A targeted gold nanoparticle has been developed as a contrast agent for photoacoustic medical imaging. We have studied cancer cell targeting by antibody conjugated gold nanorods for high contrast photoacoustic imaging. By changing the aspect ratio of the elongated "rod" shape of the gold nanoparticle, its plasmon peak absorption wavelength can be tuned to the near IR ͑700-900 nm͒ for an increased penetration depth into biological tissue. Effective cell targeting and sensitive photoacoustic detection of a single layer of cells are demonstrated. Combining ultrasound with contrast agent based photoacoustic imaging is proposed as a visual tool to compound molecular and structural information for early stage prostate cancer detection.

The zinc-dependent disintegrin metalloproteinases (a disintegrin and metalloproteinases (ADAMs) have been implicated in several disease processes, including human cancer. Previously, we demonstrated that the expression of a catalytically active member of the ADAM family, ADAM15, is associated with the progression of prostate and breast cancer. The accumulation of the soluble ectodomain of E-cadherin in human serum has also been associated with the progression of prostate and breast cancer and is thought to be mediated by metalloproteinase shedding. Utilizing two complementary models, overexpression and stable short hairpin RNA-mediated knockdown of ADAM15 in breast cancer cells, we demonstrated that ADAM15 cleaves E-cadherin in response to growth factor deprivation. We also demonstrated that the extracellular shedding of E-cadherin was abrogated by a metalloproteinase inhibitor and through the introduction of a catalytically inactive mutation in ADAM15. We have made the novel observation that this soluble E-cadherin fragment was found in complex with the HER2 and HER3 receptors in breast cancer cells. These interactions appeared to stabilize HER2 heterodimerization with HER3 and induced receptor activation and signaling through the Erk pathway, supporting both cell migration and proliferation. In this study, we provide evidence that ADAM15 catalyzes the cleavage of E-cadherin to generate a soluble fragment that in turn binds to and stimulates ErbB receptor signaling.The classic cadherins, epidermal cadherin (E-cadherin), neuronal cadherin (N-cadherin), and placental cadherin (P-cadherin), are type I transmembrane glycoproteins (1). The epidermal specific cadherin, E-cadherin, has five extracellular domain repeats that are involved in cell binding mediated by E-cadherin homotypic interaction (2). The intracellular domain consists of a conserved sequence that associates with ␤-, ␥-, and p120-catenins. The interaction of ␤-or ␥-catenin with ␣-catenin links E-cadherin to the cytoskeletal matrix to stabilize the adherens junction mediated by the homotypic E-cadherin complex (3). The involvement of E-cadherin in cell-cell interaction is well established in embryonic development, organ morphogenesis, tissue integrity, and wound healing (4). The disruption of E-cadherin by genetic mutation, promoter hypermethylation, or proteolytic cleavage leads to the loss of cell contact integrity as a consequence of adherens junction dissolution. E-cadherin disruption has been observed in multiple pathophysiological conditions, including inflammation and cancer (5). In fact, E-cadherin is considered to function as a metastasis suppressor due to its inhibition of cancer cell migration and invasion (6). Several proteases have been implicated in the extracellular cleavage of E-cadherin, including MMP3, MMP7, MT1-MMP, plasmin, kallikrein 7, and ADAM10. In addition, the cytoplasmic domain of E-cadherin is cleaved by caspace-3 and calpain (7,8). The ectodomain shedding of a stable 80-kDa soluble E-cadherin (sE-cad) 2 fragment has been sho...

Although current breast cancer treatment guidelines limit the use of HER2 blocking agents to tumors with HER2 gene amplification, recent retrospective analyses suggest that a wider group of patients may benefit from this therapy. Utilizing breast cancer cell lines, mouse xenograft models and matched human primary and metastatic tissues, we demonstrate that HER2 is selectively expressed in and regulates self-renewal of the cancer stem cell population in ER+, HER2− luminal breast cancers. Although trastuzumab had no effects on the growth of established luminal breast cancer mouse xenografts, administration after tumor inoculation blocked subsequent tumor growth. HER2 expression is increased in luminal tumors grown in mouse bone xenografts, as well as in bone metastases from breast cancer patients compared to matched primary tumors. Furthermore this increase in HER2 protein expression was not due to gene amplification but rather was mediated by RANK-ligand in the bone microenvironment. These studies suggest that the clinical efficacy of adjuvant trastuzumab may relate to the ability of this agent to target the cancer stem cell population in a process that does not require HER2 gene amplification. Furthermore these studies support a cancer stem cell model in which maximal clinical benefit is achieved when cancer stem cell targeting agents are administered in the adjuvant setting.

Nanoparticles 100 nm in diameter containing indocyanine green (ICG) have been developed as a contrast agent for photoacoustic (PA) imaging based on (photonic explorers for biomedical use by biologically localized embedding PEBBLE) technology using organically modified silicate (ormosil) as a matrix. ICG is an FDA-approved dye with strong optical absorption in the near-infrared (NIR) region, where light can penetrate deepest into biological tissue. A photoacoustic imaging system was used to study image contrast as a function of PEBBLE concentration in phantom objects. ICG-embedded ormosil PEBBLEs showed improved stability in aqueous solution compared with free ICG dye. The particles were conjugated with HER-2 antibody for breast cancer and prostate cancer cell targeting. Initial in vitro characterization shows high contrast and high efficiency for binding to prostate cancer cells. ICG can also be used as a photosensitizer (generating toxic oxygen by illumination) for photodynamic therapy. We have measured the photosensitization capability of ICG-embedded ormosil nanoparticles. This feature can be utilized to combine detection and therapeutic functions in a single agent.