Angiogenesis is a keystone in the treatment of cancer and potentially many other diseases. In cancer, first-generation antiangiogenic therapeutic approaches have demonstrated survival benefit in subsets of patients, but their high cost and notable adverse side effect risk have fueled alternative development efforts to personalize patient selection and reduce off-target effects. In parallel, rapid advances in cost-effective genomic profiling and sensitive early detection of high-risk biomarkers for cancer, atherosclerosis, and other angiogenesis-related pathologies will challenge the medical imaging community to identify, characterize, and risk stratify patients early in the natural history of these disease processes. Conventional diagnostic imaging techniques were not intended for such sensitive and specific detection, which has led to the emergence of novel noninvasive biomedical imaging approaches. The overall intent of molecular imaging is to achieve greater quantitative characterization of pathologies based on microanatomical, biochemical, or functional assessments; in many approaches, the capacity to deliver effective therapy, e.g., antiangiogenic therapy, can be combined. Agents with both diagnostic and therapy attributes have acquired the moniker "theranostics." This review will explore biomedical imaging options being pursued to better segment and treat patients with angiogenesis-influenced disease using vascular-constrained contrast platform technologies.
"Perfluorocarbon nanoparticles consist of a liquid perfluorocarbon core encapsulated within a monolayer of phospholipids [1–6]. The particles are around 250 nm in diameter allowing them to circulate easily through capillary beds. "
[Show abstract][Hide abstract] ABSTRACT: Perfluorocarbon nanoparticles offer a biologically inert, highly stable, and nontoxic platform that can be specifically designed to accomplish a range of molecular imaging and drug delivery functions in vivo. The particle surface can be decorated with targeting ligands to direct the agent to a variety of biomarkers that are associated with diseases such as cancer, cardiovascular disease, obesity, and thrombosis. The surface can also carry a high payload of imaging agents, ranging from paramagnetic metals for MRI, radionuclides for nuclear imaging, iodine for CT, and florescent tags for histology, allowing high sensitivity mapping of cellular receptors that may be expressed at very low levels in the body. In addition to these diagnostic imaging applications, the particles can be engineered to carry highly potent drugs and specifically deposit them into cell populations that display biosignatures of a variety of diseases. The highly flexible and robust nature of this combined molecular imaging and drug delivery vehicle has been exploited in a variety of animal models to demonstrate its potential impact on the care and treatment of patients suffering from some of the most debilitating diseases.
"Numerous studies have demonstrated intensive angiogenesis during the estrous cycle or pregnancy within reproductive tissues including the ovary, uterus and placenta (Reynolds et al., 1992, 2000, 2002, 2005, 2006, 2010; Reynolds and Redmer, 1995, 2001; Redmer and Reynolds, 1996; Fraser and Lunn, 2000; Jaffe, 2000; Fraser and Wulff, 2001; Grazul-Bilska et al., 2001; Shimizu et al., 2012). Angiogenesis and vascularization have been studied using several methods including (i) in vivo techniques (e.g., perfusion of blood vessels with a fluorescently labeled marker in an entire mouse, imaging of microcirculation with contrast ultrasound , and other imaging techniques (Thurston et al., 1999; Eisenblätter et al., 2010; Kagadis et al., 2010; Kiessling et al., 2010; Lanza et al., 2010; Roesli and Neri, 2010; Seevinck et al., 2010; Gheonea et al., 2011; Sboros et al., 2011; Smith et al., 2011); (ii) in situ techniques (e.g., chicken chorioallantoic membrane [CAM] assay; Redmer et al., 1988; Staton et al., 2009); (iii) in vitro techniques (e.g., migration and proliferation assays; Grazul-Bilska et al., 1995; Auerbach et al., 2003; Staton et al., 2004, 2009); (iv) histological/immunohistochemical/immunofluorescence techniques (Vonnahme et al., 2006; Grazul-Bilska et al., 2007; Borowicz et al., 2008); (v) molecular biology techniques (Grazul-Bilska et al., 2010, 2011) and/or other methods (e.g., vascular casting; Hafez et al., 2010). In addition, power and/or color Doppler ultrasonography have been used to study blood flow and vascular tissue perfusion (Rubens et al., 2006; Gebb and Dar, 2011). "
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to optimize a method to visualize tissue vascularity by perfusing the local vascular bed with a fluorescently labeled lectin, combined with immunofluorescent labeling of selected vascular/tissue markers. Ovaries with the pedicle were obtained from adult non-pregnant ewes. Immediately after collection, the ovarian artery was perfused with phosphate buffered saline (PBS) to remove blood cells, followed by perfusion with PBS containing fluorescently labeled Griffonia (Bandeiraea) simplicifolia (BS1) lectin. Then, half of ovary was fixed in formalin and another half in Carnoy's fixative. BS1 was detected in blood vessels in ovaries fixed in formalin, but not in Carnoy's fixative. Formalin fixed tissue was used for immunofluorescence staining of two markers of tissue function and/or structure, Ki67 and smooth muscle cell actin (SMCA). Ki67 was detected in granulosa and theca cells, luteal and stromal tissue, and a portion of Ki67 staining was co-localized with blood vessels. SMCA was detected in pericytes within the capillary system, in blood vessels in all ovarian compartments, and in the stroma. Thus, blood vessel perfusion with fluorescently labeled lectin combined with immunohistochemistry, microscopy, and imaging techniques provide an excellent tool to study angiogenesis, vascular architecture, and organ structures and function in physiological and pathological conditions.
"The α v β 3 integrin is known to be significantly upregulated on activated endothelial cells during neoangiogenesis . By binding to the sequence arginine-glycine-aspartate (RGD), it mediates its biologic activity, and therefore, this peptide sequence has been used to functionalize contrast agents/nanoparticles for targeting the tumor neovasculature   . "
[Show abstract][Hide abstract] ABSTRACT: One of the challenges of tailored antiangiogenic therapy is the ability to adequately monitor the angiogenic activity of a malignancy in response to treatment. The α(v)β(3) integrin, highly overexpressed on newly formed tumor vessels, has been successfully used as a target for Arg-Gly-Asp (RGD)-functionalized nanoparticle contrast agents. In the present study, an RGD-functionalized nanocarrier was used to image ongoing angiogenesis in two different xenograft tumor models with varying intensities of angiogenesis (LS174T > EW7). To that end, iron oxide nanocrystals were included in the core of the nanoparticles to provide contrast for T(2)*-weighted magnetic resonance imaging (MRI), whereas the fluorophore Cy7 was attached to the surface to enable near-infrared fluorescence (NIRF) imaging. The mouse tumor models were used to test the potential of the nanoparticle probe in combination with dual modality imaging for in vivo detection of tumor angiogenesis. Pre-contrast and post-contrast images (4 hours) were acquired at a 9.4-T MRI system and revealed significant differences in the nanoparticle accumulation patterns between the two tumor models. In the case of the highly vascularized LS174T tumors, the accumulation was more confined to the periphery of the tumors, where angiogenesis is predominantly occurring. NIRF imaging revealed significant differences in accumulation kinetics between the models. In conclusion, this technology can serve as an in vivo biomarker for antiangiogenesis treatment and angiogenesis phenotyping.
Neoplasia (New York, N.Y.) 10/2012; 14(10):964-73. DOI:10.1593/neo.121148 · 4.25 Impact Factor
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