Contrast Agent Trials in Swine
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.
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.
Citation: John V. Frangioni, Synthesis of Conjugatable Bisphosphonates for Molecular Imaging of Large Animals, Angewandte Chemie International Edition 2007, 46, No. 42, 7969–7971, doi: 10.1002/anie.200701216
Source: Angewandte Chemie
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.
Citation: John V. Frangioni, Synthesis of Conjugatable Bisphosphonates for Molecular Imaging of Large Animals, Angewandte Chemie International Edition 2007, 46, No. 42, 7969–7971, doi: 10.1002/anie.200701216
Source: Angewandte Chemie
译文：
乳房X射线造影术是早期诊断乳腺癌的方法之一。但由于该技术特异选择性无法达到期望，且无法在任何组织密度情况下都得到可信赖的结果，因此科学家一直在寻找替代技术。而使用近红外（NIR）替代X射线的近红外荧光乳房造影术是很好的选择，但是有效的造影剂很缺乏。
由波士顿哈佛医学院Beth Israel Deaconess医学中心John V. Frangioni领导的小组最近发明了一种造影剂，能使恶性乳腺肿瘤的微小钙化可见。在《应用化学》（Angewandte Chemie）上，科学家表示他们在猪体内进行了实验，结果证实新型造影剂能区分出软组织和骨骼中的特定钙盐。
当乳腺癌发展时，钙盐将在乳腺组织中沉积。这些微小钙沉积主要由羟磷灰石构成，它是含有钙和磷的盐，在骨骼中也存在。科学家选择了骨质疏松症药物pamidronate作为NIR造影剂的基础，这是一种二膦酸盐。二膦酸盐可用于治疗乳腺癌病人的骨转移，Frangioni小组在pamidronate衍生物上结合了一种在NIR光谱区域同时吸收光和荧光的染料。这一区域的光在活体组织中穿透力很好，并且不会造成损伤，且容易被探测。
由于Kumar R. Bhushan发明了一种新pamidronate衍生物的简便有效的合成技术，小组现在可以大量合成被称为Pam800的造影剂，这足够在大动物上进行实验。其中猪非常适合，因为它们的器官和人类的大小近似。
Pam800在外科上被证实对猪骨骼有很高的灵敏性。当羟磷灰石注入软组织中时，造影剂只对羟磷灰石进行高选择性和灵敏性成像。这能发现恶性肿瘤组织。在猪体内的实验证明实时NIR荧光像甚至能帮助指导软组织和骨骼外科手术的进行。(刘乐译自physorg)
