APROTININ POLYPEPTIDES FOR TRANSPORTING A COMPOUND ACROSS THE BLOOD-BRAIN BARRIER
The invention relates to improvements in the field of drug delivery. More particularly, the invention relates to polypeptides derived from aprotinin and from aprotinin analogs as well as conjugates and pharmaceutical compositions comprising these polypeptides or conjugates. The present invention also relates to the use of these polypeptides for transporting a compound or drug across the blood-brain barrier of a mammal and in the treatment and diagnosis of neurological diseases.
1 . A method for treating a mammal having a neurological disease, said method comprising administering to said mammal a conjugate comprising:
(a) a polypeptide comprising an amino acid sequence having at least 80% identity to the sequence of Angiopep-1 (SEQ ID NO:67), wherein said polypeptide has a substitution at the position corresponding to the cysteine at position 7 of the Angiopep-1 sequence; and
(b) an agent for treating said neurological disease, wherein said agent is conjugated to said polypeptide,
wherein said conjugate is capable of crossing the blood-brain barrier or an in vitro model thereof.
2 . The method of claim 1 , wherein said neurological disease is selected from the group consisting of a brain cancer, a brain metastasis, schizophrenia, epilepsy, Alzheimer's disease, Parkinson's disease, Huntington's disease, stroke, and obesity.
3 . The method of claim 2 , wherein said brain cancer is a glioma.
4 . The method of claim 3 , wherein said glioma is a glioblastoma.
5 . The method of claim 1 , wherein said percent identity is at least 85%.
6 . The method of claim 5 , wherein said percent identity is at least 90%.
7 . The method of claim 1 , wherein said substitution is a serine substitution.
8 . The method of claim 7 , wherein said polypeptide comprises the amino acid sequence of Angiopep-2 (SEQ ID NO:97).
9 . The method of claim 7 , wherein said polypeptide consists of the amino acid sequence of Angiopep-2 (SEQ ID NO:97).
10 . The method of claim 1 , wherein said agent is an anticancer drug.
11 . The method of claim 10 , wherein said anticancer drug is selected from the group consisting of paclitaxel, vinblastine, vincristine, etoposide, doxorubicin, cyclophosphamide, taxotere, melphalan, and chlorambucil, or a combination thereof
12 . The method of claim 11 , wherein said anticancer drug is paclitaxel.
13 . The method of claim 11 , wherein said anticancer drug is etoposide.
14 . The method of claim 11 , wherein said anticancer drug is doxorubicin.
15 . The method of claim 1 , wherein said agent is a small molecule drug, an antibiotic, a cellular toxin, an anti-angiogenic compound, or a polypeptide.
16 . The method of claim 15 , wherein said agent is a chemotherapeutic agent.
17 . The method of claim 15 , wherein said polypeptide is an enzyme.
18 . The method of claim 15 , wherein said anti-angiogenic compound is endostatin, catechins, chemokine IP-10, an inhibitor of matrix metalloproteinase, anastellin, vironectin, antithrombin, a tyroskinctyrosine kinase inhibitor, or a VEGF inhibitor.
19 . The method of claim 1 , wherein said administration is intra-arterial, intra-nasal, intra-peritoneal, intravenous, intramuscular, subcutaneous, transdermal, or per os.
20 - 45 . (canceled)