Fluorescent chlorotoxin conjugate and method for intra-operative visualization of cancer
Inventors
Zhang, Miqin • Ellenbogen, Richard G. • Sze, Raymond W. • Veiseh, Omid • Olson, James M. • Veiseh, Mandana • Gabikian, Patrik • Bahrami, S-Bahram
Assignees
WASHINGTON, University of • University of Washington • Fred Hutchinson Cancer Center
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Publication Number
US-8778310-B2
Publication Date
2014-07-15
Expiration Date
Abstract
A chlorotoxin conjugate detectable by fluorescence imaging that allows for intra-operative visualization of cancerous tissues, compositions that include the chlorotoxin conjugate, and methods for using the chlorotoxin conjugate.
Core Innovation
The invention relates to a fluorescent chlorotoxin conjugate for intra-operative cancer visualization. The conjugate comprises chlorotoxin and a red or near-infrared fluorescent moiety, with the fluorescent moiety preferably a cyanine moiety such as Cy5.5, covalently coupled to chlorotoxin using covalent chemistry.
The invention addresses differentiating neoplastic from non-neoplastic tissue using fluorescence imaging. The chlorotoxin conjugate is configured to bind via chlorotoxin binding sites and to target a tumor-associated matrix metalloproteinase (MMP-2) protein complex, providing tumor-specific fluorescence with minimal binding to normal tissues.
The conjugate is provided as a pharmaceutical composition including a pharmaceutically acceptable carrier and a pharmacologically effective amount of the chlorotoxin conjugate. The described imaging behavior includes prolonged in vivo activity, with biophotonic imaging reporting retention of signal over about 4–14 days compared to unbound conjugate.
Claims Coverage
The independent claims cover chlorotoxin conjugate structures and corresponding pharmaceutical compositions, with inventive features centered on covalently coupling a cyanine moiety to chlorotoxin and, in some claim sets, limiting the conjugate to one to three cyanine moieties and/or selecting native, synthetic, or recombinant chlorotoxin. The claim set includes inventive features in independent claims clm-00001, clm-00004, clm-00006, clm-00008, clm-00011, and clm-00013.
Cyanine moiety covalently coupled to chlorotoxin
A chlorotoxin conjugate comprising a cyanine moiety covalently coupled to a chlorotoxin.
From one to three cyanine moieties covalently coupled to chlorotoxin
A chlorotoxin conjugate consisting of from one to three cyanine moieties covalently coupled to a chlorotoxin.
Pharmaceutically acceptable carrier with cyanine–chlorotoxin conjugate
A composition comprising a pharmaceutically acceptable carrier and a chlorotoxin conjugate, wherein the conjugate comprises a cyanine moiety covalently coupled to a chlorotoxin.
From one to three cyanine moieties covalently coupled in the conjugate
A composition comprising a pharmaceutically acceptable carrier and a chlorotoxin conjugate, wherein the conjugate consists of from one to three cyanine moieties covalently coupled to a chlorotoxin.
Cyanine moiety covalently coupled in the conjugate
A composition comprising a pharmaceutically acceptable carrier and a chlorotoxin conjugate, wherein the conjugate consists of a cyanine moiety covalently coupled to a chlorotoxin.
Across the independent claims, the core coverage is a chlorotoxin conjugate in which a cyanine moiety is covalently coupled to chlorotoxin, and compositions that include a pharmaceutically acceptable carrier with that conjugate. Some independent claims further define the conjugate as consisting of from one to three cyanine moieties, while others specify the conjugate as consisting of a cyanine moiety covalently coupled to chlorotoxin.
Stated Advantages
Prolonged in vivo activity for biophotonic imaging over about 4–14 days.
Tumor-specific fluorescence with minimal binding to normal tissues.
Low non-tissue background fluorescence.
Detection of small-foci tumor fluorescence, reported as small as about 1.5 mm.
Documented Applications
Intra-operative cancer visualization using fluorescence imaging and fluorescence differentiation of neoplastic versus non-neoplastic tissue.
Imaging in xenograft and genetically engineered mouse models, including glioma, medulloblastoma, prostate cancer, intestinal tumors, and sarcomas.
Assessment of biodistribution and tolerability using biodistribution/tolerability assessment described in the document.
Investigation of MMP-2 involvement in tumor targeting and specificity modulation by MMP-2 inhibition.
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