Compositions and methods using siRNA molecules and siRNA cocktails for the treatment of breast cancer
The present invention provides small interfering RNA (siRNA) molecules, compositions containing the molecules, and methods of using the molecules and compositions to treat breast cancer. In one aspect, a multi-targeted siRNAi cocktail is disclosed. The siRNA molecules may be encapsulated in nanoparticles to further enhance their anti-cancer activity. The compositions may also be used in combination with other anti-cancer agents, such as bevacizumab.
1. An isolated siRNA selected from the group consisting of:
5′-r(CCUGUGGCUACAAGUUCCACCAGCA)-3′ (SEQ ID NO. 62) (sense strand sequence, Raf-1), and
5′-r(CACUACAAAGAACUGGAGUUCCAGA)-3′ (SEQ ID NO. 94) (sense strand sequence, mTOR).
2. The siRNA molecule of claim 1 wherein said siRNA molecule binds to both a human mRNA molecule and a homologous mouse mRNA molecule.
3. A composition comprising the siRNA molecule of claim 1 and a pharmaceutically acceptable carrier.
4. A composition comprising the three different isolated siRNA molecules selected from the group consisting of:
5′-r(CCUGUGGCUACAAGUUCCACCAGCA)-3′ (SEQ ID NO. 62) (sense strand sequence, Raf-1),
5′-r(CACUACAAAGAACUGGAGUUCCAGA)-3′ (SEQ ID NO. 94) (sense strand sequence, mTOR), and
5′-r(GAUCAUGGUCAAGUGCUGGAUGAUA)-3′ (SEQ ID NO. 38) (sense strand sequence, EGFR)
and a pharmaceutically acceptable carrier.
5. The composition of claim 4 comprising the three different isolated siRNA molecules at a ratio of 1:1:1, 1:1.5:0.5, or 0.5:0.5:2.
6. The composition claim 4 wherein said carrier comprises at least one of the following: saline, a sugar, a polypeptide, a polymer, a lipid, a cream, a gel, a micelle material, and a metal nanoparticle.
7. The composition of claim 4 wherein said carrier comprises a histidine-lysine copolymer that forms a nanoparticle with the siRNA molecules.
8. The composition of claim 4 further comprising a therapeutic agent that impedes or blocks tumorigenesis, angiogenesis, cell proliferation, or anti-apoptosis in the breast tissue of a mammal.
9. A nanoparticle comprising the siRNA molecule of claim 1 , a carrier, and a targeting ligand.
10. A nanoparticle comprising the three different isolated siRNA molecules selected from the group consisting of:
5′-r(CCUGUGGCUACAAGUUCCACCAGCA)-3′ (SEQ ID NO. 62) (sense strand sequence, Raf-1),
5′-r(CACUACAAAGAACUGGAGUUCCAGA)-3′ (SEQ ID NO. 94) (sense strand sequence, mTOR), and
5′-r(GAUCAUGGUCAAGUGCUGGAUGAUA)-3′ (SEQ ID NO. 38) (sense strand sequence, EGFR),
a carrier, and a targeting ligand.
11. An isolated 25 mer siRNA molecule selected from the group consisting of a molecule that binds to an mRNA molecule that encodes human Raf-1 and binds to an mRNA molecule that encodes mouse Raf-1; and a molecule that binds to an mRNA molecule that encodes human mTOR and binds to an mRNA molecule that encodes mouse mTOR wherein said molecule is selected from the group consisting of:
5′-r(CCUGUGGCUACAAGUUCCACCAGCA)-3′ (SEQ ID NO. 62) (sense strand sequence, Raf-1), and
5′-r(CACUACAAAGAACUGGAGUUCCAGA)-3′ (SEQ ID NO. 94) (sense strand sequence, mTOR).
12. A composition comprising the three different isolated 25 mer siRNA molecules selected from the group consisting of a molecule that binds to an mRNA molecule that encodes human EGFR and binds to an mRNA molecule that encodes mouse EGFR; a molecule that binds to an mRNA molecule that encodes human Raf-1 and binds to an mRNA molecule that encodes mouse Raf-1; and a molecule that binds to an mRNA molecule that encodes human mTOR and binds to an mRNA molecule that encodes mouse mTOR, wherein said molecule is selected from the group consisting of:
5′-r(GAUCAUGGUCAAGUGCUGGAUGAUA)-3′ (SEQ ID NO. 38) (sense strand sequence, EGFR),
5′-r(CCUGUGGCUACAAGUUCCACCAGCA)-3′ (SEQ ID NO. 62) (sense strand sequence, Raf-1), and
5′-r(CACUACAAAGAACUGGAGUUCCAGA)-3′ (SEQ ID NO. 94) (sense strand sequence, mTOR)
and a pharmaceutically acceptable carrier.