journal article·2015-10

PEGylation of superparamagnetic iron oxide nanoparticle for drug delivery applications with decreased toxicity: an in vivo study

Suma Prabhu, Srinivas Mutalik, Sharada Rai, Nayanabhirama Udupa, Bola Sadashiva Satish Rao

Journal of Nanoparticle Research· Volume 17· Issue 10
Publisher page

Abstract

Superparamagnetic iron oxide nanoparticles (SPIONs) are evolving as a mainstay across various applications in the field of Science and Technology. SPIONs have enticed attention on the grounds of their unique physicochemical properties as well as potential applications in magnetic hyperthermia, immunoassays, as a contrast agent in magnetic resonance imaging and targeted drug delivery among others. Toward this goal, we synthesized SPIONs by chemical co-precipitation and PEGylated it. PEGylated SPIONs (PS) were studied for its detailed in vivo toxicity profile, in view of further surface engineering for its clinical applications. The intravenous LD50(14) of the PS was ascertained as 508.16 ± 41.52 mg/kg b wt. Histopathology of the vital organs of the animals injected with acute toxic doses showed pathological changes in spleen, lung, liver, and kidney. Accumulation of SPION was found in the aforementioned organs as confirmed by Prussian blue staining. Further, 1/10th dose of LD50(14) of PS and the Bare SPION (BS) was used to analyze a detailed toxicity profile, including genotoxicity (micronuclei formation and chromosomal aberration assays), organ-specific toxicity (a detailed serum biochemical analysis), and also determination of oxidative stress. The results of toxicity profile indicated no significant toxicity due to systemic exposure of PS. Atomic absorption spectroscopy (AAS) analysis confirmed the accumulation of SPION majorly in lungs, liver spleen, and kidneys. The present study thus indicated an optimal dose of PS which could be used for surface modification for targeted drug delivery applications with least toxicity.
Source: openaire · Quality: candidate unverified · Source record ↗

Research context

OpenAlex topics: Nanoparticle-Based Drug Delivery · Iron oxide chemistry and applications · Nanoparticles: synthesis and applications

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

References (80)

Show source-provided references
1. Adamson I, Sienko A, Tenenbein M (1993) Pulmonary toxicity of deferoxamine in iron poisoned mice. Toxicol Appl Pharmacol 120:13–19. doi: 10.1006/taap.1993.108110.1006/taap.1993.1081 ↗
2. Al Faraj A (2013) Preferential magnetic nanoparticle uptake by bone marrow derived macrophages sub-populations: effect of surface coating on polarization, toxicity, and in vivo MRI detection. J Nanopart Res 15:1. doi: 10.1007/s11051-013-1797-910.1007/s11051-013-1797-9 ↗
3. Alarifi S, Ali D, Alkahtani S, Alhader M (2014) Iron oxide nanoparticles induce oxidative stress, DNA damage, and caspase activation in the human breast cancer cell line. Biol Trace Elem Res 159:416–424. doi: 10.1007/s12011-014-9972-010.1007/s12011-014-9972-0 ↗
4. Ankamwar B, Lai T, Huang J, Liu R, Hsiao M, Chen C, Hwu Y (2010) Biocompatibility of Fe3O4 nanoparticles evaluated by in vitro cytotoxicity assays using normal, glia and breast cancer cells. Nanotechnology 21:075102. doi: 10.1088/0957-4484/21/7/07510210.1088/0957-4484/21/7/075102 ↗
5. Archana P, Rao BN, Ballal M, Rao BS (2009) Thymol, a naturally occurring monocyclic dietary phenolic compound protects Chinese hamster lung fibroblasts from radiation-induced cytotoxicity. Mutat Res 680:70–77. doi: 10.1016/j.mrgentox.2009.09.01010.1016/j.mrgentox.2009.09.010 ↗
