Conjugates of somatostatin analogues
Inventors
Schneider, Eric L. • Hearn, Brian • Ashley, Gary W. • Santi, Daniel V.
Assignees
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Publication Number
US-10086049-B2
Publication Date
2018-10-02
Expiration Date
Abstract
Conjugates of carriers and hydrogels for controlling the biological half-life of somatostatin and its analogs are disclosed.
Core Innovation
The invention relates to extending the half-life of somatostatin and somatostatin analogs by means of multivalent PEG-based conjugates and derivatized crosslinked hydrogels. A somatostatin or analog moiety is coupled to a carrier molecule through a linker that is designed for controlled, releasable cleavage. The described macromolecular architecture is based on PEG (4-armed 20 kD) bearing repeated conjugate extensions in a defined structural pattern.
The linker employs a releasable β-elimination mechanism to release the peptide. The disclosure defines a β-elimination releasable linker moiety and describes coupling arrangements in which the peptide is attached via functional groups at defined peptide positions, including attachment to an α-amine or an ε-amine as described. The disclosed subject matter further describes the construction of PEG-based multivalent conjugates and dendrimeric connector scaffolds, including installation of an azido-glutamate (N3-Glu) payload onto 20 kDa PEG and coupling of an amino-linker-octreotide(Boc) to form amide-linked drug-loaded macromonomers.
For insoluble delivery, the disclosure includes derivatized crosslinked hydrogels in which the peptide is coupled to the hydrogel network through a β-elimination releasable linker. The document describes hydrogel crosslinking strategies using PEG functionalization, including PEG-(cyclooctyne) with an azido-linker-peptide construct, PEG-(cyclooctyne) or PEG-(BCN), and preparation/loading of dendrimeric-octreotide loaded degradable hydrogel microspheres. Connector formation with oxime (aminooxy) is described for aminooxy-linker-octreotide linked to the dendrimeric scaffold, including Boc-Lys dendrimers and tetra-pyruvamide.
Claims Coverage
One independent claim is provided, centered on a conjugate of formula (A) with a defined 4-armed 20 kD PEG architecture and repeated extensions corresponding to the remainder of formula (A).
Conjugate defined by PEG repetition architecture of formula (A)
A conjugate of formula (A) wherein the spheres represent 4 armed 20 kD PEG and the three remaining extensions shown from said spheres represent repetitions of the remainder of formula (A).
The claim coverage centers on a specific PEG architecture within formula (A), characterized by a four-armed 20 kD PEG portion and repeated extension units representing the remainder of formula (A).
Stated Advantages
Extending the half-life of somatostatin and somatostatin analogs.
Documented Applications
Providing a long-lived circulating source for soluble PEG conjugates or a non-circulating depot for crosslinked hydrogel formulations.
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