零價鐵（ZVI）奈米粒子具有能反應產生高活性的氧自由基特性，傳統上被廣泛用於處理難以分解的環境污染，但近期也被發現對癌細胞具有專一的細胞毒性。為了探討其中的機制，本研究設計具有不同外殼的零價鐵奈米粒子，進行其對癌細胞的專一性與非惡性細胞的相容性的機制研究。在初步五種零價鐵奈米的細胞毒性測試中，發現大部分皆有癌細胞專一性毒殺的效果，除了外殼為氧化為氧化鐵的奈米對癌細胞的毒殺能力大幅降低。即便是具有最強對癌細胞毒殺效果的銀外殼零價鐵奈米(ZVI@Ag)，在氧化後毒性也明顯降低，經元素分析這些奈米粒子的氧氣組成後，發現奈米粒子內的氧氣組成越低，具有對癌細胞越高的毒殺效果，同時保也留了對正常細胞的生物相容性，因此我們認為氧氣是影響零價鐵毒殺效果的關鍵元素。在細胞內鐵動力學測定中，在最初的2小時內癌細胞和正常細胞之間ZVI@Ag的總鐵攝取量相似，但是只有癌細胞會快速將零價鐵核心轉化為鐵離子並產生大量的細胞內ROS，接著產生自噬作用和細胞凋亡。然而，我們也發現加入鐵離子螯合劑或預氧化ZVI@Ag可以反轉ROS的產生，且中和溶酶體的酸鹼值或加入抗氧化劑亦可有效減少ZVI@Ag誘導的程序性細胞死亡。因此我們發現零價鐵奈米的抗癌機制涉及溶酶體依賴性組合的凋亡和自噬細胞死亡途徑，與細胞內鐵離子的爆發釋放和大量ROS產生有關。為了更進一步了解零價鐵奈米的鐵離子釋放與癌細胞溶酶體的關係，我們設計2種零價鐵奈米外殼分別為封閉的二氧化矽和具孔洞二氧化矽（分別表示為ZVI@SiO2和ZVI@mSiO2）來進行後續細胞毒性，細胞內鐵離子釋放及其潛在機制的研究。在OEC-M1口腔癌細胞中，只有ZVI@mSiO2具有明顯的細胞毒性，ZVI@SiO2則失去了零價鐵奈米的毒性，兩者皆對正常細胞有良好生物相容性。此外，被細胞吞噬的ZVI@mSiO2在24小時後會變形為細胞內的中空結構，而ZVI@SiO2在被吞噬後仍保持完整。細胞內鐵離子的釋放曲線也與ZVI@mSiO2的結構變形一致。細胞吞噬ZVI@mSiO2一個小時內爆發了爆炸性的鐵離子釋放，溶酶體膜的通透性增加，導致大量的氧自由基生成，隨後導致壞死和凋亡性細胞死亡。而此現象在ZVI@SiO2並未被觀察到，顯示密閉的二氧化矽殼層可以阻擋核心零價鐵奈米的鐵離子釋放，再次證明鐵離子釋放對於癌細胞的性是必要的。此外，抑制溶酶體酸化成功阻止了ZVI@mSiO2爆炸性鐵離子的釋放，顯示酸性環境對於促進零鐵奈米轉化成鐵離子釋放到細胞中是另一個關鍵。對於前面觀察到零價鐵奈米粒在細胞內結構改變的現象，為了能更清楚觀察其結構的變化，我們使用不容易被酸性影響且具有高電子密度的金殼包覆零價鐵奈米(ZVI@Au)來做更進一步的結構變化探討。基本上ZVI@Au如同其他的零價鐵奈米皆會誘導大量的氧自由基產生並引起自噬作用/凋亡等細胞死亡機制，此外亦會導致線粒體膜電位喪失，以及氧自由基代謝酵素酶穀胱甘肽過氧化酶1和4 (GPX1 and GPX4)的蛋白表現量降低而影響細胞處理氧化壓力的能力。最重要的是，我們觀察到癌細胞內的ZVI@Au也出現明顯空心和空洞結構，但在正常細胞吞噬後仍保持原始結構。通過能量色散X射線光譜儀(EDX)分析，奈米粒子核心的鐵訊號消失了，但金訊號仍保留在了粒子的殼上。這些發現顯示，ZVI核心可在癌細胞中迅速轉化為鐵離子，並引起一連串後續細胞內的反應。最後，我們在人類異種移植小鼠模型中通過靜脈注射給予零價鐵奈米粒子來確認零價鐵奈米在活體內的抗癌效果與安全性。 結果顯示ZVI@Ag，ZVI@Au和ZVI@mSiO2奈米均顯示出良好的抗癌作用，且受施打的老鼠無明顯的體重減輕。總結本研究的發現，我們證明了零價鐵奈米粒子的專一抗癌特性與其內部的氧氣組成比例相關，且與癌細胞內溶酶體酸性環境所導致的細胞內鐵離子爆炸性釋放有關。隨後造成大量氧自由基產生加上相關代謝酵素GPX1和GPX4的表現量降低，引發粒線體膜電未喪失造成後續細胞的程序性死亡。

This study demonstrated that zero-valent iron (ZVI), which is widely used to remediate environmental contamination through high-energy reactive oxygen species (ROS) production, showed differential cytotoxicity to cancer cells. The investigative approach that consistant of designing nanoparticles (NPs) with different shells for achieving efficacy toward cancer cells and compatibility to nonmalignant cells demonstrated that silver-coated ZVI NPs (ZVI@Ag) had the highest potency among ZVI NPs synthesized in this study while preserving adequate biocompatibility to nonmalignant keratinocytes. In the intracellular iron dynamic assay, the NP uptake amount of ZVI@Ag was similar between cancer cells and normal cells in the first 2 h, but only cancer cells rapidly converted the NPs to iron ions and generated large amounts of intracellular ROS, followed by apoptosis and autophagy induction. Such activity was able to be rescued by iron ion chelators or by preoxidizing the NPs. Lysosomal pH neutralization effectively reduced ZVI@Ag NP-induced programmed cell death. The anticancer mechanism involves lysosome-dependent combined apoptotic and autophagic cell death pathways associated with intracellular burst release of iron ions and massive ROS production. In addition, to evaluate the iron ion release profile of zero-valent iron (ZVI)-based nanoparticles (NPs) and their relationship with lysosomes in cancer cells, silica and mesoporous silica-coated ZVI NPs (denoted as ZVI@SiO2 and ZVI@mSiO2) were synthesized and characterized for the following study of cytotoxicity, intracellular iron ion release, and their underlying mechanisms. ZVI@mSiO2 NPs showed higher cytotoxicity than ZVI@SiO2 NPs in the OEC-M1 oral cancer cell line. In addition, internalized ZVI@mSiO2 NPs deformed into hollow and void structures within the cells after 24-h treatment, but ZVI@SiO2 NPs remained intact after internalization. The intracellular iron ion release profile was also accordant with the structural deformation of ZVI@mSiO2 NPs. Burst iron ion release occurred in ZVI@mSiO2-treated cells within an hour with increased lysosome membrane permeability, which induced massive reactive oxygen species generation followed by necrotic and apoptotic cell death. Furthermore, inhibition of endosome–lysosome system acidification