Real-Time Visualization and Quantitation of Vascular Permeability In Vivo: Implications for Drug Delivery

National Cancer Institute, United States of America
PLoS ONE (Impact Factor: 3.23). 03/2012; 7(3):e33760. DOI: 10.1371/journal.pone.0033760
Source: PubMed


The leaky, heterogeneous vasculature of human tumors prevents the even distribution of systemic drugs within cancer tissues. However, techniques for studying vascular delivery systems in vivo often require complex mammalian models and time-consuming, surgical protocols. The developing chicken embryo is a well-established model for human cancer that is easily accessible for tumor imaging. To assess this model for the in vivo analysis of tumor permeability, human tumors were grown on the chorioallantoic membrane (CAM), a thin vascular membrane which overlays the growing chick embryo. The real-time movement of small fluorescent dextrans through the tumor vasculature and surrounding tissues were used to measure vascular leak within tumor xenografts. Dextran extravasation within tumor sites was selectively enhanced an interleukin-2 (IL-2) peptide fragment or vascular endothelial growth factor (VEGF). VEGF treatment increased vascular leak in the tumor core relative to surrounding normal tissue and increased doxorubicin uptake in human tumor xenografts. This new system easily visualizes vascular permeability changes in vivo and suggests that vascular permeability may be manipulated to improve chemotherapeutic targeting to tumors.

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    • "Therefore, strategies to improve the transport of drugs to the tumor should also improve the efficacy of chemotherapy. Another recent study using chorioallantoic membrane (CAM) models indicated that increasing vascular permeability improves the tumor accumulation of doxorubicin (Pink et al., 2012). Therefore, increases in blood flow, permeability and EPR effect that are induced by M-PTX should collectively result in an enhanced accumulation of anti-cancer drugs including nanomedicines (macromolecules or nanoparticles) in tumors. "
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    • "In more recent years, advances in the CAM assays (detailed in Pink et al., 2012) led to the identification of hemopoietic cells that contributed the proteases MMP9 and MMP13 required for matrix remodeling during angiogenesis (Zijlstra et al., 2004, 2006). Advances in imaging technologies have made it possible to visualize vascular perfusion, vascularization of the CAM, and the distinct steps of angiogenesis (Lewis et al., 2006; Leong et al., 2010; Pink et al., 2012). New contrast and imaging agents that selectively label developing vessels promote visualization of specific vascular structures at the microscopic level (Lewis et al., 2006; Leong et al., 2010). "
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