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WIREs Nanomed Nanobiotechnol
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Overcoming in vivo barriers to targeted nanodelivery

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Abstract Nanoparticles have been investigated as promising nanocarriers for delivery of imaging and therapeutic agents for several decades, but have met with limited success. Although enormous progress in the fields of nanotechnology and nanoscience has been achieved, basic discoveries have not yet translated into effective targeted therapies. Nanoparticles can potentially improve the pharmacokinetics and pharmacodynamics of drugs; however, the complexity of in vivo systems imposes multiple barriers that severely inhibit efficiency and have to be overcome to fully exploit the theoretical potential of nanoparticles. Here, we address two major challenges to effective systemic nanodelivery. Both limited penetration across the vascular endothelium and uptake by the reticuloendothelial system (RES) substantially impede effectiveness of nanoparticle delivery into tissues. Although the design of nanoparticles with extended circulation half‐life is essential, it is not sufficient for effective penetration of nanoparticles across the formidable barrier formed by the vascular endothelium. Current nanodelivery systems rely on passive transvascular exchange and tissue accumulation. They require high dosages to create large concentration gradients that drive nanoparticles passively across the blood–tissue interface. However, passive accumulation has resulted in only a fractional dosage of nanoparticles penetrating into target tissue. This inevitably diminishes therapeutic efficacy and aggravates potential side effects. Although there are multiple ways to augment passive delivery, active delivery of targeted nanoparticles across the vascular endothelium could significantly increase the therapeutic index and decrease side effects of nanoparticle‐based drug delivery systems. Use of active transendothelial transport pathways, such as caveolae, may provide an effective solution to both target and deliver nanoparticles. WIREs Nanomed Nanobiotechnol 2011 3 421–437 DOI: 10.1002/wnan.143 This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Diagnostic Tools > In Vivo Nanodiagnostics and Imaging

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Caveolae‐targeting antibodies are rapidly transported out of the blood and into tissue. Mice with engrafted lung tissue were intravenously injected with fluorescently labeled control murine immunoglobulin G (IgG) (red) followed by a caveolae‐specific antibody (TX3.833, green) 60 seconds later. Fluorescent images were recorded at the given times after injection. Antibodies to noncaveolae proteins bound the endothelial cell surface but did not extravasate (bottom). (Reprinted with permission from Ref 47. Copyright 2007 Nature Publishing Group [Nature Biotechnology])

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(a) Caveolae‐targeting antibodies [anti‐aminopeptidase P2 (mAPP), light blue] are rapidly transported into the lung tissue, antibodies that bind outside of caveolae (CD34 antibodies, yellow) accumulate at the cell surface, and nonspecific immunoglobulin G (IgG) molecules (black) stay in the blood. When caveolin‐1 is decreased, caveolae‐targeting antibodies cannot be transcytosed (c). Caveolae contain targets that are sufficiently specific to enable in vivo single‐organ targeting. For instance, APP antibodies are specific for lung endothelial cells and do not accumulate in other tissues. (Reprinted with permission from Ref 125. Copyright 2007 Nature Publishing Group [Nature Biotechnology])

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In vivo computed tomography coregistered with single‐photon emission computerized tomography (CT‐SPECT) imaging of immunotargeting with radiolabeled aminopeptidase P (APP)‐specific monoclonal antibodies (mAbs). Rats were injected intravenously with 125I‐APP mAb. CT scans and corresponding fused CT‐SPECT images were acquired. Left (a), axial slices along the thoracic vertebrae; middle (b), sagittal and coronal slices; right (c), fusion of SPECT texture with CT isosurface. (Reprinted with permission from Ref 47. Copyright 2007 Nature Publishing Group [Nature Biotechnology])

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Lung tissue was imaged for 1–2 min after intravenous injection of the indicated fluorophore‐labeled antibody. Signal intensity time–space profiles were constructed by measuring the fluorescence of pixels corresponding to the yellow line in the phase image showing the blood vessel and perivascular space and plotting signal intensity in pseudocolor as a function of time. (a–e) Normal lung tissue; (f) shows lung tissue with caveolin‐1 knocked down. Antibodies specific to APP2 that target caveolae (mAPP), bind outside of caveolae (CD34) and control nonspecific murine immunoglobulin G (mIgG) were used at the indicated dosages. (Reprinted with permission from Ref 47. Copyright 2007 Nature Publishing Group [Nature Biotechnology])

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Lung vascular‐specific retargeting of PAMAM dendrimer nanoparticles by caveolae‐specific probe. PAMAM dendrimer G5 was radiolabeled with iodine‐125 and then functionalized with aminopeptidase P 2 (APP2)‐specific antibody. Images show single‐photon emission computerized tomography (SPECT) scans fused with corresponding computed tomography (CT) acquired at 1 h after intravenous injection. Panels (a) and (b): APP2‐targeted dendrimer; panels (c) and (d): untargeted dendrimer. Images show the fusion of volumetric SPECT texture with CT isosurface (a and b) and corresponding coronal plane (b and d). Note: selective accumulation of activity in the lung cavity for retargeted dendrimer, whereas the liver and spleen quantitatively sequestered untargeted dendrimer.

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Sequential transcytosis of antibodies and attached nanoparticles. Caveolae‐targeting antibodies were linked to gold nanoparticles (10–15 nm) and perfused through isolated lungs. Tissue was processed for electron microscopy at the times indicated to reveal location of gold nanoparticles. Gold nanoparticles are taken up by endothelial caveolae, transcytosed across the endothelial barrier, and released (a and b). Some gold particles even appear to be taken up by epithelial caveolae, transcytosed across the epithelium, and released into the airways (c). Scale bar = 50 nm. (Reprinted with permission from Ref 121. Copyright 2002 National Academy of Sciences [Proceedings of the National Academy of Sciences of the USA]).

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Diagnostic Tools > In Vivo Nanodiagnostics and Imaging
Therapeutic Approaches and Drug Discovery > Emerging Technologies

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