6. Auffan M et al (2008) Relation between the redox state of iron-based nanoparticles and their cytotoxicity toward Escherichia coli. Environ Sci Technol 42:6730–6735. doi: 10.1021/es800086f10.1021/es800086f ↗
7. Baalousha M (2009) Aggregation and disaggregation of iron oxide nanoparticles: influence of particle concentration, pH and natural organic matter. Sci Total Environ 407:2093–2101. doi: 10.1016/j.scitotenv.2008.11.02210.1016/j.scitotenv.2008.11.022 ↗
8. Balakumaran A, Pawelczyk E, Ren J, Sworder B, Chaudhry A, Sabatino M, Stroncek D, Frank JA, Robey PG (2010) Superparamagnetic iron oxide nanoparticles labeling of bone marrow stromal (mesenchymal) cells does not affect their “stemness”. PLoS ONE 5:e11462. doi: 10.1371/journal.pone.001146210.1371/journal.pone.0011462 ↗
9. Barhoumi L, Dewez D (2013) Toxicity of superparamagnetic iron oxide nanoparticles on green alga Chlorella vulgaris. Biomed Res Int 2013:647974. doi: 10.1155/2013/64797410.1155/2013/647974 ↗
10. Baroli B, Ennas MG, Loffredo F, Isola M, Pinna R, López-Quintela MA (2007) Penetration of metallic nanoparticles in human full-thickness skin. J Invest Dermatol 127:1701–1712. doi: 10.1038/sj.jid.570073310.1038/sj.jid.5700733 ↗
11. Barrera C, Herrera AP, Rinaldi C (2009) Colloidal dispersions of monodisperse magnetite nanoparticles modified with poly (ethylene glycol). J Colloid Interface Sci 329:107–113. doi: 10.1016/j.jcis.2008.09.07110.1016/j.jcis.2008.09.071 ↗
12. Bellin MF, Beigelman C, Precetti-Morel S (2000) Iron oxide-enhanced MR lymphography: initial experience. Eur J Radiol 34:257–264. doi: 10.1016/S0720-048X(00)00204-710.1016/S0720-048X(00)00204-7 ↗
13. Berry CC, Wells S, Charles S, Curtis AS (2003) Dextran and albumin derivatised iron oxide nanoparticles: influence on fibroblasts in vitro. Biomaterials 24:4551–4557. doi: 10.1016/S0142-9612(03)00237-010.1016/S0142-9612(03)00237-0 ↗
14. Bhasin G, Kauser H, Athar M (2002) Iron augments stage-I and stage-II tumor promotion in murine skin. Cancer Lett 183:113–122. doi: 10.1016/S0304-3835(02)00116-710.1016/S0304-3835(02)00116-7 ↗
15. Brown DM, Hutchison L, Donaldson K, Stone V (2007) The effects of PM10 particles and oxidative stress on macrophages and lung epithelial cells: modulating effects of calcium-signaling antagonist. Am J Physiol Lung Cell Mol Physiol 292:L1444–L1451. doi: 10.1152/ajplung.00162.200610.1152/ajplung.00162.2006 ↗
16. Brullot W, Reddy NK, Wouters J, Valev VK, Goderis B, Vermant J, Verbiest T (2012) Versatile ferrofluids based on polyethylene glycol coated iron oxide nanoparticles. J Magn Magn Mater 324:1919–1925. doi: 10.1016/j.jmmm.2012.01.03210.1016/j.jmmm.2012.01.032 ↗
17. Brunner TJ, Wick P, Manser P, Spohn P, Grass RN, Limbach LK, Bruinink A, Stark WJ (2006) In vitro cytotoxicity of oxide nanoparticles: comparison to asbestos, silica, and the effect of particle solubility. Environ Sci Technol 40:4374–4381. doi: 10.1021/es052069i10.1021/es052069i ↗
18. Bulte JW, Douglas T, Witwer B, Zhang S-C, Strable E, Lewis BK, Zywicke H, Miller B, van Gelderen P, Moskowitz BM (2001) Magnetodendrimers allow endosomal magnetic labeling and in vivo tracking of stem cells. Nat Biotechnol 19:1141–1147. doi: 10.1038/nbt1201-114110.1038/nbt1201-1141 ↗
19. Buyukhatipoglu K, Miller T, Morss Clyne A (2009) Flame synthesis and in vitro biocompatibility assessment of superparamagnetic iron oxide nanoparticles: cellular uptake, toxicity and proliferation studies. J Nanosci Nanotechnol 9:6834–6843. doi: 10.1166/jnn.2009.147710.1166/jnn.2009.1477 ↗
