Angewandte Chemie International Edition 2007, 46, 7969–7971
Contrast Agent Trials in Swine
New near-infrared contrast agent reveals bone- and breast-cancer-related microcalcifications
Contact: John V. Frangioni, Deaconess Medical Center/Harvard Medical School, Boston (USA)
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Synthesis of Conjugatable Bisphosphonates for Molecular Imaging of Large Animals
Mammography continues to be the method of choice for the early detection
of breast cancer. However, because this technique is not as selective or
specific as one would wish, and does not deliver reliable results for
every level of tissue density, alternatives are being sought.
Near-infrared fluorescence mammography, which works with rays of
near-infrared (NIR) light instead of X-rays, is a highly promising
technique—although effective contrast agents have thus far been lacking.
A team led by John V. Frangioni at the Beth Israel Deaconess Medical
Center of the Harvard Medical School in Boston, Massachusetts, has
developed a contrast agent that makes visible the microcalcifications
related to malignant breast tumors. The researchers report in the
journal Angewandte Chemie that in validation trials in swine
their new contrast agent distinguishes specific calcium salts in soft
tissues, as well as depicting bones.
As breast cancer develops, calcium salts are deposited in breast tissue.
These microscopic calcium deposits consist mostly of hydroxyapatite, a
salt containing calcium and phosphate that is also present in bones.
As the basis of their NIR contrast agent, the researchers chose to use
the osteoporosis drug pamidronate, a biphosphonate. Biphosphonates,
which are also used for the treatment of bone metastases in breast
cancer patients, preferentially bind to bone. Frangioni and his team
attached a dye that both absorbs light and fluoresces in the NIR region
of the spectrum to a pamidronate derivative. Light in this region of the
spectrum penetrates especially well into living tissue without damaging
it, and is also easy to detect.
Thanks to a simplified, reliable synthetic route to a new pamidronate
derivative developed by Kumar R. Bhushan, the American team has now been
able to synthesize large quantities of a contrast agent called
Pam800—enough to run a trial with large animals. Pigs are particularly
well suited to such trials because their organs are of approximately the
same size as human organs.
As confirmed by surgical incisions, intravenously administered Pam800
reveals the bones of pigs with very high sensitivity. When
hydroxyapatite is injected into the soft tissues, the contrast agent
marks only the tiny hydroxyapatite crystals with high selectivity and
sensitivity. This could allow it to selectively reveal malignant
abnormal tissue. The swine trials demonstrated that the use of real-time
NIR fluorescence images even make possible image-guided surgery of the
soft tissues and bones.