successfully compromised burst iron ion release, thereby reversing the cell fate. Furthermore, we used ZVI@Au NPs for additional intracellular structure deformation characterization. ZVI@Au NPs also induced massive ROS and caused apoptosis/autophagy like other ZVI NPs, and would lead to mitochondria membrane potential lost and ROS metabolism enzymes glutathione peroxidase 1 & 4 depletion. Most important, we observed that ZVI@Au also changed to hollow and void structure that significantly deformed from original structure after uptake by cancer cells, but still maintain original structure after uptake by normal cells. Form the energy dispersive X-ray spectrometer (EDX) analysis, the iron signal of the particle core disappeared but retained the gold signal on the particle shell. These findings showed evidenced that the ZVI core could be converted into iron ions rapidly in cancer cells and caused subsequence intracellular responses. In vivo efficacy and safety were confirmed in a human cancer xenograft mouse model through the systemic administration of the NPs. ZVI@Ag, ZVI@Au and ZVI@mSiO2 NPs all showed promising anticancer effect without significant weight loss. In conclusion, we demonstrated the anticancer property of ZVI-containing NPs as well as the iron ion release profile and ROS induction within cells, which is highly associated with the oxidative status of the NPs and lysosomal acidification.

References
Ahamed, M., H. A. Alhadlaq, M. A. M. Khan and M. J. Akhtar (2013). "Selective killing of cancer cells by iron oxide nanoparticles mediated through reactive oxygen species via p53 pathway." Journal of Nanoparticle Research 15(1).
Akter, M., M. T. Sikder, M. M. Rahman, A. Ullah, K. F. B. Hossain, S. Banik, T. Hosokawa, T. Saito and M. Kurasaki (2018). "A systematic review on silver nanoparticles-induced cytotoxicity: Physicochemical properties and perspectives." J Adv Res 9: 1-16.
Anbouhi, T. S., E. M. Esfidvajani, F. Nemati, S. Haghighat, S. Sari, F. Attar, A. Pakaghideh, M. J. Sohrabi, S. E. Mousavi and M. Falahati (2019). "Albumin binding, anticancer and antibacterial properties of synthesized zero valent iron nanoparticles." International Journal of Nanomedicine 14: 243-256.
Asefa, T. and Z. M. Tao (2012). "Biocompatibility of Mesoporous Silica Nanoparticles." Chemical Research in Toxicology 25(11): 2265-2284.
Aueviriyavit, S., D. Phummiratch and R. Maniratanachote (2014). "Mechanistic study on the biological effects of silver and gold nanoparticles in Caco-2 cells--induction of the Nrf2/HO-1 pathway by high concentrations of silver nanoparticles." Toxicol Lett 224(1): 73-83.
Azad, M. B., Y. Chen and S. B. Gibson (2009). "Regulation of autophagy by reactive oxygen species (ROS): implications for cancer progression and treatment." Antioxid Redox Signal 11(4): 777-790.
Baghbani-Arani, F., R. Movagharnia, A. Sharifian, S. Salehi and S. A. S. Shandiz (2017). "Photo-catalytic, anti-bacterial, and anti-cancer properties of phyto-mediated synthesis of silver nanoparticles from Artemisia tournefortiana Rchb extract." J Photochem Photobiol B 173: 640-649.
Belade, E., L. Armand, L. Martinon, L. Kheuang, J. Fleury-Feith, A. Baeza-Squiban, S. Lanone, M. A. Billon-Galland, J. C. Pairon and J. Boczkowski (2012). "A comparative transmission electron microscopy study of titanium dioxide and carbon black nanoparticles uptake in human lung epithelial and fibroblast cell lines." Toxicology in Vitro 26(1): 57-66.
Bertrand, N. and J. C. Leroux (2012). "The journey of a drug-carrier in the body: An anatomo-physiological perspective." Journal of Controlled Release 161(2): 152-163.
Boroughs, L. K. and R. J. DeBerardinis (2015). "Metabolic pathways promoting cancer cell survival and growth." Nat Cell Biol 17(4): 351-359.
Bray, F., J. Ferlay, I. Soerjomataram, R. L. Siegel, L. A. Torre and A. Jemal (2018). "Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries." Ca-a Cancer Journal for Clinicians 68(6): 394-424.
