Use of Ferritin-Based Metal-Encapsulated Nanocarriers as Anticancer Agents

The ability of ferritin to bind and deliver metals and metal-based drugs to human neuroblastoma SH-SY5Y cells was studied. We used heavy chain (H) ferritin-based metal-containing nanocarriers to test whether these constructs, which are able to cross the blood-brain barrier, may be used for the delivery of toxic molecules to brain cells, and to study their effect on the viability and cellular redox homeostasis of human neuroblastoma cells. We show that metal-containing nanocarriers are efficiently captured by SH-SY5Y cells. Iron-containing nanocarriers have a proliferative effect, while silver and cisplatin-encapsulated nanocarriers determine concentration-dependent neuroblastoma cell death. This work is a proof of concept for the use of ferritins for the delivery of toxic molecules to brain tumors.

[1]  J. Connor,et al.  Consequences of expressing mutants of the hemochromatosis gene (HFE) into a human neuronal cell line lacking endogenous HFE , 2007, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[2]  C. Beaumont,et al.  Early Embryonic Lethality of H Ferritin Gene Deletion in Mice* , 2000, The Journal of Biological Chemistry.

[3]  J. Connor,et al.  Receptor‐mediated transcytosis of transferrin across the blood‐brain barrier , 1987, Journal of neuroscience research.

[4]  Mauri A Kostiainen,et al.  Electrostatic assembly of binary nanoparticle superlattices using protein cages. , 2013, Nature nanotechnology.

[5]  M. Yamamoto,et al.  In vitro cytotoxicities and in vivo distribution of transferrin-platinum(II) complex. , 1995, Journal of pharmaceutical sciences.

[6]  R. Kalaria Brain Microvasculature in Aging , 1994, Neurobiology of Aging.

[7]  C. Leonetti,et al.  Antibody-drug conjugates: targeting melanoma with cisplatin encapsulated in protein-cage nanoparticles based on human ferritin. , 2013, Nanoscale.

[8]  A. Boffi,et al.  In Vivo Targeting of Cutaneous Melanoma Using an Melanoma Stimulating Hormone-Engineered Human Protein Cage with Fluorophore and Magnetic Resonance Imaging Tracers. , 2015, Journal of biomedical nanotechnology.

[9]  T. Waseem,et al.  Ferritin, a protein containing iron nanoparticles, induces reactive oxygen species formation and inhibits glutamate uptake in rat brain synaptosomes , 2008, Brain Research.

[10]  M. Büchler,et al.  Transferrin receptor is a marker of malignant phenotype in human pancreatic cancer and in neuroendocrine carcinoma of the pancreas. , 2004, European journal of cancer.

[11]  W. Jefferies,et al.  Transferrin receptor on endothelium of brain capillaries , 1984, Nature.

[12]  M. Hande,et al.  Anti-proliferative activity of silver nanoparticles , 2009, BMC Cell Biology.

[13]  J. Benoit,et al.  Transferrin Adsorption onto PLGA Nanoparticles Governs Their Interaction with Biological Systems from Blood Circulation to Brain Cancer Cells , 2011, Pharmaceutical Research.

[14]  M. Biffoni,et al.  Transferrin receptor 2 is frequently expressed in human cancer cell lines. , 2007, Blood cells, molecules & diseases.

[15]  L. Tei,et al.  Magnetic resonance visualization of tumor angiogenesis by targeting neural cell adhesion molecules with the highly sensitive gadolinium-loaded apoferritin probe. , 2006, Cancer research.

[16]  N. Elad,et al.  Improved Doxorubicin Encapsulation and Pharmacokinetics of Ferritin-Fusion Protein Nanocarriers Bearing Proline, Serine, and Alanine Elements. , 2016, Biomacromolecules.

[17]  G. Marcucci,et al.  Efficient delivery of a Bcl-2-specific antisense oligodeoxyribonucleotide (G3139) via transferrin receptor-targeted liposomes. , 2006, Journal of controlled release : official journal of the Controlled Release Society.

[18]  Xiaogang Pan,et al.  Reversal of multidrug resistance by transferrin-conjugated liposomes co-encapsulating doxorubicin and verapamil. , 2007, Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques.

[19]  A. Boffi,et al.  Metals and metal derivatives in medicine. , 2013, Mini reviews in medicinal chemistry.

[20]  Seong-Cheol Park,et al.  Encapsulation of paclitaxel into lauric acid-O-carboxymethyl chitosan-transferrin micelles for hydrophobic drug delivery and site-specific targeted delivery. , 2013, International journal of pharmaceutics.

[21]  W. Seaman,et al.  Binding and uptake of H-ferritin are mediated by human transferrin receptor-1 , 2010, Proceedings of the National Academy of Sciences.

[22]  L. Donini,et al.  Neuroprotective Effect of Brassica oleracea Sprouts Crude Juice in a Cellular Model of Alzheimer's Disease , 2015, Oxidative medicine and cellular longevity.

[23]  R. MacGillivray,et al.  Genetically engineering transferrin to improve its in vitro ability to deliver cytotoxins. , 2009, Journal of controlled release : official journal of the Controlled Release Society.

[24]  M. Walsh,et al.  Transferrin receptor expression by human bladder transitional cell carcinomas , 1987, Urological research.

[25]  A. Albertini,et al.  The role of the L-chain in ferritin iron incorporation. Studies of homo and heteropolymers. , 1994, Journal of molecular biology.

[26]  Fan Zhang,et al.  Chimeric ferritin nanocages for multiple function loading and multimodal imaging. , 2011, Nano letters.

