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WIREs Nanomed Nanobiotechnol
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Intraoperative mapping of sentinel lymph node metastases using a clinically translated ultrasmall silica nanoparticle

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The management of regional lymph nodes in patients with melanoma has undergone a significant paradigm shift over the past several decades, transitioning from the use of more aggressive surgical approaches, such as lymph node basin dissection, to the application of minimally invasive sentinel lymph node (SLN) biopsy methods to detect the presence of nodal micrometastases. SLN biopsy has enabled reliable, highly accurate, and low‐morbidity staging of regional lymph nodes in early stage melanoma as a means of guiding treatment decisions and improving patient outcomes. The accurate identification and staging of lymph nodes is an important prognostic factor, identifying those patients for whom the expected benefits of nodal resection outweigh attendant surgical risks. However, currently used standard‐of‐care technologies for SLN detection are associated with significant limitations. This has fueled the development of clinically promising platforms that can serve as intraoperative visualization tools to aid accurate and specific determination of tumor‐bearing lymph nodes, map cancer‐promoting biological properties at the cellular/molecular levels, and delineate nodes from adjacent critical structures. Among a number of promising cancer‐imaging probes that might facilitate achievement of these ends is a first‐in‐kind ultrasmall tumor‐targeting inorganic (silica) nanoparticle, designed to overcome translational challenges. The rationale driving these considerations and the application of this platform as an intraoperative treatment tool for guiding resection of cancerous lymph nodes is discussed and presented within the context of alternative imaging technologies. WIREs Nanomed Nanobiotechnol 2016, 8:535–553. doi: 10.1002/wnan.1380 This article is categorized under: Diagnostic Tools > In Vivo Nanodiagnostics and Imaging
Image‐guided SLN mapping in a spontaneous melanoma miniswine model: real‐time intraoperative optical imaging with correlative histology. Intraoperative SLN mapping was performed on the animal shown in this figure. (a–i) Two‐channel NIR optical imaging of the exposed nodal basin. Local injection of Cy5.5‐incorporated particles displayed in dual‐channel model (a) RGB color (green) and (b) NIR fluorescent channels (white). (c–f) Draining lymphatics distal to the site of injection. Fluorescence signal within the main draining proximal (c, d), mid (e), and distal (f) lymphatic channels (yellow arrows) extending toward the SLN (‘N’). Smaller caliber channels are also shown (arrowheads). Images of the SLN displayed in the (g) color and (h) NIR channels. (i) Color image of the exposed SLN. (j) Images of SLN in the color and NIR channels during excision. (Reprinted with permission from Ref . Copyright 2013 The Royal Society of Chemistry)
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Imaging of metastatic disease in a spontaneous melanoma miniswine model. (a) Whole‐body 18F‐FDG PET‐CT sagittal and axial views demonstrating primary tumor (green arrow) and single SLN (white arrow) posteriorly within the right (Rt) neck after i.v. injection. ant, anterior. (b) High‐resolution PET‐CT scan reveals bilateral nodes 1 h after subdermal, 4‐quadrant, peritumoral injection of 124I‐cRGDY‐PEG‐C dots (SLN, arrow; left‐sided node, arrowhead). (c, d) Gross images of the cut surfaces of the black‐pigmented SLN (asterisk, c) and contralateral metastatic node (arrowhead, d) in the left posterior neck. (e) Low‐power view of H&E‐stained SLN demonstrating scattered melanomatous clusters (white arrowhead). (f) Corresponding high‐power view of H&E‐stained SLN, revealing melanoma cells (yellow arrowheads) and melanophages (white arrowhead). (g) Low‐power image of a melanoma‐specific marker, HMB‐45 (white arrowhead), in representative SLN tissue. (h) High‐power image of HMB‐45‐stained SLN tissue. (i) Low‐power view of H&E‐stained contralateral lymph node showing scattered melanomatous clusters (white arrowhead). (j) High‐power image of contralateral node showing infiltration of melanomatous cells (yellow arrowheads). (k) Low‐power image of representative normal porcine nodal tissue. (l) High‐power image of representative normal porcine nodal tissue. Scale bars: 1 mm (e, g, i, k); 20 mm (f, h, j, l). (Reprinted with permission from Ref . Copyright 2013 The Royal Society of Chemistry)
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Minimally invasive surgery utilizing a handheld fluorescence camera system. (a) ArteMIS™ Spectrum handheld fluorescence camera system for open and laparoscopic procedures. (b) Minimally invasive surgery using laparoscopic tools. (c) System components (top to bottom): camera, laparoscope, and ring light. (d) Handheld gamma probe for radiodetection. (Reprinted with permission from Ref . Copyright 2013 The Royal Society of Chemistry)
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Real‐time intraoperative fluorescence camera system technology: comparison with conventional imaging modalities. Device parameters for CT, PET, and MRI versus those used for the FDA‐approved Artemis™ Spectrum handheld fluorescence camera system.
