Cyclized NGR peptide compounds, compositions, and methods of their use
Inventors
Wood, Bradford J. • Dreher, Matthew • Negussie, Ayele H.
Assignees
US Department of Health and Human Services
Publication Number
US-8636978-B2
Publication Date
2014-01-28
Expiration Date
2029-06-15
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Abstract
Cyclized peptide compounds containing the NGR motif of formula (I) or a pharmaceutically-acceptable salt thereof are disclosed. Compositions comprising the cyclized peptide compounds and methods of their use are also disclosed.
Core Innovation
The invention relates to cyclized peptide compounds containing the NGR motif, specifically compounds of formula I or pharmaceutically-acceptable salts thereof, compositions comprising these compounds, and methods of their use. These compounds are designed for targeting therapeutic and diagnostic agents to cancer cells, particularly tumors expressing aminopeptidase N isoform CD13 (APN/CD13). The compositions include the cyclized peptides, lipid bilayers, therapeutic or diagnostic agents, and optional polyethylene glycol, aiming to selectively target cancerous tissues.
The background identifies the problem that traditional cancer therapies targeting cancer cells directly face limited access to those cells. More recent strategies focus on targeting tumor vasculature to suppress or destroy blood vessels feeding tumors. Tumor vessel endothelial cells express proteins like APN/CD13 that are low or absent in normal vessels. The NGR peptide motif specifically binds APN/CD13 and has been used for targeting drugs and cytokines to tumors. However, linear and disulfide-bridged cyclic NGR peptides suffer from instability under physiological conditions, leading to a need for permanently cyclized NGR peptide compounds to improve targeting and stability.
The core innovation addresses this need by providing permanently cyclized NGR peptide compounds of formula I, which are stable and can be conjugated to lipid bilayers such as liposomes. These compositions can carry therapeutic or diagnostic agents and can be administered to patients to target cancer tissues expressing APN/CD13. The invention also includes methods of administration and the use of such compositions to selectively target tumor vasculature and cancer cells, potentially improving efficacy over existing linear or disulfide-bridged cyclic peptides.
Claims Coverage
The patent includes two independent claims introducing novel chemical compounds and compositions, as well as methods for cancer imaging and treatment. There are three main inventive features extracted from these claims.
Cyclized NGR peptide compound of formula I
A compound of formula I represented by SEQ ID NO:1, with defined substituents R1 through R16, including specific embodiments where substituents correspond to amino acid residues and protecting groups, providing a permanently cyclized peptide containing the NGR motif for targeting APN/CD13.
Composition comprising the cyclized peptide compound with lipid bilayer and agents
A composition comprising (i) a compound of formula I or a pharmaceutically acceptable salt thereof; (ii) a lipid bilayer such as liposomes; (iii) at least one therapeutic agent (anti-tumor, anti-angiogenic, anti-neoplastic, e.g., anthracyclines) or diagnostic agent (fluorophore, radioisotopes, etc.); and (iv) optional polyethylene glycol, where the compound can be conjugated to the lipid bilayer.
Methods of imaging or treating cancer using the composition targeting APN/CD13
Methods of selectively imaging or treating cancerous tissue in a patient by administering compositions comprising the cyclized NGR peptide compound, where the targeted tissue expresses aminopeptidase N isoform CD13 (APN/CD13), enabling selective delivery and imaging or therapy of tumor vasculature and cancer cells.
These inventive features establish the chemical basis of permanently cyclized NGR peptide compounds, their incorporation into liposomal and similar compositions with therapeutic or diagnostic agents, and their use in selectively targeting and imaging or treating tumors via APN/CD13 expression.
Stated Advantages
Cyclized NGR peptides show greater stability under physiological conditions compared to disulfide-bridged cyclic peptides.
The cyclic peptides exhibit higher binding affinity and selectivity for APN/CD13, leading to improved targeting of tumor vasculature and cancer cells.
Compositions with cyclic peptides conjugated to liposomes allow controlled delivery and release of therapeutic agents, potentially enhanced by regional hyperthermia.
Documented Applications
Targeting therapeutic agents to tumor vasculature and cancerous tissue expressing APN/CD13 to improve treatment efficacy.
Delivering diagnostic agents such as fluorophores or radioisotopes for imaging tumors expressing APN/CD13.
Use of compositions comprising cyclic NGR peptides conjugated to low temperature sensitive liposomes to release payloads in response to hyperthermia at tumor sites.
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