Journal Article

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BACKGROUND: Lung cancer is the leading cause of cancer-related death in the United States, with more than half of the cancers are located peripherally. Computed tomography (CT) has been utilized in the last decade to detect early peripheral lung cancer. However, due to the high false diagnosis rate of CT, further biopsy is often necessary to confirm cancerous cases. This renders intervention for peripheral lung nodules (especially for small peripheral lung cancer) difficult and time-consuming, and it is highly desirable to develop new, on-the-spot earlier lung cancer diagnosis and treatment strategies. PURPOSE: The objective of this study is to develop a minimally invasive multimodality image-guided (MIMIG) intervention system to detect lesions, confirm small peripheral lung cancer, and potentially guide on-the-spot treatment at an early stage. Accurate image guidance and real-time optical imaging of nodules are thus the key techniques to be explored in this work. METHODS: The MIMIG system uses CT images and electromagnetic (EM) tracking to help interventional radiologists target the lesion efficiently. After targeting the lesion, a fiber-optic probe coupled with optical molecular imaging contrast agents is used to confirm the existence of cancerous tissues on-site at microscopic resolution. Using the software developed, pulmonary vessels, airways, and nodules can be segmented and visualized for surgical planning; the segmented results are then transformed onto the intra-procedural CT for interventional guidance using EM tracking. Endomicroscopy through a fiber-optic probe is then performed to visualize tumor tissues. Experiments using IntegriSense 680 fluorescent contrast agent labeling alphavbeta3 integrin were carried out for rabbit lung cancer models. Confirmed cancers could then be treated on-the-spot using radio-frequency ablation (RFA). RESULTS: The prototype system is evaluated using the rabbit VX2 lung cancer model to evaluate the targeting accuracy, guidance efficiency, and performance of molecular imaging. Using this system, we achieved an average targeting accuracy of 3.04 mm, and the IntegriSense signals within the VX2 tumors were found to be at least two-fold higher than those of normal tissues. The results demonstrate great potential for applying the system in human trials in the future if an optical molecular imaging agent is approved by the Food and Drug Administration (FDA). CONCLUSIONS: The MIMIG system was developed for on-the-spot interventional diagnosis of peripheral lung tumors by combining image-guidance and molecular imaging. The system can be potentially applied to human trials on diagnosing and treating earlier stage lung cancer. For current clinical applications, where a biopsy is unavoidable, the MIMIG system without contrast agents could be used for biopsy guidance to improve the accuracy and efficiency.

Journal Article

ProSense, IntegriSense, MMPSense, Annexin-Vivo, Annexin vivo, IVIS, Animals; Antineoplastic Agents/administration & dosage/pharmacology; Carcinoma/*diagnosis/*metabolism/pathology; Cathepsins/metabolism; Cell Line, Tumor; Disease Progression; Female; Fluorescent Dyes/chemistry/metabolism; Integrin alphaVbeta3/metabolism; Integrins/genetics/*metabolism; Magnetic Resonance Imaging; Matrix Metalloproteinases/metabolism; Mice; Mice, Transgenic; *Molecular Imaging; Ovarian Neoplasms/*diagnosis/drug therapy/*metabolism; Peptide Hydrolases/*metabolism; Protein Binding; Tumor Burden/drug effects

Most patients with epithelial ovarian cancer (EOC) experience drug-resistant disease recurrence. Identification of new treatments is a high priority, and preclinical studies in mouse models of EOC may expedite this goal. We previously developed methods for magnetic resonance imaging (MRI) for tumor detection and quantification in a transgenic mouse model of EOC. The goal of this study was to determine whether three-dimensional (3D) fluorescence molecular tomography (FMT) and fluorescent molecular imaging probes could be effectively used for in vivo detection of ovarian tumors and response to therapy. Ovarian tumor-bearing TgMISIIR-TAg mice injected with fluorescent probes were subjected to MRI and FMT. Tumor-specific probe retention was identified in vivo by alignment of the 3D data sets, confirmed by ex vivo fluorescent imaging and correlated with histopathologic findings. Mice were treated with standard chemotherapy, and changes in fluorescent probe binding were detected by MRI and FMT. Ovarian tumors were detected using probes specific for cathepsin proteases, matrix metalloproteinases (MMPs), and integrin alpha(v)beta(3). Cathepsin and integrin alpha(v)beta(3) probe activation and retention correlated strongly with tumor volume. MMP probe activation was readily detected in tumors but correlated less strongly with tumor volume. Tumor regression associated with response to therapy was detected and quantified by serial MRI and FMT. These results demonstrate the feasibility and sensitivity of FMT for detection and quantification of tumor-associated biologic targets in ovarian tumors and support the translational utility of molecular imaging to assess functional response to therapy in mouse models of EOC.