20. Chen BA, Jin N, Wang J, Ding J, Gao C, Cheng J, Xia G, Gao F, Zhou Y, Chen Y, Zhou G, Li X, Zhang Y, Tang M, Wang X (2010) The effect of magnetic nanoparticles of Fe3O4 on immune function in normal ICR mice. Int J Nanomed 5:593. doi: 10.2147/IJN.S1216210.2147/IJN.S12162 ↗
21. Cho WS, Cho M, Kim SR, Choi M, Lee JY, Han BS, Park SN, Yu MK, Jon S, Jeong J (2009) Pulmonary toxicity and kinetic study of Cy5. 5-conjugated superparamagnetic iron oxide nanoparticles by optical imaging. Toxicol Appl Pharmacol 239:106–115. doi: 10.1016/j.taap.2009.05.02610.1016/j.taap.2009.05.026 ↗
22. Cho WS, Duffin R, Thielbeer F, Bradley M, Megson IL, MacNee W, Poland CA, Tran CL, Donaldson K (2012) Zeta potential and solubility to toxic ions as mechanisms of lung inflammation caused by metal/metal-oxide nanoparticles. Toxicol Sci 126:469–477. doi: 10.1093/toxsci/kfs00610.1093/toxsci/kfs006 ↗
23. DeNicola GM, Karreth FA, Humpton TJ, Gopinathan A, Wei C, Frese K, Mangal D, Kenneth HY, Yeo CJ, Calhoun ES (2011) Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Nature 475:106–109. doi: 10.1038/nature1018910.1038/nature10189 ↗
24. Dick CA, Brown DM, Donaldson K, Stone V (2003) The role of free radicals in the toxic and inflammatory effects of four different ultrafine particle types. Inhal Toxicol 15:39–52. doi: 10.1080/0895837030445410.1080/08958370304454 ↗
25. Drexler KE (2006) Engines of creation 2.0 The coming era of nanotechnology, WOWIO, e-book edition Cerca con Google
26. Du B, Han S, Li H, Zhao F, Su X, Cao X, Zhang Z (2015) Multi-functional liposomes showing radiofrequency-triggered release and magnetic resonance imaging for tumor multi-mechanism therapy. Nanoscale 7:5411–5426. doi: 10.1039/c4nr04257c10.1039/C4NR04257C ↗
27. Easo SL, Mohanan PV (2015) In vitro hematological and in vivo immunotoxicity assessment of dextran stabilized iron oxide nanoparticles. Coll Surf B Biointerfaces 134:122–130. doi: 10.1016/j.colsurfb.2015.06.04610.1016/j.colsurfb.2015.06.046 ↗
28. Elias A, Tsourkas A (2009) Imaging circulating cells and lymphoid tissues with iron oxide nanoparticles. Hematol Am Soc Hematol Educ Progr 2009:720–726. doi: 10.1182/asheducation-2009.1.72010.1182/asheducation-2009.1.720 ↗
29. Ferin J, Oberdorster G, Penney DP (1992) Pulmonary retention of ultrafine and fine particles in rats. Am J Respir Cell Mol Biol 6:535–542. doi: 10.1165/ajrcmb/6.5.53510.1165/ajrcmb/6.5.535 ↗
30. Finkel T, Holbrook NJ (2000) Oxidants, oxidative stress and the biology of ageing. Nature 408:239–247. doi: 10.1038/3504168710.1038/35041687 ↗
31. Ganasoundari A, Devi PU, Rao B (1998) Enhancement of bone marrow radioprotection and reduction of WR-2721 toxicity by Ocimum sanctum. Mutat Res 397:303–312. doi: 10.1016/S0027-5107(97)00230-310.1016/S0027-5107(97)00230-3 ↗
32. Gupta AK, Gupta M (2005) Synthesis and surface engineering of iron oxide nanoparticles for biomedical applications. Biomaterials 26:3995–4021. doi: 10.1016/j.biomaterials.2004.10.01210.1016/j.biomaterials.2004.10.012 ↗
33. Hamley IW (2003) Nanotechnology with soft materials Angew. Chem Int Ed 42:1692–1712. doi: 10.1002/anie.20020054610.1002/anie.200200546 ↗
34. Huang J, Bu L, Xie J, Chen K, Cheng Z, Li X, Chen X (2010) Effects of nanoparticle size on cellular uptake and liver MRI with polyvinylpyrrolidone-coated iron oxide nanoparticles. ACS Nano 4:7151–7160. doi: 10.1021/nn101643u10.1021/nn101643u ↗
