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      Ultrasmall nanoparticles induce ferroptosis in nutrient-deprived cancer cells and suppress tumour growth

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          Abstract

          The design of cancer-targeting particles with precisely-tuned physiocochemical properties may enhance delivery of therapeutics and access to pharmacological targets. However, molecular level understanding of the interactions driving the fate of nanomedicine in biological systems remains elusive. Here, we show that ultrasmall (< 10 nm in diameter) poly(ethylene glycol) (PEG)-coated silica nanoparticles, functionalized with melanoma-targeting peptides, can induce a form of programmed cell death known as ferroptosis in starved cancer cells and cancer-bearing mice. Tumor xenografts in mice intravenously injected with nanoparticles using a high-dose multiple injection scheme exhibit reduced growth or regression, in a manner that is reversed by the pharmacological inhibitor of ferroptosis, liproxstatin-1. These data demonstrate that ferroptosis can be targeted by ultrasmall silica nanoparticles and may have therapeutic potential.

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          Synchronized renal tubular cell death involves ferroptosis.

          Andreas Linkermann, Rachid Skouta, Nina Himmerkus … (2014)
          Receptor-interacting protein kinase 3 (RIPK3)-mediated necroptosis is thought to be the pathophysiologically predominant pathway that leads to regulated necrosis of parenchymal cells in ischemia-reperfusion injury (IRI), and loss of either Fas-associated protein with death domain (FADD) or caspase-8 is known to sensitize tissues to undergo spontaneous necroptosis. Here, we demonstrate that renal tubules do not undergo sensitization to necroptosis upon genetic ablation of either FADD or caspase-8 and that the RIPK1 inhibitor necrostatin-1 (Nec-1) does not protect freshly isolated tubules from hypoxic injury. In contrast, iron-dependent ferroptosis directly causes synchronized necrosis of renal tubules, as demonstrated by intravital microscopy in models of IRI and oxalate crystal-induced acute kidney injury. To suppress ferroptosis in vivo, we generated a novel third-generation ferrostatin (termed 16-86), which we demonstrate to be more stable, to metabolism and plasma, and more potent, compared with the first-in-class compound ferrostatin-1 (Fer-1). Even in conditions with extraordinarily severe IRI, 16-86 exerts strong protection to an extent which has not previously allowed survival in any murine setting. In addition, 16-86 further potentiates the strong protective effect on IRI mediated by combination therapy with necrostatins and compounds that inhibit mitochondrial permeability transition. Renal tubules thus represent a tissue that is not sensitized to necroptosis by loss of FADD or caspase-8. Finally, ferroptosis mediates postischemic and toxic renal necrosis, which may be therapeutically targeted by ferrostatins and by combination therapy.
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            Autosis is a Na+,K+-ATPase-regulated form of cell death triggered by autophagy-inducing peptides, starvation, and hypoxia-ischemia.

            Yang Liu, Sanae Shoji-Kawata, Rhea Sumpter … (2013)
            A long-standing controversy is whether autophagy is a bona fide cause of mammalian cell death. We used a cell-penetrating autophagy-inducing peptide, Tat-Beclin 1, derived from the autophagy protein Beclin 1, to investigate whether high levels of autophagy result in cell death by autophagy. Here we show that Tat-Beclin 1 induces dose-dependent death that is blocked by pharmacological or genetic inhibition of autophagy, but not of apoptosis or necroptosis. This death, termed "autosis," has unique morphological features, including increased autophagosomes/autolysosomes and nuclear convolution at early stages, and focal swelling of the perinuclear space at late stages. We also observed autotic death in cells during stress conditions, including in a subpopulation of nutrient-starved cells in vitro and in hippocampal neurons of neonatal rats subjected to cerebral hypoxia-ischemia in vivo. A chemical screen of ~5,000 known bioactive compounds revealed that cardiac glycosides, antagonists of Na(+),K(+)-ATPase, inhibit autotic cell death in vitro and in vivo. Furthermore, genetic knockdown of the Na(+),K(+)-ATPase α1 subunit blocks peptide and starvation-induced autosis in vitro. Thus, we have identified a unique form of autophagy-dependent cell death, a Food and Drug Administration-approved class of compounds that inhibit such death, and a crucial role for Na(+),K(+)-ATPase in its regulation. These findings have implications for understanding how cells die during certain stress conditions and how such cell death might be prevented.
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              Clinical translation of an ultrasmall inorganic optical-PET imaging nanoparticle probe.

