Aptamer modulators of estrogen receptors
View Patent ↗The present invention relates to a nucleic acid aptamer molecule that includes a domain that binds to an estrogen receptor, molecular complexes that include the nucleic acid aptamer molecule and an estrogen receptor, and constructed DMA molecules and expression systems, as well as host cells, that the contain an RNA aptamer molecule of the invention. Use of these aptamers and encoding constructs to inhibiting estrogen receptor activity in a cell and to treat estrogen receptor-positive cancers is also described.
1. A nucleic acid aptamer molecule comprising a domain that binds to an estrogen receptor, wherein the nucleic acid aptamer molecule comprises a nucleotide sequence according to one of SEQ ID NOS: 1-4, 11, 12, 15-18, or minimal effective ER-binding fragments thereof.
2. The nucleic acid aptamer molecule according to claim 1 , wherein the nucleic acid aptamer molecule comprises a nucleotide sequence according to SEQ ID NO: 1, SEQ ID NO: 11, SEQ ID NO: 12, or minimal effective ER-binding fragments thereof.
3. The nucleic acid aptamer molecule according to claim 1 , wherein the nucleic acid aptamer molecule comprises a nucleotide sequence according to one of SEQ ID NOS: 15-18, or minimal effective ER-binding fragments thereof.
4. A molecular complex comprising the nucleic acid aptamer molecule according to claim 1 and an estrogen receptor.
5. A constructed DNA molecule comprising a first region encoding a nucleic acid aptamer molecule according to claim 1 , wherein the nucleic acid aptamer molecule comprises RNA.
6. An expression system comprising an expression vector into which is inserted a DNA molecule according to claim 5 .
7. An isolated host cell containing the expression system of claim 6 .
8. A method of inhibiting estrogen receptor activity in a cell, the method comprising:
contacting an estrogen receptor in a cell with a nucleic acid aptamer molecule according to claim 1 , whereby said nucleic acid aptamer molecule binds to said estrogen receptor and inhibits activity thereof.
9. The method according to claim 8 , where the estrogen receptor activity comprises nuclear signaling or transcriptional activation.
10. The method according to claim 9 , wherein the transcriptional activation level of the estrogen receptor is reduced by about 30 to about 50 percent in the cell.
11. The method according to claim 8 , wherein said contacting is carried out with an agent comprising the nucleic acid aptamer molecule, whereby the agent is taken up by the cell and the nucleic acid aptamer molecule is released internally into the cell.
12. The method according to claim 11 , wherein the agent comprises a cationic polymer, modified cationic polymer, peptide molecular transporter, lipid, liposome, non-cationic polymer, or a second nucleic acid aptamer molecule that binds specifically to a cancer cell surface receptor, which second nucleic acid aptamer is covalently or non-covalently linked to the nucleic acid aptamer molecule that binds to the hER.
13. The method according to claim 8 , further comprising:
introducing an expression system encoding the nucleic acid aptamer molecule into the cell; and expressing the nucleic acid aptamer molecule in the cell.
14. The method according to claim 8 , wherein the cell is a breast cancer cell, ovarian cancer cell, uterine cancer cell, or endometrial cancer.
15. A method of treating a patient for an estrogen dependent cancer comprising:
administering to the patient an agent comprising or encoding a nucleic acid aptamer molecule according to claim 1 , whereby the agent is taken up by an estrogen dependent-cancer cell and the nucleic acid aptamer molecule inhibits activity of the estrogen receptor in the cancer cell and thereby inhibits cancer cell growth.