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A novel group of compounds that can reveal the presence of calcifications in breast tissue using near-infrared fluorescent optical imaging, has been synthesised by US researchers. The team developed a simplified, efficient synthesis of 3-amino tetramethyl 1-hydroxypropylidenebisphosphonate (a methylester-protected pamidronate) and used NMR spectroscopy to track their success. Kumar Bhushan, Eiichi Tanaka, and John Frangioni at Harvard Medical School in Boston, Massachusetts, explain how mammography has become the standard for early diagnosis of breast cancer. However, this technique suffers from relatively low sensitivity and specificity and misses one in five cancers, nor is it viable for some groups of patients. In contrast, a detection method that could reveal the presence of microcalcifications ubiquitous in early breast cancer could circumvent some of the issues. Microcalcifications of hydroxyapatite (HA) form within the soft breast tissue in the early stages of breast cancer and as such a highly specific compound that can target these tiny deposits as well as produce a high contrast picture in NIR imaging could lead to a highly sensitive technique. Hydroxyapatite is also the initial deposit produced by bone-forming osteoblast cells during normal bone growth. The team's methylester-protected pamidronate is a close relative of the osteoporosis drug, bisphosphonate, which can distinguish between HA and another calcium salt found in benign breast tumours, calcium oxalate. The compound thus provides a starting point for the preparation of conjugated NIR fluorescent agents that are highly specific to HA and can produce an intense signal in NIR imaging. Previously, the team reported limited success in NIR fluorescence imaging with a small-animal model using their first generation contrast agent Pam78. The limiting factor in this earlier work was simply the low yields possible in the synthesis of the agent. Their new approach based on non-aqueous reaction conditions, provides much higher yields, making it viable for large mammal studies. The final compound, Pam800, was, the researchers explain, purified by preparative high-performance liquid chromatography and analysed by liquid chromatography mass spectrometry (LCMS) and NMR spectroscopy. The high yield of Pam800 possible with their approach allowed them to carry out pre-clinical studies on pigs as an animal model for evaluating real-time NIR fluorescence imaging of HA in soft tissue akin to breast tissue and in bone. Related links:
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