Bystrom, L. M., M. L. Guzman and S. Rivella (2014). "Iron and reactive oxygen species: friends or foes of cancer cells?" Antioxid Redox Signal 20(12): 1917-1924.
Canton, I., M. Massignani, N. Patikarnmonthon, L. Chierico, J. Robertson, S. A. Renshaw, N. J. Warren, J. P. Madsen, S. P. Armes, A. L. Lewis and G. Battaglia (2013). "Fully synthetic polymer vesicles for intracellular delivery of antibodies in live cells." Faseb Journal 27(1): 98-108.
Carroll, K. J., D. M. Hudgins, S. Spurgeon, K. M. Kemner, B. Mishra, M. I. Boyanov, L. W. Brown, M. L. Taheri and E. E. Carpenter (2010). "One-Pot Aqueous Synthesis of Fe and Ag Core/Shell Nanoparticles." Chemistry of Materials 22(23): 6291-6296.
Chen, B., W. Wu and X. Wang (2011). "Magnetic iron oxide nanoparticles for tumor-targeted therapy." Curr Cancer Drug Targets 11(2): 184-189.
Chen, G., F. Wang, D. Trachootham and P. Huang (2010). "Preferential killing of cancer cells with mitochondrial dysfunction by natural compounds." Mitochondrion 10(6): 614-625.
Chou, S. W., Y. H. Shau, P. C. Wu, Y. S. Yang, D. B. Shieh and C. C. Chen (2010). "In vitro and in vivo studies of FePt nanoparticles for dual modal CT/MRI molecular imaging." J Am Chem Soc 132(38): 13270-13278.
Commisso, C., S. M. Davidson, R. G. Soydaner-Azeloglu, S. J. Parker, J. J. Kamphorst, S. Hackett, E. Grabocka, M. Nofal, J. A. Drebin, C. B. Thompson, J. D. Rabinowitz, C. M. Metallo, M. G. Vander Heiden and D. Bar-Sagi (2013). "Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells." Nature 497(7451): 633-637.
Davidson, S. M. and M. G. Vander Heiden (2017). "Critical Functions of the Lysosome in Cancer Biology." Annual Review of Pharmacology and Toxicology, Vol 57 57: 481-507.
Davidson, S. M. and M. G. Vander Heiden (2017). "Critical Functions of the Lysosome in Cancer Biology." Annu Rev Pharmacol Toxicol 57: 481-507.
Diao, M. H. and M. S. Yao (2009). "Use of zero-valent iron nanoparticles in inactivating microbes." Water Research 43(20): 5243-5251.
Dong, T. G., S. Q. Dong, C. Catalano, R. Moore, X. Y. Liang and J. J. Mekalanos (2015). "Generation of reactive oxygen species by lethal attacks from competing microbes." Proceedings of the National Academy of Sciences of the United States of America 112(7): 2181-2186.
Dziedzic, A., R. Kubina, R. J. Buldak, M. Skonieczna and K. Cholewa (2016). "Silver Nanoparticles Exhibit the Dose-Dependent Anti-Proliferative Effect against Human Squamous Carcinoma Cells Attenuated in the Presence of Berberine." Molecules 21(3): 365.
Eid, R., N. T. Arab and M. T. Greenwood (2017). "Iron mediated toxicity and programmed cell death: A review and a re-examination of existing paradigms." Biochim Biophys Acta Mol Cell Res 1864(2): 399-430.
El-Hussein, A. and M. R. Hamblin (2017). "ROS generation and DNA damage with photo-inactivation mediated by silver nanoparticles in lung cancer cell line." IET Nanobiotechnol 11(2): 173-178.
Enami, S., Y. Sakamoto and A. J. Colussi (2014). "Fenton chemistry at aqueous interfaces." Proceedings of the National Academy of Sciences of the United States of America 111(2): 623-628.
Farokhzad, O. C. and R. Langer (2009). "Impact of Nanotechnology on Drug Delivery." Acs Nano 3(1): 16-20.
Fawcett, H., J. S. Mader, M. Robichaud, C. Giacomantonio and D. W. Hoskin (2005). "Contribution of reactive oxygen species and caspase-3 to apoptosis and attenuated ICAM-1 expression by paclitaxel-treated MDA-MB-435 breast carcinoma cells." International Journal of Oncology 27(6): 1717-1726.
Feng, Q., Y. Liu, J. Huang, K. Chen, J. Huang and K. Xiao (2018). "Uptake, distribution, clearance, and toxicity of iron oxide nanoparticles with different sizes and coatings." Sci Rep 8(1): 2082.
Feng, Q. Y., Y. P. Liu, J. Huang, K. Chen, J. X. Huang and K. Xiao (2018). "Uptake, distribution, clearance, and toxicity of iron oxide nanoparticles with different sizes and coatings." Scientific Reports 8.
Festjens, N., T. Vanden Berghe and P. Vandenabeele (2006). "Necrosis, a well-orchestrated form of cell demise: Signalling cascades, important mediators and concomitant immune response." Biochimica Et Biophysica Acta-Bioenergetics 1757(9-10): 1371-1387.
Fu, F., D. D. Dionysiou and H. Liu (2014). "The use of zero-valent iron for groundwater remediation and wastewater treatment: a review." J Hazard Mater 267: 194-205.
Gao, F., N. J. Ma, H. Zhou, Q. Wang, H. Zhang, P. Wang, H. L. Hou, H. Wen and L. J. Li (2016). "Zinc oxide nanoparticles-induced epigenetic change and G2/M arrest are associated with apoptosis in human epidermal keratinocytes." International Journal of Nanomedicine 11: 3859-3874.
