Thiol-mediated drug attachment to targeting peptides
Compositions and methods for thiol-specific attachment of therapeutic and diagnostic agents to somatostatin and other targeting peptides.
1 . A composition comprising a somatostatin analog of the formula:
(A−B)
wherein:
A is cysteine, or a peptide chain comprising one or more cysteine residues, which is suitable for binding to a drug or chelator via a thiol linkage; and
B is a naturally occurring or synthetic somatostatin peptide, or fragment thereof, that binds to a somatostatin receptor.
2 . The composition of claim 1 , wherein A comprises the peptide sequence of any one of SEQ ID NOs:1-3, or wherein A is a single cysteine residue.
3 . The composition of claim 1 , wherein B comprises SEQ ID NO:4.
4 . The composition of claim 1 , wherein the somatostatin analog comprises a peptide of any one of SEQ ID NOs:5-7.
5 . The composition of claim 1 , further comprising a drug, or chelator suitable for binding a drug, wherein the drug or chelator is bound to the one or more cysteines by a thiol linkage.
6 . The composition of claim 5 , wherein the drug is a therapeutic agent or a detectable label.
7 . The composition of claim 6 , wherein the therapeutic agent is a radioisotope, a cytotoxin, an immunostimulatory agent, an anti-angiogenic agent, a therapeutic gene, or a chemotherapeutic agent.
8 . The composition of claim 5 , wherein the chelator is a maleimido derivative of DTPA or a maleimido derivative of a DTPA analog.
9 . The composition of claim 1 , further comprising a somatostatin analog that specifically binds to mammalian SSTR-positive cells in vivo.
10 . The composition of claim 1 , wherein the SSTR-positive cells are human cancer cells.
11 . A method for detecting SSTR-positive cells in a mammalian subject comprising:
(a) administering to the subject a composition comprising a somatostatin analog of the formula:
(A−B)
wherein:
A is cysteine, or a peptide chain comprising one or more cysteine residues, wherein a detectable label is bound to the one or more cysteine residues via a thiol linkage; and
B is a naturally occurring or synthetic somatostatin peptide, or fragment thereof, which binds to a somatostatin receptor; and
(b) detecting the detectable label, whereby SSTR-positive cells are detected.
12 . The method of claim 11 , wherein A comprises the peptide sequence of any one of SEQ ID NOs:1-3, or wherein A is a single cysteine residue.
13 . The method of claim 11 , wherein B comprises SEQ ID NO:4.
14 . The method of claim 11 , wherein the somatostatin analog comprises a peptide of any one of SEQ ID NOs:5-7.
15 . A method for treating an SSTR-associated disorder in a mammalian subject, the method comprising administering to the subject a composition comprising a somatostatin analog of the formula:
(A−B)
wherein:
A is cysteine, or a peptide chain comprising one or more cysteine residues, wherein a therapeutic agent is bound to the one or more cysteine residues via a thiol linkage; and
B is a naturally occurring or synthetic somatostatin peptide, or fragment thereof, which binds to a somatostatin receptor; and
whereby a SSTR-associated disorder is treated.
16 . The method of claim 15 , wherein A comprises the peptide sequence of any one of SEQ ID NOs:1-3, or wherein A is a single cysteine residue.
17 . The method of claim 15 , wherein B comprises SEQ ID NO:4.
18 . The method of claim 15 , wherein the somatostatin analog comprises a peptide of any one of SEQ ID NOs:5-7.
19 . The method of claim 15 , wherein the therapeutic agent is selected from the group consisting of a radioisotope, a cytotoxin, an immunostimulatory agent, an anti-angiogenic agent, a therapeutic gene, and a chemotherapeutic agent.
20 . The method of claim 15 , wherein the SSTR-associated disorder is cancer.