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Tumor-specific Ligand
Targeting molecules such as antibodies and peptides are being investigated as tumor-specific ligands. One such ligand is chlorotoxin (CTX), a 36–amino acid peptide initially isolated from the venom of the scorpion Leiurus quinquestriatus. The peptide has demonstrated specificity as a tumor-targeting agent in a variety of formats, including radiolabeled, conjugated to fluorescent tags, or incorporated into nanoparticles. All clinical trials to date conducted with CTX indicate that it has negligible toxicity in humans. These unique properties make CTX attractive as a targeted imaging agent for cancer. In transgenic and xenograft mouse models of glioma, medulloblastoma, prostate cancer, sarcoma, and colorectal cancer, a CTX-Cy5.5 conjugate ("Tumor Paint") was shown to bind to both primary tumor and metastatic lesions. Subsequent work with CTX conjugated to a variety of near-infrared (NIR) fluorophores confirmed and extended these results, supporting the peptide's specificity and breadth of tumor recognition. BLZ-100 is a CTX–indocyanine green (ICG) conjugate that is being advanced toward human clinical trials.
In the past few years there has been an increased interest in NIR light fluorescence imaging. Near-infrared contrast agents such as ICG offer well-recognized advantages over ultraviolet or visible light imaging. These include better tissue penetration of incident light, less scatter of emitted photons, and low tissue autofluorescence. There are multiple imaging systems that have been developed by both academic and industrial groups. There are separate systems for open surgeries, laparoscopic surgeries, and robot-assisted surgeries that vary based on specific challenges. Some of the important criteria for developing a new imaging system are based on concentration of the fluorophores, type of tissue due to varying tissue penetration depths, ergonomics, and cost. Additionally, NIR imaging systems have to optimize the excitation light fluence, and there is a choice between coherent and incoherent light sources. Incoherent light sources are easier to work with, require fewer precautions for skin and eye exposure, and face fewer regulatory hurdles, but require high energy to produce adequate fluorescence. Coherent sources (lasers) are usually restricted due to skin and eye exposure to 10–25 mW/cm to negate the need for protective glasses, but if the photobleaching effect on the fluorophore is absent at higher energies and the use of protective glasses is not an issue during the surgery, it may be possible to use higher energy. Considering these factors, we would like to report development of a "proof-of-concept" intraoperative NIR imaging system to detect a novel tumor ligand attached to an NIR dye (ICG) for use in brain tumor surgeries.
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