Gao, J. H., G. L. Liang, B. Zhang, Y. Kuang, X. X. Zhang and B. Xu (2007). "FePt@CoS2 yolk-shell nanocrystals as a potent agent to kill HeLa cells." Journal of the American Chemical Society 129(5): 1428-1433.
Gershell, L. J. and J. H. Atkins (2003). "A brief history of novel drug discovery technologies." Nature Reviews Drug Discovery 2(4): 321-327.
Gheju, M. (2011). "Hexavalent Chromium Reduction with Zero-Valent Iron (ZVI) in Aquatic Systems." Water Air and Soil Pollution 222(1-4): 103-148.
Ghosh, I., A. Mukherjee and A. Mukherjee (2017). "In planta genotoxicity of nZVI: influence of colloidal stability on uptake, DNA damage, oxidative stress and cell death." Mutagenesis 32(3): 371-387.
Grcic, I., S. Papic, K. Zizek and N. Koprivanac (2012). "Zero-valent iron (ZVI) Fenton oxidation of reactive dye wastewater under UV-C and solar irradiation." Chemical Engineering Journal 195: 77-90.
Grieger, K. D., A. Fjordboge, N. B. Hartmann, E. Eriksson, P. L. Bjerg and A. Baun (2010). "Environmental benefits and risks of zero-valent iron nanoparticles (nZVI) for in situ remediation: risk mitigation or trade-off?" J Contam Hydrol 118(3-4): 165-183.
Haigler, H. T., J. A. McKanna and S. Cohen (1979). "Rapid stimulation of pinocytosis in human carcinoma cells A-431 by epidermal growth factor." J Cell Biol 83(1): 82-90.
Hainaut, P. and A. Plymoth (2013). "Targeting the hallmarks of cancer: towards a rational approach to next-generation cancer therapy." Curr Opin Oncol 25(1): 50-51.
Hanahan, D. and R. A. Weinberg (2011). "Hallmarks of cancer: the next generation." Cell 144(5): 646-674.
Hanini, A., A. Schmitt, K. Kacem, F. Chau, S. Ammar and J. Gavard (2011). "Evaluation of iron oxide nanoparticle biocompatibility." Int J Nanomedicine 6: 787-794.
Heneweer, C., J. P. Holland, V. Divilov, S. Carlin and J. S. Lewis (2011). "Magnitude of Enhanced Permeability and Retention Effect in Tumors with Different Phenotypes: Zr-89-Albumin as a Model System." Journal of Nuclear Medicine 52(4): 625-633.
Holley, A. K., S. K. Dhar and D. K. St Clair (2010). "Manganese superoxide dismutase versus p53: the mitochondrial center." Ann N Y Acad Sci 1201: 72-78.
Hsueh, Y. H., P. H. Tsai, K. S. Lin, W. J. Ke and C. L. Chiang (2017). "Antimicrobial effects of zero-valent iron nanoparticles on gram-positive Bacillus strains and gram-negative Escherichia coli strains." Journal of Nanobiotechnology 15.
Huang, K. J., Y. H. Wei, Y. C. Chiu, S. R. Wu and D. B. Shieh (2019). "Assessment of zero-valent iron-based nanotherapeutics for ferroptosis induction and resensitization strategy in cancer cells." Biomaterials Science 7(4): 1311-1322.
Hughes, M. F., T. C. Long, W. K. Boyes and R. Ramabhadran (2013). "Whole-body retention and distribution of orally administered radiolabelled zerovalent iron nanoparticles in mice." Nanotoxicology 7(6): 1064-1069.
Ishwarya, R., B. Vaseeharan, R. Anuradha, R. Rekha, M. Govindarajan, N. S. Alharbi, S. Kadaikunnan, J. M. Khaled and G. Benelli (2017). "Eco-friendly fabrication of Ag nanostructures using the seed extract of Pedalium murex, an ancient Indian medicinal plant: Histopathological effects on the Zika virus vector Aedes aegypti and inhibition of biofilm-forming pathogenic bacteria." J Photochem Photobiol B 174: 133-143.
Ito, A., H. Honda and T. Kobayashi (2006). "Cancer immunotherapy based on intracellular hyperthermia using magnetite nanoparticles: a novel concept of "heat-controlled necrosis" with heat shock protein expression." Cancer Immunology Immunotherapy 55(3): 320-328.
Jordan, V. C. (2008). "Tamoxifen: Catalyst for the change to targeted therapy." European Journal of Cancer 44(1): 30-38.
Kadar, E., O. Dyson, R. D. Handy and S. N. Al-Subiai (2013). "Are reproduction impairments of free spawning marine invertebrates exposed to zero-valent nano-iron associated with dissolution of nanoparticles?" Nanotoxicology 7(2): 135-143.
Karihtala, P. and Y. Soini (2007). "Reactive oxygen species and antioxidant mechanisms in human tissues and their relation to malignancies." Apmis 115(2): 81-103.
Karlsson, H. L., P. Cronholm, J. Gustafsson and L. Moller (2008). "Copper oxide nanoparticles are highly toxic: A comparison between metal oxide nanoparticles and carbon nanotubes." Chemical Research in Toxicology 21(9): 1726-1732.
Katsoyiannis, I. A., T. Ruettimann and S. J. Hug (2008). "pH dependence of Fenton reagent generation and As(III) oxidation and removal by corrosion of zero valent iron in aerated water." Environmental Science & Technology 42(19): 7424-7430.
Katzel, J. A., M. P. Fanucchi and Z. J. Li (2009). "Recent advances of novel targeted therapy in non-small cell lung cancer." Journal of Hematology & Oncology 2.
Keenan, C. R., R. Goth-Goldstein, D. Lucas and D. L. Sedlak (2009). "Oxidative Stress Induced by Zero-Valent Iron Nanoparticles and Fe(II) in Human Bronchial Epithelial Cells." Environmental Science & Technology 43(12): 4555-4560.
