Angiogenesis imaging with vascular-constrained particles: The why and how

ArticleinEuropean Journal of Nuclear Medicine 37 Suppl 1(S1):S114-26 · August 2010with9 Reads
DOI: 10.1007/s00259-010-1502-5 · Source: PubMed
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 phospho- lipids123456. The particles are around 250 nm in diameter allowing them to circulate easily through capillary beds. "
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    • "[2] In nanomedicine, the hydrophobic nature of paclitaxel has favored its incorporation into many nanoparticle formulations, including into the phospholipid outer membrane of perfluorocarbon nanoparticles. [3] Perfluorocarbon (PFC) nanoparticles have been targeted to a myriad of epitopes for diagnostic imaging and site-specific drug delivery for applications in atherosclerosis, restenosis, cancer and rheumatoid arthritis.4567 Early comparisons of hydrophobic drugs, including doxorubicin, paclitaxel, and fumagillin , revealed that fumagillin, a potent anti-angiogenic mycotoxin, was retained best in dissolution studies and was effective in vivo. "
    [Show abstract] [Hide abstract] ABSTRACT: In nanomedicine, the hydrophobic nature of paclitaxel has favored its incorporation into many nanoparticle formulations for anti-cancer chemotherapy. At lower doses taxanes are reported to elicit anti-angiogenic responses. In the present study, the facile synthesis, development and characterization of a new lipase-labile docetaxel prodrug is reported and shown to be an effective anti-angiogenic agent in vitro and in vivo. The Sn 2 phosphatidylcholine prodrug was stably incorporated into the lipid membrane of αvβ3-integrin targeted perfluorocarbon (PFC) nanoparticles (αvβ3-Dxtl-PD NP) and did not appreciably release during dissolution against PBS buffer or plasma over three days. Overnight exposure of αvβ3-Dxtl-PD NP to plasma spiked with phospholipase enzyme failed to liberate the taxane from the membrane until the nanoparticle integrity was compromised with alcohol. The bioactivity and efficacy of αvβ3-Dxtl-PD NP in endothelial cell culture was as effective as Taxol(®) or free docetaxel in methanol at equimolar doses over 96 hours. The anti-angiogenesis effectiveness of αvβ3-Dxtl-PD NP was demonstrated in the Vx2 rabbit model using MR imaging of angiogenesis with the same αvβ3-PFC nanoparticle platform. Nontargeted Dxtl-PD NP had a similar MR anti-angiogenesis response as the integrin-targeted agent, but microscopically measured decreases in tumor cell proliferation and increased apoptosis were detected only for the targeted drug. Equivalent dosages of Abraxane(®) given over the same treatment schedule had no effect on angiogenesis when compared to control rabbits receiving saline only. These data demonstrate that αvβ3-Dxtl-PD NP can reduce MR detectable angiogenesis and slow tumor progression in the Vx2 model, whereas equivalent systemic treatment with free taxane had no benefit.
    Full-text · Article · Mar 2014
    • "Numerous studies have demonstrated intensive angiogenesis during the estrous cycle or pregnancy within reproductive tissues including the ovary, uterus and placenta (Reynolds et al., 1992Reynolds et al., , 2000Reynolds et al., , 2002Reynolds et al., , 2005Reynolds et al., , 2006Reynolds et al., , 2010 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 Staton et al., , 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) 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). "
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