35. Hussain S, Hess K, Gearhart J, Geiss K, Schlager J (2005) In vitro toxicity of nanoparticles in BRL 3A rat liver cells. Toxicol In Vitro 19:975–983. doi: 10.1016/j.tiv.2005.06.03410.1016/j.tiv.2005.06.034 ↗
36. Jain TK, Reddy MK, Morales MA, Leslie-Pelecky DL, Labhasetwar V (2008) Biodistribution, clearance, and biocompatibility of iron oxide magnetic nanoparticles in rats. Mol Pharm 5:316–327. doi: 10.1021/mp700128510.1021/mp7001285 ↗
37. Jeng HA, Swanson J (2006) Toxicity of metal oxide nanoparticles in mammalian cells. J Environ Sci Health A Tox Hazard Subst Environ Eng 41:2699–2711. doi: 10.1080/1093452060096617710.1080/10934520600966177 ↗
38. Jokerst JV, Lobovkina T, Zare RN, Gambhir SS (2011) Nanoparticle PEGylation for imaging and therapy. Nanomedicine (Lond) 6:715–728. doi: 10.2217/nnm.11.1910.2217/nnm.11.19 ↗
39. Karlsson HL, Holgersson Å, Möller L (2008) Mechanisms related to the genotoxicity of particles in the subway and from other sources. Chem Res Toxicol 21:726–731. doi: 10.1021/tx700356810.1021/tx7003568 ↗
40. Kedziorek DA, Muja N, Walczak P, Ruiz-Cabello J, Gilad AA, Jie CC, Bulte JW (2010) Gene expression profiling reveals early cellular responses to intracellular magnetic labeling with superparamagnetic iron oxide nanoparticles. Magn Reson Med 63:1031–1043. doi: 10.1002/mrm.2229010.1002/mrm.22290 ↗
41. Kim JS, Yoon TJ, Yu KN, Kim BG, Park SJ, Kim HW, Lee KH, Park SB, Lee JK, Cho MH (2006) Toxicity and tissue distribution of magnetic nanoparticles in mice. Toxicol Sci 89:338–347. doi: 10.1093/toxsci/kfj02710.1093/toxsci/kfj027 ↗
42. Kumar R, Inbaraj BS, Chen B (2010) Surface modification of superparamagnetic iron nanoparticles with calcium salt of poly (γ-glutamic acid) as coating material. Mater Res Bull 45:1603–1607. doi: 10.1016/j.materresbull.2010.07.01710.1016/j.materresbull.2010.07.017 ↗
43. Kumari M, Rajak S, Singh SP, Kumari SI, Kumar PU, Murty US, Mahboob M, Grover P, Rahman MF (2012) Repeated oral dose toxicity of iron oxide nanoparticles: biochemical and histopathological alterations in different tissues of rats. J Nanosci Nanotechnol 12:2149–2159. doi: 10.1166/jnn.2012.579610.1166/jnn.2012.5796 ↗
44. Kumari M, Rajak S, Singh SP, Murty US, Mahboob M, Grover P, Rahman MF (2013) Biochemical alterations induced by acute oral doses of iron oxide nanoparticles in Wistar rats. Drug Chem Toxicol 36:296–305. doi: 10.3109/01480545.2012.72098810.3109/01480545.2012.720988 ↗
45. Kwon JT, Hwang SK, Jin H, Kim DS, Minai Tehrani A, Yoon HJ, Choi M, Yoon TJ, Han DY, Kang YW (2008) Body distribution of inhaled fluorescent magnetic nanoparticles in the mice. J Occup Health 50:1–6. doi: 10.1539/joh.50.110.1539/joh.50.1 ↗
46. Larsen EK, Nielsen T, Wittenborn T, Birkedal H, Vorup Jensen T, Jakobsen MH, Ostergaard L, Horsman MR, Besenbacher F, Howard KA, Kjems J (2009) Size-dependent accumulation of PEGylated silane-coated magnetic iron oxide nanoparticles in murine tumors. ACS Nano 3:1947–1951. doi: 10.1021/nn900330m10.1021/nn900330m ↗
47. Leonard A, Lauwerys R (1980) Carcinogenicity and mutagenicity of chromium. Mutat Res 76:227–239. doi: 10.1016/0165-1110(80)90018-410.1016/0165-1110(80)90018-4 ↗
48. Lewinski N, Graczyk H, Riediker M (2013) Human inhalation exposure to iron oxide particles. Bio Nano Mat 14:5–23. doi: 10.1515/bnm-2013-0007
49. Limbach LK, Li Y, Grass RN, Brunner TJ, Hintermann MA, Muller M, Gunther D, Stark WJ (2005) Oxide nanoparticle uptake in human lung fibroblasts: effects of particle size, agglomeration, and diffusion at low concentrations. Environ Sci Technol 39:9370–9376. doi: 10.1021/es051043o10.1021/es051043o ↗