Kievit, F. M. and M. Zhang (2011). "Surface engineering of iron oxide nanoparticles for targeted cancer therapy." Acc Chem Res 44(10): 853-862.
Kim, S. W., J. H. Jung, K. Lamsal, Y. S. Kim, J. S. Min and Y. S. Lee (2012). "Antifungal Effects of Silver Nanoparticles (AgNPs) against Various Plant Pathogenic Fungi." Mycobiology 40(1): 53-58.
Kimmelman, A. C. (2011). "The dynamic nature of autophagy in cancer." Genes Dev 25(19): 1999-2010.
Kirkegaard, T. and M. Jaattela (2009). "Lysosomal involvement in cell death and cancer." Biochim Biophys Acta 1793(4): 746-754.
Kryston, T. B., A. B. Georgiev, P. Pissis and A. G. Georgakilas (2011). "Role of oxidative stress and DNA damage in human carcinogenesis." Mutat Res 711(1-2): 193-201.
Lacroix, L. M., N. F. Huls, D. Ho, X. L. Sun, K. Cheng and S. H. Sun (2011). "Stable Single-Crystalline Body Centered Cubic Fe Nanoparticles." Nano Letters 11(4): 1641-1645.
Langer, R. (2001). "Perspectives: Drug delivery - Drugs on target." Science 293(5527): 58-59.
Lee, C., J. Y. Kim, W. I. Lee, K. L. Nelson, J. Yoon and D. L. Sedlak (2008). "Bactericidal effect of zero-valent iron nanoparticles on Escherichia coli." Environmental Science & Technology 42(13): 4927-4933.
Lee, H., D. H. Dam, J. W. Ha, J. Yue and T. W. Odom (2015). "Enhanced Human Epidermal Growth Factor Receptor 2 Degradation in Breast Cancer Cells by Lysosome-Targeting Gold Nanoconstructs." ACS Nano 9(10): 9859-9867.
Lefevre, E., N. Bossa, M. R. Wiesner and C. K. Gunsch (2016). "A review of the environmental implications of in situ remediation by nanoscale zero valent iron (nZVI): Behavior, transport and impacts on microbial communities." Science of the Total Environment 565: 889-901.
Levine, B. and G. Kroemer (2008). "Autophagy in the pathogenesis of disease." Cell 132(1): 27-42.
Li, J., X. M. Zhao, L. Chen, H. Y. Guo, F. F. Lv, K. Jia, K. Yv, F. Q. Wang, C. A. Li, J. Qian, C. L. Zheng and Y. X. Zuo (2010). "Safety and pharmacokinetics of novel selective vascular endothelial growth factor receptor-2 inhibitor YN968D1 in patients with advanced malignancies." Bmc Cancer 10.
Li, J. X., X. Y. Zhang, Y. K. Sun, L. P. Liang, B. C. Pan, W. M. Zhang and X. H. Guan (2017). "Advances in Sulfidation of Zerovalent Iron for Water Decontamination." Environmental Science & Technology 51(23): 13533-13544.
Li, T. J., C. M. Chang, P. Y. Chang, Y. C. Chuang, C. C. Huang, W. C. Su and D. B. Shieh (2016). "Handheld energy-efficient magneto-optical real-time quantitative PCR device for target DNA enrichment and quantification." Npg Asia Materials 8.
Li, T. J., C. C. Huang, P. W. Ruan, K. Y. Chuang, K. J. Huang, D. B. Shieh and C. S. Yeh (2013). "In vivo anti-cancer efficacy of magnetite nanocrystal-based system using locoregional hyperthermia combined with 5-fluorouracil chemotherapy." Biomaterials 34(32): 7873-7883.
Liendo, M. A., G. E. Navarro and C. H. Sampaio (2013). "Nano and Micro ZVI in Aqueous Media: Copper Uptake and Solution Behavior." Water Air and Soil Pollution 224(5).
Lin, S. C., C. J. Liu, C. P. Chiu, S. M. Chang, S. Y. Lu and Y. J. Chen (2004). "Establishment of OC3 oral carcinoma cell line and identification of NF-kappa B activation responses to areca nut extract." Journal of Oral Pathology & Medicine 33(2): 79-86.
Lin, Y. S. and C. L. Haynes (2010). "Impacts of Mesoporous Silica Nanoparticle Size, Pore Ordering, and Pore Integrity on Hemolytic Activity." Journal of the American Chemical Society 132(13): 4834-4842.
Lin, Y. Z., D. L. Epstein and P. B. Liton (2010). "Intralysosomal Iron Induces Lysosomal Membrane Permeabilization and Cathepsin D-Mediated Cell Death in Trabecular Meshwork Cells Exposed to Oxidative Stress." Investigative Ophthalmology & Visual Science 51(12): 6483-6495.
Liu, Y. and G. V. Lowry (2006). "Effect of particle age (Fe0 content) and solution pH on NZVI reactivity: H2 evolution and TCE dechlorination." Environ Sci Technol 40(19): 6085-6090.
Ludwig, R. D., D. J. A. Smyth, D. W. Blowes, L. E. Spink, R. T. Wilkin, D. G. Jewett and C. J. Weisener (2009). "Treatment of Arsenic, Heavy Metals, and Acidity Using a Mixed ZVI-Compost PRB." Environmental Science & Technology 43(6): 1970-1976.
Luengo, A., D. Y. Gui and M. G. Vander Heiden (2017). "Targeting Metabolism for Cancer Therapy." Cell Chemical Biology 24(9): 1161-1180.
Maciejko, J. J. (2017). "Managing Cardiovascular Risk in Lysosomal Acid Lipase Deficiency (vol 17, pg 217, 2017)." American Journal of Cardiovascular Drugs 17(3): 233-233.
