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WIREs Nanomed Nanobiotechnol
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Image‐guided tumor surgery: will there be a role for fluorescent nanoparticles?

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Image‐guided surgery (IGS) using fluorescent nanoparticles (NPs) has the potential to substantially impact patient treatment. The use of fluorescence imaging provides surgeons with real‐time feedback on the location of diseased tissue using safe, low‐cost imaging agents and instrumentation. Fluorescent NPs are likely to play a role as they are capable of taking advantage of the enhanced permeability and retention (EPR) effect and can be modified to avoid clearance, increase circulation time, and specifically target tumors. Clinical trials of IGS using the FDA‐approved fluorophores indocyanine green and methylene blue have already shown preliminary successes, and incorporation of fluorescent NPs will likely improve detection by providing higher signal to background ratio and reducing false‐positive rates through active targeting. Preclinical development of fluorescent NP formulations is advancing rapidly, with strategies ranging from passive targeting to active targeting of cell surface receptors, creating pH‐responsive NPs, and increasing cell uptake through cleavable proteins. This collective effort could lead to clinical trials using fluorescent NPs in the near future. WIREs Nanomed Nanobiotechnol 2016, 8:498–511. doi: 10.1002/wnan.1381 This article is categorized under: Diagnostic Tools > In Vivo Nanodiagnostics and Imaging Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease
Fluorescence IGS instrumentation requires three main optical components: an excitation source, a collection source for both fluorescence and white light, and a display for overlaying the fluorescence signal onto the white channel for anatomical localization. Processing and algorithm components are also necessary for overlay and display. Fluorescence light sources are typically either laser or LED based, and a number of systems are currently available with both of these options. Display is commonly performed with overhead monitors, but research into goggle display for surgeons has also been performed. Fluorescence is then used in conjunction with visual and tactile feedback to improve tumor resection to reduce incidence of PMs and local metastases.
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(a) Ultra pH‐sensitive nanoprobes (UPSi) were targeted to αvβ3‐expressing tumors using cyclic‐argenine‐glycine‐aspartate (cRGD) linkers. This shows specifically activated fluorescence in the tumor of cRGD‐UPSi, and the prevention of specific uptake of cRGD‐UPSi by blocking with the cRGD ligand. (b) ICG‐loaded SPIO NPs (left) show increased fluorescence signal compared to free ICG‐treated mice (right) 24 h after tail vein injection. (c) Delivery of MMP activatable cell‐penetrating peptides bound to dendrimeric NPs and Cy5 (ACPPD‐Cy5) improved tumor to skin and tumor to muscle signal ratios over commercially available MMP probes ProSense and MMPSense. (d) ICG‐loaded hyaluronic acid‐derived NPs improved tumor contrast over mice injected compared to mice injected with free ICG. These results demonstrate the potential for multiple active targeting avenues, multimodality imaging, and use of existing FDA‐approved fluorophores with biocompatible materials to improve tumor resection. (a. Reprinted with permission from Ref . Copyright 2014 Macmillan Publishers Ltd). A nanoparticle‐based strategy for the imaging of a broad range of tumours by nonlinear amplification of microenvironment signals. (b. Reprinted with permission from Ref . Copyright 2013 Elsevier). Indocyanine green‐loaded SPIO nanoparticles with phospholipid‐PEG coating for dual‐modal imaging and photothermal therapy, 7711. (c. Reprinted with permission from Ref . Copyright 2010 National Academy of Sciences). Activatable cell‐penetrating peptides linked to nanoparticles as dual probes for in vivo fluorescence and MR imaging of proteases. (d. Reprinted with permission from Ref . Copyright 2015 American Chemical Society). Indocyanine green‐loaded nanoparticles for image‐guided tumor surgery.
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NPs are injected systemically where they circulate to tumors and extravasate across the vascular endothelium. These discontinuities may range in size from 200 to 2000 nm, allowing for extravasation of NPs. Once NPs have extravasated they are retained in the tumor stroma due to their size. NPs may then be broken down by extracellular enzymes or taken up into lysosomes where they may be specifically activated. NPs may also be constitutively active, or may activate upon transferring fluorophores to serum proteins, causing increased tumor signal through passive targeting. NPs delivered in this way rely solely on the EPR effect for delivery, whereas targeted NPs rely on both the EPR effect as well as specific proteins or conditions found in tumors such as matrix metalloproteinases (MMPs) or low pH. Clearance of NPs from systemic circulation and other tissues may or may not be necessary, depending on the fluorescence activation and concentration in other tissues at the time of surgery. Formulations will require additional testing to determine optimal surgical timing after injection.
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Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease
Diagnostic Tools > In Vivo Nanodiagnostics and Imaging

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