              Evan Phillips, Oula Penate Medina, Pat B Zanzonico … (2014)
              A first-in-human clinical trial of ultrasmall inorganic hybrid nanoparticles, "C dots" (Cornell dots), in patients with metastatic melanoma is described for the imaging of cancer. These renally excreted silica particles were labeled with (124)I for positron emission tomography (PET) imaging and modified with cRGDY peptides for molecular targeting. (124)I-cRGDY-PEG-C dot particles are inherently fluorescent, containing the dye, Cy5, so they may be used as hybrid PET-optical imaging agents for lesion detection, cancer staging, and treatment management in humans. However, the clinical translation of nanoparticle probes, including quantum dots, has not kept pace with the accelerated growth in minimally invasive surgical tools that rely on optical imaging agents. The safety, pharmacokinetics, clearance properties, and radiation dosimetry of (124)I-cRGDY-PEG-C dots were assessed by serial PET and computerized tomography after intravenous administration in patients. Metabolic profiles and laboratory tests of blood and urine specimens, obtained before and after particle injection, were monitored over a 2-week interval. Findings are consistent with a well-tolerated inorganic particle tracer exhibiting in vivo stability and distinct, reproducible pharmacokinetic signatures defined by renal excretion. No toxic or adverse events attributable to the particles were observed. Coupled with preferential uptake and localization of the probe at sites of disease, these first-in-human results suggest safe use of these particles in human cancer diagnostics.
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 101283273
                Journal ID (pubmed-jr-id): 34218
                Journal ID (nlm-ta): Nat Nanotechnol
                Journal ID (iso-abbrev): Nat Nanotechnol
                Title: Nature nanotechnology
                ISSN (Print): 1748-3387
                ISSN (Electronic): 1748-3395
                Publication date Nihms-submitted: 6 August 2016
                Publication date (Electronic): 26 September 2016
                Publication date (Print): November 2016
                Publication date PMC-release: 26 March 2017
                Volume: 11
                Issue: 11
                Pages: 977-985
                Affiliations
                [1 ]Cell Biology Program, Sloan Kettering Institute for Cancer Research, New York, NY 10065, USA
                [2 ]BCMB Allied Program, Weill Cornell Medical College, New York, NY 10065, USA
                [3 ]Department of Radiology, Sloan Kettering Institute for Cancer Research, New York, NY 10065, USA
                [4 ]Department of Materials Science & Engineering, Cornell University, Ithaca, NY 14853, USA
                [5 ]Helmholtz Zentrum München, Institute of Developmental Genetics, 85764 Neuherberg, Germany
                [6 ]Tri-Institutional Laboratory of Comparative Pathology, The Rockefeller University, Sloan Kettering Institute for Cancer Research, Weill Cornell Medical College, New York, NY 10065, USA
                [7 ]Department of Epidemiology and Biostatistics, Sloan Kettering Institute for Cancer Research, New York, NY 10065, USA
                [8 ]Department of Medical Physics, Sloan Kettering Institute for Cancer Research, New York, NY 10065, USA
                [9 ]Department of Biochemistry, University of Missouri, Columbia, MO 65211
                [10 ]Molecular Pharmacology Program, Sloan Kettering Institute for Cancer Research, New York, NY 10065, USA
                Author notes
                Correspondence and requests for materials should be addressed to: M. Overholtzer, overhom1@ 123456mskcc.org and M. Bradbury, bradburm@ 123456mskcc.org
                [*]

                These authors contributed equally.

                Correspondence and requests for materials should be addressed to M.O. and M.B..

                Article
                Manuscript ID: NIHMS808620
                DOI: 10.1038/nnano.2016.164
                PMC ID: 5108575
                PubMed ID: 27668796
                SO-VID: 0ae9f4c3-42ec-4ebe-8f95-1f4c7746f353
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                Reprints and permission information is available online at www.nature.com/reprints.

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                ScienceOpen disciplines: Nanotechnology

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