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Schematic of SLN mapping in the head and neck using 124I‐cRGDY‐PEG‐Cdots. (a) Injection of 124I‐cRGDY‐PEG‐C dots about an oral cavity lesion with drainage to preauricular and submandibular nodes. (b) 124I‐cRGDY‐PEG‐ylated core‐shell silica nanoparticle with surface‐bearing radiolabels and peptides and core‐containing reactive dye molecules (insets). (Reprinted with permission from Ref . Copyright 2013 The Royal Society of Chemistry)
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3D integrated 18F‐FDG and 124I‐cRGDY‐PEG‐C dot PET‐CT. (a–c) 3D volume rendered images were generated from CT and PET imaging data shown in this figure. (a) PET‐CT fusion image (coronal view) shows no evident nodal metastases (asterisks). Increased activity within bony structures is identified. (b, c) High‐resolution PET‐CT fusion images showing coronal (b) and superior views (c) of bilateral metastatic nodes (open arrows) and lymphatic channels (curved arrows) within the neck following local injection of 124I‐cRGDY‐PEG‐C dots. (Reprinted with permission from Ref . Copyright 2013 The Royal Society of Chemistry)
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Discrimination of inflammation from metastatic disease: comparison of 18F‐FDG and 124I‐cRGDY‐PEG‐C dot tracers. (a–d) Imaging of inflammatory changes using 18F‐FDG‐PET with tissue correlation. (a) Axial CT scan of the 18F‐FDG PET study shows calcification within the left posterior neck (yellow arrows). (b) Fused axial 18F‐FDG PET‐CT reveals hypermetabolic activity at this same site (yellow arrows). Increased PET signal is also seen in metabolically active osseous structures (asterisks). (c) Low and (d) high‐power views of H&E‐stained calcified tissue demonstrate extensive infiltration of inflammatory cells. (e–k) Metastatic disease detection following injection of 124I‐cRGDY‐PEG C dots about the tumor site. (e) Preinjection axial CT scan of 124I‐cRGDY‐PEG‐C dots shows calcified soft tissues within the posterior neck (yellow arrows). (f) Co‐registered PET‐CT shows no evident activity corresponding to calcified areas (arrow), but demonstrates a PET‐avid node on the right (arrowhead). (g) Axial CT at a more superior level shows nodes (arrowheads) bilaterally and a calcified focus (yellow arrow). (h) Fused PET‐CT demonstrates PET‐avid nodes (N) and lymphatic drainage (curved arrow). Calcification shows no activity (arrow). (i) Low‐ and (j) high‐power views confirm the presence of nodal metastases. (k) Single frame from a three‐dimensional (3D) PET image reconstruction shows multiple bilateral metastatic nodes (arrowheads) and lymphatic channels (solid arrow) draining the injection site (white asterisk). Bladder activity is seen (dashed arrow) with no significant tracer accumulation in the liver (black asterisk). Bladder activity is seen with no significant tracer accumulation in the liver. Scale bars: 500 mm (c, d); 100 mm (i, j). (Reprinted with permission from Ref . Copyright 2013 The Royal Society of Chemistry)
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