Malins, D. C., N. L. Polissar and S. J. Gunselman (1996). "Progression of human breast cancers to the metastatic state is linked to hydroxyl radical-induced DNA damage." Proceedings of the National Academy of Sciences of the United States of America 93(6): 2557-2563.
Manikandan, R., B. Manikandan, T. Raman, K. Arunagirinathan, N. M. Prabhu, M. Jothi Basu, M. Perumal, S. Palanisamy and A. Munusamy (2015). "Biosynthesis of silver nanoparticles using ethanolic petals extract of Rosa indica and characterization of its antibacterial, anticancer and anti-inflammatory activities." Spectrochim Acta A Mol Biomol Spectrosc 138: 120-129.
Mijatovic, T., V. Mathieu, J. F. Gaussin, N. De Neve, F. Ribaucour, E. Van Quaquebeke, P. Dumont, F. Darro and R. Kiss (2006). "Cardenolide-induced lysosomal membrane permeabilization demonstrates therapeutic benefits in experimental human non-small cell lung cancers." Neoplasia 8(5): 402-412.
Misinzo, G., P. L. Delputte and H. J. Nauwynck (2008). "Inhibition of endosome-lysosome system acidification enhances porcine circovirus 2 infection of porcine epithelial cells." Journal of Virology 82(3): 1128-1135.
Mosesson, Y., G. B. Mills and Y. Yarden (2008). "Derailed endocytosis: an emerging feature of cancer." Nat Rev Cancer 8(11): 835-850.
Mueller, N. C., J. Braun, J. Bruns, M. Cernik, P. Rissing, D. Rickerby and B. Nowack (2012). "Application of nanoscale zero valent iron (NZVI) for groundwater remediation in Europe." Environ Sci Pollut Res Int 19(2): 550-558.
Nidheesh, P. V. (2015). "Heterogeneous Fenton catalysts for the abatement of organic pollutants from aqueous solution: a review." Rsc Advances 5(51): 40552-40577.
Niu, Y. T., M. H. Yu, A. Meka, Y. Liu, J. Zhang, Y. N. Yang and C. Z. Yu (2016). "Understanding the contribution of surface roughness and hydrophobic modification of silica nanoparticles to enhanced therapeutic protein delivery." Journal of Materials Chemistry B 4(2): 212-219.
Noubactep, C., S. Care and R. Crane (2012). "Nanoscale Metallic Iron for Environmental Remediation: Prospects and Limitations." Water Air and Soil Pollution 223(3): 1363-1382.
Novack, G. D. (2009). "Ophthalmic Drug Delivery: Development and Regulatory Considerations." Clinical Pharmacology & Therapeutics 85(5): 539-543.
Oh, B. T., C. L. Just and P. J. Alvarez (2001). "Hexahydro-1,3,5-trinitro-1,3,5-triazine mineralization by zerovalent iron and mixed anaerobic cultures." Environ Sci Technol 35(21): 4341-4346.
Panzarini, E., S. Mariano, E. Carata, F. Mura, M. Rossi and L. Dini (2018). "Intracellular Transport of Silver and Gold Nanoparticles and Biological Responses: An Update." International Journal of Molecular Sciences 19(5).
Pereira, C. S., H. Ribeiro and M. F. Macedo (2017). "From Lysosomal Storage Diseases to NKT Cell Activation and Back." International Journal of Molecular Sciences 18(3).
Perera, R., S. Stoykova, B. N. Nicolay, K. N. Ross, J. Fitamant, M. Boukhali, J. Lengrand, V. Deshpande, M. K. Selig, C. R. Ferrone, J. Settleman, G. Stephanopoulos, N. J. Dyson, R. Zoncu, S. Ramaswamy, W. Haas and N. Bardeesy (2015). "Transcriptional control of autophagy-lysosome function drives pancreatic cancer metabolism." Nature 524(7565): 361-U251.
Piao, M. J., K. A. Kang, I. K. Lee, H. S. Kim, S. Kim, J. Y. Choi, J. Choi and J. W. Hyun (2011). "Silver nanoparticles induce oxidative cell damage in human liver cells through inhibition of reduced glutathione and induction of mitochondria-involved apoptosis." Toxicol Lett 201(1): 92-100.
Piao, S. and R. K. Amaravadi (2016). "Targeting the lysosome in cancer." Ann N Y Acad Sci 1371(1): 45-54.
Prijic, S., J. Scancar, R. Romih, M. Cemazar, V. B. Bregar, A. Znidarsic and G. Sersa (2010). "Increased cellular uptake of biocompatible superparamagnetic iron oxide nanoparticles into malignant cells by an external magnetic field." J Membr Biol 236(1): 167-179.
Rajendran, L., H. J. Knolker and K. Simons (2010). "Subcellular targeting strategies for drug design and delivery." Nature Reviews Drug Discovery 9(1): 29-42.
Rasmussen, J. W., E. Martinez, P. Louka and D. G. Wingettt (2010). "Zinc oxide nanoparticles for selective destruction of tumor cells and potential for drug delivery applications." Expert Opinion on Drug Delivery 7(9): 1063-1077.
Sabella, S., R. P. Carney, V. Brunetti, M. A. Malvindi, N. Al-Juffali, G. Vecchio, S. M. Janes, O. M. Bakr, R. Cingolani, F. Stellacci and P. P. Pompa (2014). "A general mechanism for intracellular toxicity of metal-containing nanoparticles." Nanoscale 6(12): 7052-7061.
Sabella, S., R. P. Carney, V. Brunetti, M. A. Malvindi, N. Al-Juffali, G. Vecchio, S. M. Janes, O. M. Bakr, R. Cingolani, F. Stellacci and P. P. Pompa (2014). "A general mechanism for intracellular toxicity of metal-containing nanoparticles." Nanoscale 6(12): 7052-7061.