50. Limbach LK, Wick P, Manser P, Grass RN, Bruinink A, Stark WJ (2007) Exposure of engineered nanoparticles to human lung epithelial cells: influence of chemical composition and catalytic activity on oxidative stress. Environ Sci Technol 41:4158–4163. doi: 10.1021/es062629t10.1021/es062629t ↗
51. Luo C, Li Y, Yang L, Wang X, Long J, Liu J (2014) Superparamagnetic iron oxide nanoparticles exacerbate the risks of reactive oxygen species-mediated external stresses. Arch Toxicol 89:357–369. doi: 10.1007/s00204-014-1267-x10.1007/s00204-014-1267-x ↗
52. Mahmoudi M, Laurent S, Shokrgozar MA, Hosseinkhani M (2011a) Toxicity evaluations of superparamagnetic iron oxide nanoparticles: cell “vision” versus physicochemical properties of nanoparticles. ACS Nano 5:7263–7276. doi: 10.1021/nn202108810.1021/nn2021088 ↗
53. Mahmoudi M, Sant S, Wang B, Laurent S, Sen T (2011b) Superparamagnetic iron oxide nanoparticles (SPIONs): development, surface modification and applications in chemotherapy. Adv Drug Deliv Rev 63:24–46. doi: 10.1016/j.addr.2010.05.00610.1016/j.addr.2010.05.006 ↗
54. Mahmoudi M, Simchi A, Imani M, Milani AS, Stroeve P (2009) An in vitro study of bare and poly (ethylene glycol)-co-fumarate-coated superparamagnetic iron oxide nanoparticles: a new toxicity identification procedure. Nanotechnology 20:225104. doi: 10.1088/0957-4484/20/22/22510410.1088/0957-4484/20/22/225104 ↗
55. Mesárošová M, Kozics K, Babelova A, Regendova E, Pastorek M, Vnukova D, Buliakova B, Razga F, Gabelova A (2014) The role of reactive oxygen species in the genotoxicity of surface-modified magnetite nanoparticles. Toxicol Lett 226:303–313. doi: 10.1016/j.toxlet.2014.02.02510.1016/j.toxlet.2014.02.025 ↗
56. Moller P, Jacobsen NR, Folkmann JK, Danielsen PH, Mikkelsen L, Hemmingsen JG, Vesterdal LK, Forchhammer L, Wallin H, Loft S (2010) Role of oxidative damage in toxicity of particulates. Free Radic Res 44:1–46. doi: 10.3109/1071576090330069110.3109/10715760903300691 ↗
57. Nance EA, Woodworth GF, Sailor KA, Shih TY, Xu Q, Swaminathan G, Xiang D, Eberhart C, Hanes J (2012) A dense poly(Ethylene Glycol) coating improves penetration of large polymeric nanoparticles within brain tissue. Sci Transl Med 4:149ra119. doi: 10.1126/scitranslmed.300359410.1126/scitranslmed.3003594 ↗
58. Nel A, Xia T, Madler L, Li N (2006) Toxic potential of materials at the nanolevel. Science 311:622–627. doi: 10.1126/science.111439710.1126/science.1114397 ↗
59. Owens DE III, Peppas NA (2006) Opsonization, biodistribution and pharmacokinetics of polymeric nanoparticles. Int J Pharm 307:93–102. doi: 10.1016/j.ijpharm.2005.10.01010.1016/j.ijpharm.2005.10.010 ↗
60. Park S, Lim J, Kim J, Yun H, Kim C (2006) Toxicity estimation of magnetic fluids in a biological test. J Magn Magn Mater 304:e406–e408. doi: 10.1016/j.jmmm.2006.01.20510.1016/j.jmmm.2006.01.205 ↗
61. Park Y, Whitaker RD, Nap RJ, Paulsen JL, Mathiyazhagan V, Doerrer LH, Song YQ, Hürlimann MD, Szleifer I, Wong JY (2012) Stability of superparamagnetic iron oxide nanoparticles at different pH values: experimental and theoretical analysis. Langmuir 28:6246–6255. doi: 10.1021/la204628c10.1021/la204628c ↗
62. Puntarulo S (2005) Iron, oxidative stress and human health. Mol Aspects Med 26:299–312. doi: 10.1016/j.mam.2005.07.00110.1016/j.mam.2005.07.001 ↗
