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WIREs Nanomed Nanobiotechnol
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Lymph node staging using dedicated magnetic resonance contrast agents—the accumulation mechanism revisited

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When diagnosing cancer, assessing the nodal stage is tremendously important in determining the patient's prognosis. Computed tomography (CT) and magnetic resonance (MR) imaging (MRI) assessments of the regional lymph node (LN) size and shape are currently used for the initial nodal staging in clinical settings, although this approach has a rather low sensitivity, and biopsy often leads to restaging of the LNs. Acknowledging the great medical need to accurately stage LNs, scientists and clinicians have been working since the late 1980s on MR contrast agents that provide more reliable staging results. Different types of molecules (i.e., iron oxide nanoparticles and Gd‐based contrast agent) have shown promising LN accumulation and imaging results, but no clinically approved, dedicated LN staging contrast agent is currently available. The literature describes a mechanism of contrast agent accumulation in the LNs that considers some but not all published experimental evidence. However, confidence in the mechanism of LN accumulation is a prerequisite for the directed synthesis of compounds for accurate and sensitive LN staging. To improve our understanding of the LN contrast agent accumulation mechanism, we reviewed the published data on the enrichment of colloidal MR contrast agent candidates in LNs, and we suggest an extended mechanism for contrast agent enrichment in LNs. For further clarification, physiology and results from drug targeting studies are considered where applicable. WIREs Nanomed Nanobiotechnol 2015, 7:238–249. doi: 10.1002/wnan.1290 This article is categorized under: Diagnostic Tools > In Vivo Nanodiagnostics and Imaging
Illustration of colloids used for MR lymphography. Three different types of colloids described for MR lymphography are illustrated. In liposomes (a) the contrast agent is encapsulated by a lipid bilayer, the surface is determined by the lipids used for liposome preparation. SPIO (b) consists of an iron oxide core surrounded by an organic (as shown in blue) or inorganic coating material which is needed for colloidal stability and bio‐compatibility. The coating material determines the surface characteristics of SPIOs. Organic coats are usually much larger than the iron oxide core itself. Gadolinium‐conjugated polymers (c) consist of long polymeric molecules (dark blue) having multiple gadolinium‐containing chelates (light blue) attached to it. The polymer will form a coiled structure in suspension. A transmission electron microscopy (TEM) image of a typical iron oxide nanoparticle suspension is shown in (d), illustrating a broad size distribution. Note that only the iron oxide core particles are visible; the organic coating material collapses during TEM probe preparation. The field of view measures 100 nm.
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Suggested mechanism of (U)SPIO accumulation in LNs. A suggested path of (U)SPIOs (black dots) through peripheral tissue (left) and LN tissue (right) is depicted. In metastatic LNs, normal LN tissue is displaced by tumor tissue. M, metastases; MΦ, phagocytic cell; HEV, high endothelial vessels; ECM, extra cellular matrix. See the main text for explanations.
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Drawing of a normal LN. Lymph enters the LN through afferent lymphatics into the subcapsular sinus (s) and drains through cortical gaps (g) and medullary sinuses (ms) toward the efferent lymphatic. HEVs are specialized venules residing in the extrafollicular zone (e) and the deep cortex periphery of the LN. Cells of the immune system enter LNs from the blood through the HEV endothelium and relocate according to their function for the follicular nodules (fn), deep cortex center (DCC), deep cortex periphery (DCP), or medullary cord (mc). Phagocytic cells (MΦ) are mainly located in the cortical medullary sinuses and medullary cords.
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