Colorectal cancer is a major cause of cancer death. Morbidity, mortality and healthcare costs can be reduced if the
disease can be detected at an early stage. Screening is a viable approach as there is a clear link to risk factors such as
age. We have developed a fluorescent contrast agent for use during colonoscopy. The agent is administered
intravenously and is targeted to an early stage molecular marker for colorectal cancer. The agent consists of a targeting
section comprising a peptide, and a fluorescent reporter molecule. Clinical imaging of the agent is to be performed with
a far red fluorescence imaging channel (635 nm excitation/660-700 nm emission) as an adjunct to white light colonoscopy. Preclinical proof of mechanism results are presented. The compound has a Kd of ~3nM. Two human xenograft tumour models were used. Tumour cells were implanted and grown subcutaneously in nude mice. Imaging using a fluorescence reflectance imaging system and quantitative biodistribution studies were performed. Substances tested include the
targeted agent, and a scrambled sequence of the peptide (no binding) used as a negative control. Competition studies were also performed by co-administration of 180 times excess unlabelled peptide. Positive imaging contrast was shown in the tumours, with a clear relationship to expression levels (confirmed with quantitative biodistribution data). There was a significant difference between the positive and negative control substances, and a significant reduction in contrast
in the competition experiment.
|