Journal Article

IVIS, Xen29, Xen 29, Staphylococcus aureus Xen29, Animals; Female; Magnetic Resonance Imaging/*methods; Mice; Mice, Inbred BALB C; Staphylococcal Infections/*pathology; Staphylococcus aureus/*pathogenicity; Thigh/*microbiology/*pathology

BACKGROUND: During the last years, (19)F-MRI and perfluorocarbon nanoemulsion (PFC) emerged as a powerful contrast agent based MRI methodology to track cells and to visualize inflammation. We applied this new modality to visualize deep tissue abscesses during acute and chronic phase of inflammation caused by Staphylococcus aureus infection. METHODOLOGY AND PRINCIPAL FINDINGS: In this study, a murine thigh infection model was used to induce abscess formation and PFC or CLIO (cross linked ironoxides) was administered during acute or chronic phase of inflammation. 24 h after inoculation, the contrast agent accumulation was imaged at the site of infection by MRI. Measurements revealed a strong accumulation of PFC at the abscess rim at acute and chronic phase of infection. The pattern was similar to CLIO accumulation at chronic phase and formed a hollow sphere around the edema area. Histology revealed strong influx of neutrophils at the site of infection and to a smaller extend macrophages during acute phase and strong influx of macrophages at chronic phase of inflammation. CONCLUSION AND SIGNIFICANCE: We introduce (19)F-MRI in combination with PFC nanoemulsions as a new platform to visualize abscess formation in a murine thigh infection model of S. aureus. The possibility to track immune cells in vivo by this modality offers new opportunities to investigate host immune response, the efficacy of antibacterial therapies and the influence of virulence factors for pathogenesis.

Journal Article

Animals; Antineoplastic Agents; Apoptosis; Bioware; Caspase 3; Cell Line, Tumor; Female; Firefly Luciferin; Humans; Luminescent Agents; MDA-MB-231-D3H2LN cells; Mice; Mice, SCID; SKOV3-luc-D3 cells; Molecular Imaging; Neoplasms; Oligopeptides; Taxoids

Apoptosis is a highly regulated process of programmed cell death essential for normal physiology. Dysregulation of apoptosis contributes to the development and progression of various diseases, including cancer, neurodegenerative disorders, and chronic heart failure. Quantitative noninvasive imaging of apoptosis in preclinical models would allow for dynamic longitudinal screening of compounds and facilitates a more rapid determination of therapeutic efficacy. In this study, we report the in vivo characterization of Z-DEVD-aminoluciferin, a modified firefly luciferase substrate that in apoptotic cells is cleaved by caspase-3 to liberate aminoluciferin, which can be consumed by luciferase to generate a luminescent signal. In two oncology models, namely SKOV3-luc and MDA-MB-231-luc-LN, at 24, 48, and 72 h after treatment with docetaxel, animals were injected with Z-DEVD-aminoluciferin and bioluminescent images were acquired. Significantly more light was detected at 24 (P<0.05), 48 (P<0.01), and 72 h (P<0.01) in the docetaxel-treated group compared with the vehicle-treated group, with caspase-3 activation at these time points confirmed using immunohistochemistry. Importantly, whereas significant differences between groups were detected as early as 24 h after treatment by molecular imaging, caliper measurements were unable to detect a difference for 4-5 additional days. Taken together, these data show that in vivo imaging of apoptosis using Z-DEVD-aminoluciferin could provide a sensitive and rapid method for early detection of drug efficacy, which could potentially be used by numerous therapeutic programs.

Journal Article

In vivo imaging; AngioSense

Extract:

With the advent of tissue regeneration and gene therapy for heart disease, evaluation of coronary circulation and cardiac function in vivo, especially in a disease model, is extremely important. Conventional methods such as microcomputed tomography, high-resolution magnetic resonance angiography, and high-resolution ultrasound have become invaluable tools in cardiovascular research. However, the disadvantages and limitations of these approaches sometimes preclude researchers from conducting important and specific studies on coronary circulation and cardiac function. Therefore, we developed and applied a novel real-time, in vivo fluorescent optical imaging system for use in the mouse cardiovascular system. We report the use of this system for repeatedly assessing coronary circulation, cardiovascular structure, and cardiac function in live mice...