Saftig, P. and J. Klumperman (2009). "Lysosome biogenesis and lysosomal membrane proteins: trafficking meets function." Nature Reviews Molecular Cell Biology 10(9): 623-635.
Saftig, P., B. Schroder and J. Blanz (2010). "Lysosomal membrane proteins: life between acid and neutral conditions." Biochem Soc Trans 38(6): 1420-1423.
Segura, Y., F. Martinez, J. A. Melero and J. L. G. Fierro (2015). "Zero valent iron (ZVI) mediated Fenton degradation of industrial wastewater: Treatment performance and characterization of final composites." Chemical Engineering Journal 269: 298-305.
Settembre, C., C. Di Malta, V. A. Polito, M. Garcia Arencibia, F. Vetrini, S. Erdin, S. U. Erdin, T. Huynh, D. Medina, P. Colella, M. Sardiello, D. C. Rubinsztein and A. Ballabio (2011). "TFEB links autophagy to lysosomal biogenesis." Science 332(6036): 1429-1433.
Settembre, C., A. Fraldi, D. L. Medina and A. Ballabio (2013). "Signals from the lysosome: a control centre for cellular clearance and energy metabolism." Nature Reviews Molecular Cell Biology 14(5): 283-296.
Settembre, C., A. Fraldi, D. L. Medina and A. Ballabio (2013). "Signals from the lysosome: a control centre for cellular clearance and energy metabolism." Nat Rev Mol Cell Biol 14(5): 283-296.
Settembre, C., R. Zoncu, D. L. Medina, F. Vetrini, S. Erdin, S. Erdin, T. Huynh, M. Ferron, G. Karsenty, M. C. Vellard, V. Facchinetti, D. M. Sabatini and A. Ballabio (2012). "A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB." EMBO J 31(5): 1095-1108.
Simizu, S., M. Takada, K. Umezawa and M. Imoto (1998). "Requirement of caspase-3(-like) protease-mediated hydrogen peroxide production for apoptosis induced by various anticancer drugs." Journal of Biological Chemistry 273(41): 26900-26907.
Singh, R. and H. S. Nalwa (2011). "Medical Applications of Nanoparticles in Biological Imaging, Cell Labeling, Antimicrobial Agents, and Anticancer Nanodrugs." Journal of Biomedical Nanotechnology 7(4): 489-503.
Sonini, Y., J. Kallio, P. Hirvikoski, H. Helin, P. Kellokumpu-Lehtinen, S. W. Kang, T. L. J. Tammela, M. Peltoniemi, P. M. Martikainen and V. L. Kinnula (2006). "Oxidative/nitrosative stress and peroxiredoxin 2 are associated with grade and prognosis of human renal carcinoma." Apmis 114(5): 329-337.
Spitz, D. R., J. E. Sim, L. A. Ridnour, S. S. Galoforo and Y. J. Lee (2000). "Glucose deprivation-induced oxidative stress in human tumor cells. A fundamental defect in metabolism?" Ann N Y Acad Sci 899: 349-362.
Sukhai, M. A., S. Prabha, R. Hurren, A. C. Rutledge, A. Y. Lee, S. Sriskanthadevan, H. Sun, X. M. Wang, M. Skrtic, A. Seneviratne, M. Cusimano, B. Jhas, M. Gronda, N. MacLean, E. E. Cho, P. A. Spagnuolo, S. Sharmeen, M. Gebbia, M. Urbanus, K. Eppert, D. Dissanayake, A. Jonet, A. Dassonville-Klimpt, X. M. Li, A. Datti, P. S. Ohashi, J. Wrana, I. Rogers, P. Sonnet, W. Y. Ellis, S. J. Corey, C. Eaves, M. D. Minden, J. C. Y. Wang, J. E. Dick, C. Nislow, G. Giaever and A. D. Schimmer (2013). "Lysosomal disruption preferentially targets acute myeloid leukemia cells and progenitors." Journal of Clinical Investigation 123(1): 315-328.
Sun, Z. L., L. Y. Yang, K. F. Chen, G. W. Chen, Y. P. Peng, J. K. Chen, G. L. Suo, J. T. Yu, W. C. Wang and C. H. Lin (2016). "Nano zerovalent iron particles induce pulmonary and cardiovascular toxicity in an in vitro human co-culture model." Nanotoxicology 10(7): 881-890.
Taccola, L., V. Raffa, C. Riggio, O. Vittorio, M. C. Iorio, R. Vanacore, A. Pietrabissa and A. Cuschieri (2011). "Zinc oxide nanoparticles as selective killers of proliferating cells." International Journal of Nanomedicine 6.
Tang, F. Q., L. L. Li and D. Chen (2012). "Mesoporous Silica Nanoparticles: Synthesis, Biocompatibility and Drug Delivery." Advanced Materials 24(12): 1504-1534.
Tassa, C., S. Y. Shaw and R. Weissleder (2011). "Dextran-coated iron oxide nanoparticles: a versatile platform for targeted molecular imaging, molecular diagnostics, and therapy." Acc Chem Res 44(10): 842-852.
Thurber, A., D. G. Wingett, J. W. Rasmussen, J. Layne, L. Johnson, D. A. Tenne, J. H. Zhang, C. B. Hanna and A. Punnoose (2012). "Improving the selective cancer killing ability of ZnO nanoparticles using Fe doping." Nanotoxicology 6(4): 440-452.
Tosco, T., M. P. Papini, C. C. Viggi and R. Sethi (2014). "Nanoscale zerovalent iron particles for groundwater remediation: a review." Journal of Cleaner Production 77: 10-21.
Trachootham, D., J. Alexandre and P. Huang (2009). "Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach?" Nat Rev Drug Discov 8(7): 579-591.
