Imaging agents for imaging protease activity and uses thereof
Inventors
Chen, Xiaoyuan • Lee, Seulki • Zhu, Lei
Assignees
US Department of Health and Human Services
Publication Number
US-10646591-B2
Publication Date
2020-05-12
Expiration Date
2032-09-07
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Abstract
Disclosed are imaging agents having the following Formula I: wherein F is a near infrared fluorophore, S is an enzymatically cleavable oligopeptide, Q is a fluorescence quencher molecule, and M is a moiety selected from the group consisting of PEG or derivative thereof and a targeting ligand, and wherein F, Q and M are linked to separate amino acids of the enzymatically cleavable oligopeptide. Compositions comprising such compounds, as well as methods of use, methods of identifying a cell or a population of cells in vivo expressing a protease of interest, and methods of treating a disease through imaging are also disclosed.
Core Innovation
The invention provides imaging agents of formula I comprising a near infrared fluorophore (F), an enzymatically cleavable oligopeptide (S), a fluorescence quencher molecule (Q), and a moiety (M) selected from polyethylene glycol (PEG) or its derivatives and targeting ligands. F, Q, and M are linked to separate amino acids of the enzymatically cleavable oligopeptide. These imaging agents are optically silent in their native state and are activated in the presence of specific proteases, generating a near-infrared fluorescence signal.
The background identifies the problem of existing protease imaging probes being limited in in vivo applications due to instability, short half-life, long activation time, and nonspecific activation after systemic administration. There is an unmet need for fast acting and/or extended-use activatable imaging agents that permit real-time video imaging of protease expression in vivo. The present invention addresses this by providing imaging agents modified with small molecular weight PEG or targeting ligands that offer enhanced target-to-background ratios and fast activation in vivo.
Claims Coverage
The patent contains three independent claims related to imaging agents of formula I and compositions comprising them. The main inventive features focus on the structural components of the imaging agent and their specific selections.
Imaging agent comprising a near infrared fluorophore, enzymatically cleavable oligopeptide, fluorescence quencher, and PEG or targeting ligand
An imaging agent of formula I wherein the fluorophore (F) is a near infrared fluorophore, the oligopeptide (S) is enzymatically cleavable, the quencher (Q) is a fluorescence quencher molecule, and the moiety (M) is selected from PEG or a derivative thereof or a targeting ligand, with F, Q, and M linked to separate amino acids of the oligopeptide.
Near infrared fluorophore selection
The near infrared fluorophore (F) is selected from the group consisting of Cy5.5, Cy7, Cy7.5, and IRDye800CW.
Fluorescence quencher selection
The fluorescence quencher (Q) is selected from Black Hole Quencher-3 (BHQ-3) or QSY-7.
Composition comprising the imaging agent and a carrier
A composition comprising the imaging agent of formula I and a pharmaceutically acceptable carrier.
The claims protect the imaging agents characterized by the combination of a near infrared fluorophore, an enzymatically cleavable oligopeptide, specific fluorescence quenchers, and PEG or targeting ligand moieties, as well as compositions comprising these agents with carriers.
Stated Advantages
The imaging agents provide significantly enhanced target-to-background ratios in tumors overexpressing target proteases.
They are fast acting with reduced activation time in vivo, allowing real-time video imaging of protease activity.
Small molecular weight PEG conjugation improves probe solubility and in vivo imaging performance.
Documented Applications
Identifying cells or populations of cells in vivo expressing a protease of interest, including tumor cells.
Diagnosing diseases overexpressing proteases such as pulmonary fibrosis, liver fibrosis, and cancer.
Monitoring protease activity and the efficacy of protease inhibitors in vivo in real-time.
Image-guided surgery, microsurgery, photodynamic therapy, or treatment procedures aided by imaging.
Non-invasive monitoring of pulmonary fibrosis progression using protease imaging in bleomycin-induced mouse models.
Non-invasive monitoring of liver fibrosis progression in a carbon tetrachloride-induced animal model.
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