63. Qian L, Meng T, Ming M, Ning G (2005) Study on cytotoxicity and oxidative effects of different sizes of hematite (Fe2O3) nanoparticles on CHL cell in vitro. China J Mod Med 13:001
64. Randhawa MA (2009) Calculation of LD50 values from the method of Miller and Tainter, 1944. J Ayub Med Coll Abbottabad 21:184–185
65. Rao BN, Rao BS, Aithal BK, Kumar MS (2009) Radiomodifying and anticlastogenic effect of Zingerone on Swiss albino mice exposed to whole body gamma radiation. Mutat Res 677:33–41. doi: 10.1016/j.mrgentox.2009.05.00410.1016/j.mrgentox.2009.05.004 ↗
66. Reichard JF, Motz GT, Puga A (2007) Heme oxygenase-1 induction by NRF2 requires inactivation of the transcriptional repressor BACH1. Nucl Acids Res 35:7074–7086. doi: 10.1093/nar/gkm63810.1093/nar/gkm638 ↗
67. Schwegmann H, Feitz AJ, Frimmel FH (2010) Influence of the zeta potential on the sorption and toxicity of iron oxide nanoparticles on S. cerevisiae and E. coli. J Colloid Interface Sci 347:43–48. doi: 10.1016/j.jcis.2010.02.02810.1016/j.jcis.2010.02.028 ↗
68. Singh N (2009) Conference scene-nanotoxicology: health and environmental impacts. Nanomedicine 4:385–390. doi: 10.2217/nnm.09.2010.2217/nnm.09.20 ↗
69. Singh N, Jenkins GJ, Asadi R, Doak SH (2010) Potential toxicity of superparamagnetic iron oxide nanoparticles (SPION). Nano Rev 1:5358. doi: 10.3402/nano.v1i0.535810.3402/nano.v1i0.5358 ↗
70. Smith MT (1996) The mechanism of benzene-induced leukemia: a hypothesis and speculations on the causes of leukemia. Environ Health Perspect 6:1219–122510.1289/ehp.961041219 ↗
71. Soenen SJ, De Cuyper M (2010) Assessing iron oxide nanoparticle toxicity in vitro: current status and future prospects. Nanomedicine 5:1261–1275. doi: 10.2217/nnm.10.10610.2217/nnm.10.106 ↗
72. Stumm W, Morgan JJ (1996) Aquatic chemistry: chemical equilibria and rates in natural waters. Wiley interscience, New York
73. Thomas DJ, Styblo M, Lin S (2001) The cellular metabolism and systemic toxicity of arsenic. Toxicol Appl Pharmacol 176:127–144. doi: 10.1006/taap.2001.925810.1006/taap.2001.9258 ↗
74. Unfried K, Albrecht C, Klotz LO, Von Mikecz A, Grether-Beck S, Schins RPF (2007) Cellular responses to nanoparticles: target structures and mechanisms. Nanotoxicology 1:52–71. doi: 10.1080/0022293070131493210.1080/00222930701314932 ↗
75. Wahajuddin SA (2012) Superparamagnetic iron oxide nanoparticles: magnetic nanoplatforms as drug carriers. Int J Nanomed 7:3445. doi: 10.2147/IJN.S3032010.2147/IJN.S30320 ↗
76. Wang L, Wang L, Ding W, Zhang F (2010) Acute toxicity of ferric oxide and zinc oxide nanoparticles in rats. J Nanosci Nanotechnol 10:8617–8624. doi: 10.1166/jnn.2010.248310.1166/jnn.2010.2483 ↗
77. Xie J, Liu G, Eden HS, Ai H, Chen X (2011) Surface-engineered magnetic nanoparticle platforms for cancer imaging and therapy. Acc Chem Res 44:883–892. doi: 10.1021/ar200044b10.1021/ar200044b ↗
78. Yang L, Kuang H, Zhang W, Aguilar ZP, Xiong Y, Lai W, Xu H, Wei H (2015) Size dependent biodistribution and toxicokinetics of iron oxide magnetic nanoparticles in mice. Nanoscale 7:625–636. doi: 10.1039/C4NR05061D10.1039/C4NR05061D ↗
79. Zhao S, Lin X, Zhang L, Sun L, Li J, Yang W, Sun Z (2012) The in vivo investigation of Fe3O4-nanoparticles acute toxicity in mice. BME 24:229–235. doi: 10.4015/S1016237212500056
80. Zhu MT, Feng WY, Wang B, Wang TC, Gu YQ, Wang M, Wang Y, Ouyang H, Zhao YL, Chai ZF (2008) Comparative study of pulmonary responses to nano-and submicron-sized ferric oxide in rats. Toxicology 247:102–111. doi: 10.1016/j.tox.2008.02.01110.1016/j.tox.2008.02.011 ↗