Uskokovic, V., S. Pernal and V. M. Wu (2017). "Earthicle: The Design of a Conceptually New Type of Particle." Acs Applied Materials & Interfaces 9(2): 1305-1321.
Waclawek, S., J. Nosek, L. Cadrova, V. Antos and M. Cernik (2015). "Use of Various Zero Valent Irons for Degradation of Chlorinated Ethenes and Ethanes." Ecological Chemistry and Engineering S-Chemia I Inzynieria Ekologiczna S 22(4): 577-587.
Weinberg, S. E. and N. S. Chandel (2015). "Targeting mitochondria metabolism for cancer therapy." Nature Chemical Biology 11(1): 9-15.
White, E. (2015). "The role for autophagy in cancer." J Clin Invest 125(1): 42-46.
Wilhelm, S., A. J. Tavares, Q. Dai, S. Ohta, J. Audet, H. F. Dvorak and W. C. W. Chan (2016). "Analysis of nanoparticle delivery to tumours." Nature Reviews Materials 1(5).
Wu, S. L., M. Vosatka, K. Vogel-Mikus, A. Kavcic, M. Kelemen, L. Sepec, P. Pelicon, R. Skala, A. R. V. Powter, M. Teodoro, Z. Michalkova and M. Komarek (2018). "Nano Zero-Valent Iron Mediated Metal(loid) Uptake and Translocation by Arbuscular Mycorrhizal Symbioses." Environmental Science & Technology 52(14): 7640-7651.
Wu, W., Z. Wu, T. Yu, C. Jiang and W. S. Kim (2015). "Recent progress on magnetic iron oxide nanoparticles: synthesis, surface functional strategies and biomedical applications." Sci Technol Adv Mater 16(2): 023501.
Wu, Y. N., D. H. Chen, X. Y. Shi, C. C. Lian, T. Y. Wang, C. S. Yeh, K. R. Ratinac, P. Thordarson, F. Braet and D. B. Shieh (2011). "Cancer-cell-specific cytotoxicity of non-oxidized iron elements in iron core-gold shell NPs." Nanomedicine-Nanotechnology Biology and Medicine 7(4): 420-427.
Wu, Y. N., D. B. Shieh, L. X. Yang, H. S. Sheu, R. K. Zheng, P. Thordarson, D. H. Chen and F. Braet (2018). "Characterization of Iron Core-Gold Shell Nanoparticles for Anti-Cancer Treatments: Chemical and Structural Transformations During Storage and Use." Materials 11(12).
Wu, Y. N., P. C. Wu, L. X. Yang, K. R. Ratinac, P. Thordarson, K. A. Jahn, D. H. Chen, D. B. Shieh and F. Braet (2013). "The anticancer properties of iron core-gold shell nanoparticles in colorectal cancer cells." International Journal of Nanomedicine 8: 3321-3331.
Wu, Y. N., L. X. Yang, X. Y. Shi, I. C. Li, J. M. Biazik, K. R. Ratinac, D. H. Chen, P. Thordarson, D. B. Shieh and F. Braet (2011). "The selective growth inhibition of oral cancer by iron core-gold shell nanoparticles through mitochondria-mediated autophagy." Biomaterials 32(20): 4565-4573.
Xu, C. J., Z. L. Yuan, N. Kohler, J. M. Kim, M. A. Chung and S. H. Sun (2009). "FePt Nanoparticles as an Fe Reservoir for Controlled Fe Release and Tumor Inhibition." Journal of the American Chemical Society 131(42): 15346-15351.
Xu, H. and D. Ren (2015). "Lysosomal physiology." Annu Rev Physiol 77: 57-80.
Xu, K. and P. J. Thornalley (2001). "Involvement of glutathione metabolism in the cytotoxicity of the phenethyl isothiocyanate and its cysteine conjugate to human leukaemia cells in vitro." Biochemical Pharmacology 61(2): 165-177.
Yang, C. Y. and C. L. Meng (1994). "Regulation of Pg Synthase by Egf and Pdgf in Human Oral, Breast, Stomach, and Fibrosarcoma Cancer Cell-Lines." Journal of Dental Research 73(8): 1407-1415.
Yang, L. X., Y. N. Wu, P. W. Wang, W. C. Su and D. B. Shieh (2019). "Iron Release Profile of Silica-Modified Zero-Valent Iron NPs and Their Implication in Cancer Therapy." International Journal of Molecular Sciences 20(18).
Yang, T. I., R. N. C. Brown, L. CKempel and P. Kofinas (2011). "Controlled synthesis of core-shell iron-silica nanoparticles and their magneto-dielectric properties in polymer composites." Nanotechnology 22(10).
Yang, Z. J., C. E. Chee, S. Huang and F. A. Sinicrope (2011). "The role of autophagy in cancer: therapeutic implications." Mol Cancer Ther 10(9): 1533-1541.
Yoshino, H., M. Tokumura and Y. Kawase (2014). "Simultaneous removal of nitrate, hydrogen peroxide and phosphate in semiconductor acidic wastewater by zero-valent iron." Journal of Environmental Science and Health Part a-Toxic/Hazardous Substances & Environmental Engineering 49(9): 998-1006.
Youan, B. B. C. (2008). "Impact of nanoscience and nanotechnology on controlled drug delivery." Nanomedicine 3(4): 401-406.
Zhou, W. L., E. E. Carpenter, J. Lin, A. Kumbhar, J. Sims and C. J. O'Connor (2001). "Nanostructures of gold coated iron core-shell nanoparticles and the nanobands assembled under magnetic field." European Physical Journal D 16(1-3): 289-292.
Zong, W. X. and C. B. Thompson (2006). "Necrotic death as a cell fate." Genes & Development 20(1): 1-15.