Methods and reagents for efficient and targeted delivery of therapeutic molecules to CXCR4 cells
Conjugates comprising a targeting moiety specific for the CXCR4 and based on the polyphemusin-derived peptide and a therapeutic or imaging agent are provided. Therapeutic and diagnostic methods with the conjugates which require specific targeting to CXCR4+ cells are provided as well.
1. A conjugate comprising
(i) a targeting peptide comprising the sequence RRWCYRKCYKGYCYRKCR (SEQ ID NO: 5) and
(ii) a therapeutic antitumor agent selected from the group consisting of: a cytotoxic polypeptide, an antiangiogenic polypeptide, a polypeptide encoded by a tumor suppressor gene, a pro-apoptotic polypeptide, a polypeptide having anti-metastatic activity, a polypeptide encoded by a polynucleotide which activates the immune response toward a tumor, a tumor suppressor gene, a silencing agent, a suicide gene, and a polynucleotide which activates the immune response toward tumor; and
wherein the targeting peptide specifically binds to CXCR4 and promotes internalization of the therapeutic agent in a cell expressing CXCR4, wherein the cell is selected from the group consisting of breast cancer cells, prostate cancer cells, lung cancer cells, ovarian cancer cells, colon cancer cells, pancreatic cancer cells, kidney cancer cells, brain cancer cells, non-Hodgkin's lymphoma cancer cells and chronic lymphocytic leukemia cancer cells.
2. The conjugate according to claim 1 wherein the targeting peptide consists of the sequence RRWCYRKCYKGYCYRKCR (SEQ ID NO: 5).
3. The conjugate according to claim 1 wherein the therapeutic antitumor agent is a polypeptide selected from the group consisting of a cytotoxic polypeptide, an antiangiogenic polypeptide, a pro-apoptotic polypeptide and a polypeptide having anti-metastatic activity.
4. The conjugate according to claim 3 wherein the therapeutic antitumor agent and the targeting peptide are part of a fusion protein.
5. The conjugate according to claim 1 wherein the therapeutic antitumor agent is a polynucleotide which activates the immune response toward tumor.
6. The conjugate according to claim 1 wherein the therapeutic antitumor agent is provided within a nanotransporter and wherein the nanotransporter is coupled to the targeting peptide.
7. The conjugate according to claim 1 wherein the silencing agent is selected from the group of a siRNA, a shRNA and an antisense oligonucleotide.
8. A method for the treatment of cancer in a subject in need thereof wherein said cancer contains cells that express CXCR4 and wherein the cells are selected from the group consisting of breast cancer cells, prostate cancer cells, lung cancer cells, ovarian cancer cells, colon cancer cells, pancreatic cancer cells, kidney cancer cells, brain cancer cells, non-Hodgkin's lymphoma cancer cells and chronic lymphocytic leukemia cancer cells, said method comprising the administration of a conjugate according to claim 1 .
9. The method according to claim 8 wherein the cancer is pancreatic or colorectal cancer.