Fluorescence imaging of bombesin and transferrin receptor expression is comparable to 18F-FDG PET in early detection of sorafenib-induced changes in tumor metabolism.

Physical measurement of tumor volume reduction is the most commonly used approach to assess tumor progression and treatment efficacy in mouse tumor models. However, it is relatively insensitive, and often requires long treatment courses to achieve gross physical tumor destruction. As alternatives, several non-invasive imaging methods such as bioluminescence imaging (BLI), fluorescence imaging (FLI) and positron emission tomography (PET) have been developed for more accurate measurement.

Detection and quantification of enzymatically active prostate-specific antigen in vivo.

Assays for blood levels of prostate-specific antigen (PSA), performed in prostate cancer detection, measure mostly inactive/complexed PSA and do not provide information regarding enzymatically active PSA, which is biologically more relevant. Thus, we designed and synthesized an enzymatically cleavable peptide sequence labeled with near-infrared (NIR) fluorophores (ex/em 740/770  nm) and coupled it to a pharmacokinetic modifier designed to improve its plasma kinetics. In its native state, the agent, PSA750 FAST™ (PSA750), is optically quenched (>95%) and only becomes fluorescent upon cleavage by active PSA, yielding a significant increase in signal.

Noninvasive in vivo quantification of neutrophil elastase activity in acute experimental mouse lung injury.

We developed a neutrophil elastase-specific near-infrared fluorescence imaging agent, which, combined with fluorescence molecular tomographic imaging, allowed us to detect and quantify neutrophil elastase activity in vivo, in real time, and noninvasively in an acute model of lung injury (ALI). Significantly higher fluorescent signal was quantified in mice with LPS/fMLP-induced ALI as compared to healthy controls, correlating with increases in the number of bronchoalveolar lavage cells, neutrophils, and elastase activity. The agent was significantly activated ex vivo in lung sections from ALI but not from control mice, and this activation was ablated by the specific inhibitor sivelestat.

Adnectin CT-322 inhibits tumor growth and affects microvascular architecture and function in Colo205 tumor xenografts.

Antiangiogenesis has become a promising pillar in modern cancer therapy. This study investigates the antiangiogenic effects of the PEGylated Adnectin™, CT-322, in a murine Colo-205 xenograft tumor model. CT-322 specifically binds to and blocks vascular endothelial growth factor receptor (VEGFR-2).

Optical tomographic imaging discriminates between disease-modifying anti-rheumatic drug (DMARD) and non-DMARD efficacy in collagen antibody-induced arthritis.

Introduction: Standard measurements used to assess murine models of rheumatoid arthritis, notably paw thickness and clinical score, do not align well with certain aspects of disease severity as assessed by histopathology. We tested the hypothesis that non-invasive optical tomographic imaging of molecular biomarkers of inflammation and bone turnover would provide a superior quantitative readout and would discriminate between a disease-modifying anti-rheumatic drug (DMARD) and a non-DMARD treatment.

Methods: Using two protease-activated near-infrared fluorescence imaging agents to detect inflammation-associated cathepsin and matrix metalloprotease activity, and a third agent to detect bone turnover, we quantified fluorescence in paws of mice with collagen antibody-induced arthritis.

Dual in vivo quantification of integrin-targeted and protease-activated agents in cancer using fluorescence molecular tomography (FMT).

Purpose: Integrins, especially α(v)β(3) and α(v)β(5), are upregulated in tumor cells and activated endothelial cells and as such, serve as cancer biomarkers. We developed a novel near-infrared-labeled optical agent for the in vivo detection and quantification of α(v)β(3)/α(v)β(5).

Procedures: A small peptidomimetic α(v)β(3) antagonist was synthesized, coupled to a near-infrared fluorescent (NIRF) dye, and tested for binding specificity using integrin-overexpressing cells, inhibition of vitronectin-mediated cell attachment, binding to tumor and endothelial cells in vitro, and competition studies.

