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      External and Internal Stimuli-Responsive Metallic Nanotherapeutics for Enhanced Anticancer Therapy


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          Therapeutic, diagnostic, and imaging approaches based on nanotechnology offer distinct advantages in cancer treatment. Various nanotherapeutics have been presented as potential alternatives to traditional anticancer therapies such as chemotherapy, radiotherapy, and surgical intervention. Notably, the advantage of nanotherapeutics is mainly attributable to their accumulation and targeting ability toward cancer cells, multiple drug-carrying abilities, combined therapies, and imaging approaches. To date, numerous nanoparticle formulations have been developed for anticancer therapy and among them, metallic nanotherapeutics reportedly demonstrate promising cancer therapeutic and diagnostic efficiencies owing to their dense surface functionalization ability, uniform size distribution, and shape-dependent optical responses, easy and cost-effective synthesis procedure, and multiple anti-cancer effects. Metallic nanotherapeutics can remodel the tumor microenvironment by changing unfavorable therapeutic conditions into therapeutically accessible ones with the help of different stimuli, including light, heat, ultrasound, an alternative magnetic field, redox, and reactive oxygen species. The combination of metallic nanotherapeutics with both external and internal stimuli can be used to trigger the on-demand release of therapeutic molecules, augmenting the therapeutic efficacies of anticancer therapies such as photothermal therapy, photodynamic therapy, magnetic hyperthermia, sonodynamic therapy, chemodynamic therapy, and immunotherapy. In this review, we have summarized the role of different metallic nanotherapeutics in anti-cancer therapy, as well as their combinational effects with multiple stimuli for enhanced anticancer therapy.

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          Ferroptosis: an iron-dependent form of nonapoptotic cell death.

          Nonapoptotic forms of cell death may facilitate the selective elimination of some tumor cells or be activated in specific pathological states. The oncogenic RAS-selective lethal small molecule erastin triggers a unique iron-dependent form of nonapoptotic cell death that we term ferroptosis. Ferroptosis is dependent upon intracellular iron, but not other metals, and is morphologically, biochemically, and genetically distinct from apoptosis, necrosis, and autophagy. We identify the small molecule ferrostatin-1 as a potent inhibitor of ferroptosis in cancer cells and glutamate-induced cell death in organotypic rat brain slices, suggesting similarities between these two processes. Indeed, erastin, like glutamate, inhibits cystine uptake by the cystine/glutamate antiporter (system x(c)(-)), creating a void in the antioxidant defenses of the cell and ultimately leading to iron-dependent, oxidative death. Thus, activation of ferroptosis results in the nonapoptotic destruction of certain cancer cells, whereas inhibition of this process may protect organisms from neurodegeneration. Copyright © 2012 Elsevier Inc. All rights reserved.
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            Cancer nanomedicine: progress, challenges and opportunities

            The intrinsic limits of conventional cancer therapies prompted the development and application of various nanotechnologies for more effective and safer cancer treatment, herein referred to as cancer nanomedicine. Considerable technological success has been achieved in this field, but the main obstacles to nanomedicine becoming a
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              Hypoxia in cancer: significance and impact on clinical outcome.

              Hypoxia, a characteristic feature of locally advanced solid tumors, has emerged as a pivotal factor of the tumor (patho-)physiome since it can promote tumor progression and resistance to therapy. Hypoxia represents a "Janus face" in tumor biology because (a) it is associated with restrained proliferation, differentiation, necrosis or apoptosis, and (b) it can also lead to the development of an aggressive phenotype. Independent of standard prognostic factors, such as tumor stage and nodal status, hypoxia has been suggested as an adverse prognostic factor for patient outcome. Studies of tumor hypoxia involving the direct assessment of the oxygenation status have suggested worse disease-free survival for patients with hypoxic cervical cancers or soft tissue sarcomas. In head & neck cancers the studies suggest that hypoxia is prognostic for survival and local control. Technical limitations of the direct O(2) sensing technique have prompted the use of surrogate markers for tumor hypoxia, such as hypoxia-related endogenous proteins (e.g., HIF-1alpha, GLUT-1, CA IX) or exogenous bioreductive drugs. In many - albeit not in all - studies endogenous markers showed prognostic significance for patient outcome. The prognostic relevance of exogenous markers, however, appears to be limited. Noninvasive assessment of hypoxia using imaging techniques can be achieved with PET or SPECT detection of radiolabeled tracers or with MRI techniques (e.g., BOLD). Clinical experience with these methods regarding patient prognosis is so far only limited. In the clinical studies performed up until now, the lack of standardized treatment protocols, inconsistencies of the endpoints characterizing the oxygenation status and methodological differences (e.g., different immunohistochemical staining procedures) may compromise the power of the prognostic parameter used.

                Author and article information

                Front Mol Biosci
                Front Mol Biosci
                Front. Mol. Biosci.
                Frontiers in Molecular Biosciences
                Frontiers Media S.A.
                11 January 2021
                : 7
                [1] 1Department of Biomedical Sciences, Chonnam National University Medical School , Jeollanam-do, South Korea
                [2] 2Department of Polymer Science and Engineering, Chungnam National University , Daejeon, South Korea
                Author notes

                Edited by: Weien Yuan, Shanghai Jiao Tong University, China

                Reviewed by: David J. Lundy, Taipei Medical University, Taiwan; Koichiro Uto, National Institute for Materials Science, Japan

                *Correspondence: In-Kyu Park pik96@ 123456jnu.ac.kr

                This article was submitted to Nanobiotechnology, a section of the journal Frontiers in Molecular Biosciences

                Copyright © 2021 Mohapatra, Uthaman and Park.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 12, Tables: 2, Equations: 0, References: 204, Pages: 31, Words: 22617
                Funded by: National Research Foundation of Korea 10.13039/501100003725
                Award ID: 2017M3A9E2056372
                Award ID: 2018R1A5A2024181
                Award ID: 2019M3E5D1A02068082
                Award ID: 2020R1A2C2005620
                Molecular Biosciences

                metallic nanotherapeutics,internal-stimuli,external-stimuli,phototherapy,sonodynamic therapy,magnetic hyperthermia,immunotherapy,clinical status


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