[27]  E. Shusta,et al.  Targeting receptor-mediated transport for delivery of biologics across the blood-brain barrier. , 2015, Annual review of pharmacology and toxicology.

[28]  I. Orienti,et al.  Sodium Ascorbate induces apoptosis in neuroblastoma cell lines by interfering with iron uptake , 2007, Molecular Cancer.

[29]  Jan C M van Hest,et al.  Functionalization of protein-based nanocages for drug delivery applications. , 2014, Nanoscale.

[30]  Alexander Böker,et al.  Ferritin: a versatile building block for bionanotechnology. , 2015, Chemical reviews.

[31]  M. Noguchi,et al.  Transferrin receptor expression in adenocarcinoma of the lung as a histopathologic indicator of prognosis. , 1990, Chest.

[32]  A. Ilari,et al.  Silver ion incorporation and nanoparticle formation inside the cavity of Pyrococcus furiosus ferritin: structural and size-distribution analyses. , 2010, Journal of the American Chemical Society.

[33]  M. Young,et al.  Intracellular Distribution of Macrophage Targeting Ferritin–Iron Oxide Nanocomposite , 2009 .

[34]  Dongling Yang,et al.  H-ferritin–nanocaged doxorubicin nanoparticles specifically target and kill tumors with a single-dose injection , 2014, Proceedings of the National Academy of Sciences.

[35]  Q. Lan,et al.  Transferrin-modified Doxorubicin-loaded biodegradable nanoparticles exhibit enhanced efficacy in treating brain glioma-bearing rats. , 2013, Cancer biotherapy & radiopharmaceuticals.

[36]  C. Innocenti,et al.  A smart platform for hyperthermia application in cancer treatment: cobalt-doped ferrite nanoparticles mineralized in human ferritin cages. , 2014, ACS nano.

[37]  P. Harrison,et al.  Influence of site-directed modifications on the formation of iron cores in ferritin. , 1991, Journal of molecular biology.

[38]  L. Pieroni,et al.  New insights into neuroblastoma cisplatin resistance: a comparative proteomic and meta-mining investigation. , 2011, Journal of proteome research.

[39]  T. Coccini,et al.  Assessment of Cellular Responses after Short- and Long-Term Exposure to Silver Nanoparticles in Human Neuroblastoma (SH-SY5Y) and Astrocytoma (D384) Cells , 2014, TheScientificWorldJournal.

[40]  Suzy V. Torti,et al.  Mouse brains deficient in H‐ferritin have normal iron concentration but a protein profile of iron deficiency and increased evidence of oxidative stress , 2003, Journal of neuroscience research.

[41]  N. Kadowaki,et al.  H-Ferritin Is Preferentially Incorporated by Human Erythroid Cells through Transferrin Receptor 1 in a Threshold-Dependent Manner , 2015, PloS one.

[42]  Tom C. Karagiannis,et al.  Transferrin Receptor-Mediated Endocytosis: A Useful Target for Cancer Therapy , 2014, The Journal of Membrane Biology.

[43]  C. Innocenti,et al.  Synthesis of iron oxide nanoparticles in Listeria innocua Dps (DNA-binding protein from starved cells): a study with the wild-type protein and a catalytic centre mutant. , 2010, Chemistry.

[44]  M. Bellini,et al.  Protein nanocages for self-triggered nuclear delivery of DNA-targeted chemotherapeutics in Cancer Cells. , 2014, Journal of controlled release : official journal of the Controlled Release Society.

[45]  J. Connor,et al.  Transferrin is required for normal distribution of 59Fe and 54Mn in mouse brain , 1999, Journal of the Neurological Sciences.

[46]  S. Xie,et al.  Cisplatin regulates SH-SY5Y cell growth through downregulation of BDNF via miR-16. , 2013, Oncology reports.

[47]  M. Dehouck,et al.  Receptor-mediated transcytosis of transferrin through blood-brain barrier endothelial cells. , 1996, The American journal of physiology.

[48]  N. Žarković,et al.  Altered iron metabolism, transferrin receptor 1 and ferritin in patients with colon cancer. , 2006, Cancer letters.

[49]  R. Jain,et al.  Delivering nanomedicine to solid tumors , 2010, Nature Reviews Clinical Oncology.

[50]  M. Ferrari,et al.  Engineering multi-stage nanovectors for controlled degradation and tunable release kinetics. , 2013, Biomaterials.

[51]  M. Gramiccia,et al.  Inhibitory Effect of Silver Nanoparticles on Trypanothione Reductase Activity and Leishmania infantum Proliferation. , 2011, ACS medicinal chemistry letters.

[52]  J. Connor,et al.  Ferritin: a novel mechanism for delivery of iron to the brain and other organs. , 2007, American journal of physiology. Cell physiology.

[53]  P. Harrison,et al.  The ferritins: molecular properties, iron storage function and cellular regulation. , 1996, Biochimica et biophysica acta.

[54]  D. Mason,et al.  Transferrin receptors in human tissues: their distribution and possible clinical relevance. , 1983, Journal of clinical pathology.

[55]  B. Nemesure,et al.  Differential Expression of Transferrin Receptor (TfR) in a Spectrum of Normal to Malignant Breast Tissues: Implications for In Situ and Invasive Carcinoma , 2011, Applied immunohistochemistry & molecular morphology : AIMM.

[56]  E. Chiancone,et al.  Iron and proteins for iron storage and detoxification , 2004, Biometals.