Fluorescence molecular tomography enables in vivo visualization and quantification of nonunion fracture repair induced by genetically engineered mesenchymal stem cells.

Fluorescence molecular tomography (FMT) is a novel tomographic near-infrared (NIR) imaging modality that enables 3D quantitative determination of fluorochrome distribution in tissues of live small animals at any depth. This study demonstrates a noninvasive, quantitative method of monitoring engineered bone remodeling via FMT. Murine mesenchymal stem cells overexpressing the osteogenic gene BMP2 (mMSCs-BMP2) were implanted into the thigh muscle and into a radial nonunion bone defect model in C3H/HeN mice.

Gamma-irradiation modulates vascular smooth muscle cell and extracellular matrix function: Implications for neointimal development.

Objective: Migration of vascular smooth muscle cells (SMCs) into the subintimal space, and their proliferation and resultant deposition of extracellular matrix are key processes in the development of intimal hyperplasia, leading to vascular recurrent stenosis. The purpose of this study was to investigate the effects of clinically administered doses of gamma-radiation on SMCs and extracellular matrix proteins in vitro, to better understand how it impinges on cellular and extracellular components of recurrent stenosis.

Methods: The effects of gamma-irradiation (10, 20 Gy) on SMC migration into three-dimensional collagen matrix gels was quantitated by calibrated light microscopy, and the release of metalloproteinases into conditioned media was investigated with an enzyme-linked immunosorbent assay and zymography.

Free radical attenuation prevents thrombosis and enables photochemical inhibition of vein graft intimal hyperplasia.

Objective: Photodynamic therapy (PDT) inhibits post-interventional stenosis in balloon-injured arteries, but causes thrombosis when applied to vein grafts. This may result from added free radicals produced during the hypoxia-reperfusion injury of vein graft implantation. The purposes of this study were to determine whether a free radical scavenger could inhibit vein graft thrombosis, enabling PDT to inhibit intimal hyperplasia; and to investigate the role of neutrophils, also a source of radicals, in this setting.

Effects of UVR and UVR-induced cytokines on production of extracellular matrix proteins and proteases by dermal fibroblasts cultured in collagen gels%.

Synthesis of extracellular matrix (ECM) proteins and their degradation by matrix metalloproteinases (MMP) are part of the dermal remodeling resulting from chronic exposure of skin to ultraviolet radiation (UVR). We have compared two alternative mechanisms for these responses, namely, a direct mechanism in which UV-B or UV-A is absorbed by fibroblasts and an indirect mechanism in which cytokines, produced in skin in response to UVR, stimulate production of the ECM proteins and MMP. These studies were carried out on human dermal fibroblasts grown in contracted, free-floating 9 day old collagen gels as a dermal equivalent.

Photodynamic therapy for cutaneous proliferative vascular tumors in a mouse model.

Photodynamic therapy with benzoporphyrin derivative monoacid ring A and red light (PDT-BPD) has been used to treat human choroidal hemangiomas, and may be useful for cutaneous vascular lesions. The potential for PDT-BPD to inhibit selectively vascular tumor growth was tested in a mouse angiosarcoma model, of which the tumor growth mimics the proliferative phase of hemangiomas. Vascular tumors arising after intradermal injection of immortalized murine endothelial cells were exposed to 50 to 150 J per cm2 of 690 nm laser light 15 min after intravenous injection of 1 mg per kg BPD.

Mechanisms of reduced human vascular cell migration after photodynamic therapy.

Restenosis results from intimal hyperplasia and constrictive remodeling following cardiovascular interventions. Photodynamic therapy (PDT) has been shown to inhibit intimal hyperplasia in vivo by preventing neointimal repopulation of the treated vessel. This study was undertaken in an attempt to further dissect the mechanisms by which PDT acts on secreted and extracellular matrix proteins to inhibit migration of cultured human vascular cells.