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WIREs Nanomed Nanobiotechnol
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Gold nanoparticle‐mediated photothermal therapy: applications and opportunities for multimodal cancer treatment

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Photothermal therapy (PTT), in which nanoparticles embedded within tumors generate heat in response to exogenously applied laser light, has been well documented as an independent strategy for highly selective cancer treatment. Gold‐based nanoparticles are the main mediators of PTT because they offer: (1) biocompatibility, (2) small diameters that enable tumor penetration upon systemic delivery, (3) simple gold‐thiol bioconjugation chemistry for the attachment of desired molecules, (4) efficient light‐to‐heat conversion, and (5) the ability to be tuned to absorb near‐infrared light, which penetrates tissue more deeply than other wavelengths of light. In addition to acting as a standalone therapy, gold nanoparticle‐mediated PTT has recently been evaluated in combination with other therapies, such as chemotherapy, gene regulation, and immunotherapy, for enhanced anti‐tumor effects. When delivered independently, the therapeutic success of molecular agents is hindered by premature degradation, insufficient tumor delivery, and off‐target toxicity. PTT can overcome these limitations by enhancing tumor‐ or cell‐specific delivery of these agents or by sensitizing cancer cells to these additional therapies. All together, these benefits can enhance the therapeutic success of both PTT and the secondary treatment while lowering the required doses of the individual agents, leading to fewer off‐target effects. Given the benefits of combining gold nanoparticle‐mediated PTT with other treatment strategies, many exciting opportunities for multimodal cancer treatment are emerging that will ultimately lead to improved patient outcomes. WIREs Nanomed Nanobiotechnol 2017, 9:e1449. doi: 10.1002/wnan.1449 This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease
(a) In photothermal therapy, systemically‐delivered nanoparticles accumulate within solid tumors via the enhanced permeability and retention effect, which exploits the leaky tumor vasculature. Once within the tumor, near‐infrared light is applied to cause the nanoparticles to generate heat to kill the surrounding tumor tissue. (b) Four of the most commonly employed AuNPs for photothermal therapy include silica core/gold shell nanoshells, gold nanorods, hollow gold nanocages, and nanostars. (Nanorod, nanocage, and nanostar images reprinted with permission from Ref . Copyright 2011 Wiley, Ref . Copyright 2007 Wiley‐VCH Verlag GmbH & Co. KGaA, and Ref . Copyright 2015 Elsevier)
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(a) Silica core/gold shell nanoshells accumulated within tumor tissue can be visualized with optical coherence tomography, as depicted by increased signal throughout the tissue depth. (b) In vivo ultrasonic and photoacoustic images demonstrate enhanced signal from biodegradable gold‐based NPs accumulated within the tumor. NPs were composed of clusters of small gold nanoparticles that produced an ultrastrong plasmonic coupling effect for imaging and PTT. The arrow indicates NPs. ((a) Reprinted with permission from Ref . Copyright 2007 American Chemical Society and (b) Ref . Copyright 2013 Wiley‐VCH Verlag GmbH & Co. KGaA)
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Schematic depicting the impact of combined photothermal therapy and immunotherapy on primary tumors and metastases. (Reprinted with minor modifications with permission from Ref . Copyright 2016 World Scientific Publishing Company)
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Mechanisms of light‐triggered gene regulation using AuNPs. (a) Following cellular uptake, NIR‐absorbing AuNPs functionalized with gene regulation agents become trapped within endosomes, limiting their ability to deliver the payload for effective gene silencing. Upon NIR light application, the AuNPs generate sufficient heat to rupture the surrounding endosome and release the AuNPs into the cell cytosol without harming overall cell integrity. (b) Schematic of the mechanisms of light induced release of oligonucleotides from AuNP surfaces. Under pulsed laser irradiation, the gold‐thiol bond between the molecules and AuNPs breaks, releasing the entire duplex. Alternatively, continuous wave laser irradiation can denature the linkage between the two strands to release only single stranded oligonucleotides.
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(a) Breast cancer cells treated with silica core/gold shell nanoshells and doxorubicin (red) and exposed to NIR light display increased drug uptake compared to cells that were not irradiated. Blue indicates nuclei, yellow arrows indicate cytoplasmic regions of cells not irradiated, and white arrows indicate enhanced doxorubicin content in the cytoplasm following irradiation. (Reprinted with permission from Ref . Copyright 2015 Dovepress) (b) Tumor tissue extracted from mice treated with nanorod‐mediated hyperthermia and doxorubicin‐loaded liposomes targeted to p32, a protein, that is upregulated in response to stress, shows enhanced liposome (green) and doxorubicin (red) distribution compared to mice treated with hyperthermia and untargeted liposomes. (Reprinted with permission from Ref . Copyright 2010 PNAS) (c) Schematics showing the mechanisms of light induced release of drugs from AuNPs.
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Schematics demonstrating the physiological and biological effects of photothermal therapy. (a) The heat generated by AuNPs in response to NIR light enhances the permeability of tumor vasculature and cell membranes to increase the accumulation of secondary therapies, such as chemotherapeutic drugs. (b) PTT can lead to either cellular necrosis or apoptosis, which cause different cellular and immune responses. The mechanism of cell death depends on the applied irradiation parameters.
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Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease
Therapeutic Approaches and Drug Discovery > Emerging Technologies

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