Targeted delivery using tissue-specific peptidomimetic ligands
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Publication Number
US-9181225-B2
Publication Date
2015-11-10
Expiration Date
Abstract
Compositions and methods for tissue-specific targeted delivery of therapeutic agents through the use of tissue-specific peptidomimetic ligands are disclosed herein. The ligand comprises a composition of formula A-scaffold-A′ and one or more hydrophobic anchors covalently linked to the scaffold. The A and A′ compounds linked to the scaffold comprise monovalent peptidomimetic compounds wherein each monovalent peptidomimetic compound is selected from the group consisting of fragments IKs, GKs, IDs, GSs, GTs, VSs, TKs, KTs, ARs, KIs, KEs, AEs, GRs, YSs, IRs, and morpholino.
Core Innovation
The document describes tissue-specific targeting ligands incorporated into a lipid bilayer for targeted delivery of therapeutic agents. The targeting ligand is a composition of A-scaffold-A′, where the scaffold has the stated formula and the dotted lines represent points of attachment to A and A′. A and A′ comprise monovalent peptidomimetic compounds, and the composition is incorporated into a lipid bilayer.
The scaffold-supported monovalent peptidomimetic compositions are used to form a ligand-functionalized delivery system that includes a therapeutic agent carrier and a tissue-specific targeting ligand. The document further describes embodiments where the therapeutic agent carrier is a liposome, including a cationic liposome having an internal lipid bilayer and an external lipid bilayer.
The document also describes methods to prepare small molecule complexes for targeted delivery by covalently coupling two or more unprotected monovalent peptidomimetic compounds to a scaffold. In addition, the document describes methods for isolating peptidomimetic compounds that bind specifically to a target tissue, including preparing a peptidomimetic library of A-scaffold-A′ compositions, contacting the target tissue, isolating specifically binding compounds, and characterizing the formula of the composition that bound.
Claims Coverage
The partial content includes seven independent claims. Across these claims, the inventive coverage centers on the A-scaffold-A′ ligand architecture with monovalent peptidomimetic compounds, incorporation into lipid carriers including liposomes, and screening or isolation workflows that use peptidomimetic libraries and characterized binding specificity.
A-scaffold-A′ monovalent peptidomimetic ligand in a lipid bilayer
A tissue-specific targeting ligand for targeted delivery of therapeutic agents comprising a composition of formula A-scaffold-A′, wherein the scaffold has the stated formula with dotted attachment points, and wherein A and A′ comprise monovalent peptidomimetic compounds, each having the stated monovalent peptidomimetic formula, and the composition is incorporated into a lipid bilayer.
Covalent coupling of unprotected monovalent peptidomimetics to a scaffold for a small-molecule complex
A method for synthesizing a small molecule complex for targeted delivery of therapeutic agents to a tissue by coupling covalently two or more unprotected monovalent peptidomimetic compounds of formulas A and A′ to a scaffold having the stated formula and dotted attachment points, wherein A and A′ comprise monovalent peptidomimetic compounds each having the stated formula.
Ligand-functionalized delivery system using a therapeutic agent carrier with A-scaffold-A′
A ligand-functionalized delivery system comprising a therapeutic agent carrier and a tissue-specific targeting ligand, wherein the targeting ligand includes a composition of formula A-scaffold-A′ with the stated scaffold formula, dotted attachment points, and A and A′ comprising monovalent peptidomimetic compounds having the stated formula.
Targeted delivery using a liposome complex masked with a reversible masking reagent
A method of delivering a payload to a target tissue by preparing a composition of formula A-scaffold-A′ with the stated scaffold and monovalent peptidomimetic components, incorporating the composition into a liposome that encapsulates a therapeutic agent to form a targeted liposome complex, combining the targeted liposome complex with a reversible masking reagent, and administering a therapeutically effective amount of the masked targeted liposome complex to a patient.
Isolating peptidomimetic binders using an A-scaffold-A′ peptidomimetic library
A method of isolating a peptidomimetic compound for binding to a target tissue by preparing a peptidomimetic library of compositions of formula A-scaffold-A′ with the stated scaffold formula and dotted attachment points, contacting the target tissue with the peptidomimetic compounds, isolating those peptidomimetic compounds that bind specifically to the target tissue, and characterizing the formula of the composition that bound specifically.
Screening peptidomimetic compounds that bind to a target tissue or cell
A method of screening for a peptidomimetic compound that binds to a target tissue or cell by preparing a peptidomimetic library of compositions of formula A-scaffold-A′ with the stated scaffold formula and dotted attachment points, mixing the peptidomimetic compounds with lipids to form liposomes, contacting a target tissue with the peptidomimetic compounds, isolating those peptidomimetic compounds that bind specifically to the target tissue, and characterizing the formula of the composition that bound specifically.
Screening peptidomimetic binders using liposomes containing a nucleic acid for delivery
A method of screening for a peptidomimetic compound that binds to a target tissue or cell by preparing a peptidomimetic library of compositions of formula A-scaffold-A′ with the stated scaffold formula and dotted attachment points, mixing the peptidomimetic compounds with lipids to form liposomes that further comprise a nucleic acid for delivery to a cell, contacting a target tissue with the peptidomimetic compounds, isolating those peptidomimetic compounds that bind specifically to the target tissue, and characterizing the formula of the composition that bound specifically.
The independent claims consistently require the A-scaffold-A′ architecture with monovalent peptidomimetic compounds and expand it into targeted delivery systems by incorporating the composition into lipid carriers including liposomes. They further cover synthesis via covalent coupling and screening or isolation approaches in which peptidomimetic libraries are evaluated for specific binding.
Stated Advantages
Preferential enhancement of transfection of tumor endothelium versus normal endothelium/cancer cells.
Improved tumor endothelium transfection and anti-angiogenic efficacy using TSP1 plasmid delivery with KB1023-coated, reversibly masked BIV complexes.
Quantified reductions in tumor growth.
Reduced off-target transfection in non-target tissues.
Documented Applications
High-throughput luciferase-based selection/screening of bivalent/monovalent peptidomimetic ligands on bilamellar invaginated vesicles (BIVs) to preferentially enhance transfection of tumor endothelium versus normal endothelium/cancer cells.
Co-culture and in vivo evaluation of improved tumor endothelium transfection and anti-angiogenic efficacy using TSP1 plasmid delivery with KB1023-coated, reversibly masked BIV complexes, including quantified reductions in tumor growth and reduced off-target transfection.
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