand is a ‘cyclic’ 10mer RGD peptide with the sequence H-ACRGDMFGCA-OH, and -(D)CR(D)WKTCT-(ol).

### Claim 16 (depends on 14)

The nanoparticle of claim 14 wherein said RVG peptide ligand is YTIWMPENPRPGTPCDIFTNSRGKRASNG or YTIWMPENPRPGTPCDIFTNS-RGKRASNGGGGRRRRRRRRR.