Natarajan et al. BMC Mat (2019) 1:2 https://doi.org/10.1186/s42833-019-0002-6 BMC Materials REVIEW Open Access Multifunctional magnetic iron oxide nanoparticles: diverse synthetic approaches, surface modifcations, cytotoxicity towards biomedical and industrial applications Subramanian Natarajan1, Kannan Harini2, Gnana Prakash Gajula3, Bruno Sarmento4,5,6,7* , Maria Teresa Neves‑Petersen8 and Viruthachalam Thiagarajan1* Abstract Magnetic iron oxide nanoparticles (MIONPs) play a major role in the emerging felds of nanotechnology to facilitate rapid advancements in biomedical and industrial platforms. The superparamagnetic properties of MIONPs and their environment friendly synthetic methods with well‑defned particle size have become indispensable to obtain their full potential in a variety of applications ranging from cellular to diverse areas of biomedical science. Thus, the broad‑ ened scope and need for MIONPs in their demanding felds of applications required to be highlighted for a com‑ prehensive understanding of their state‑of‑the‑art. Many synthetic methods, however, do not entirely abolish their undesired cytotoxic efects caused by free radical production and high iron dosage. In addition, the agglomeration of MIONPs has also been a major problem. To alleviate these issues, suitable surface modifcation strategies adaptive to MIONPs has been suggested not only for the efective cytotoxicity control but also to minimize their agglomeration. The surface modifcation using inorganic and organic polymeric materials would represent an efcient strategy to utilize the diagnostic and therapeutic potentials of MIONPs in various human diseases including cancer. This review article elaborates the structural and magnetic properties of MIONPs, specifcally magnetite, maghemite and hematite, followed by the important synthetic methods that can be exploited for biomedical approaches. The in vivo cytotoxic efects and the possible surface modifcations employed to eliminate the cytotoxicity thereby enhancing the nano‑ particle efcacy are also critically discussed. The roles and applications of surface modifed MIONPs in medical and industrial platforms have been described for the benefts of global well‑being. Keywords: Magnetic iron oxide nanoparticles (MIONPs), Synthetic methods, Cytotoxicity, Surface modifcation, Applications Introduction and distinct electrical, optical, magnetic and chemical Te specifc diverse applications of nanoparticles arise properties as against their bulk materials [1]. Nanoma- from the physical characteristics of the nanomaterials terials are categorized as ‘closely packed materials’ and they are comprised of. Nanomaterials often reveal novel ‘nanodispersions’ which include ‘‘nanostructured’’ mate- rials, i.e., an isotropic material with a macroscopic com- position consisting of compact nanometre-sized units *Correspondence: [email protected]; [email protected]; such as the fundamental replicating structural and func- [email protected] 1 Photonics and Biophotonics Lab, School of Chemistry, Bharathidasan tional elements [2]. Nanoparticles are pertained to make University, Tiruchirappalli 620 024, India revolutionary technological changes in escalating the 4 INEB‑Instituto de Engenharia Biomédica, University of Porto, Rua Alfredo standards and quality of human health with transforma- Allen 208, 4200‑135 Porto, Portugal Full list of author information is available at the end of the article tive and innovative diagnostic, therapeutic and even © The Author(s) 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat iveco mmons .org/licen ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Natarajan et al. BMC Mat (2019) 1:2 Page 2 of 22 theranostic tools (that combine the diagnostic and thera- MIONPs can be directed in the presence of an external peutic approaches in a single agent) [3]. magnetic feld gradient, since it obeys Coulomb’s law Magnetic nanoparticles (MNPs) can be exploited for for magnetism. To highlight the industrial demands of desired applications under the manipulation of an exter- MIONPs, one needs to understand the exposure of dyes nal magnetic feld. It can be synthesized with a cost efec- and heavy metals in drinking water that causes undesir- tive and wide spread material like iron as in the case of able toxicity to living beings. In recent years, a great deal magnetic iron oxide nanoparticles (MIONPs) which is of interest has been developed in using MIONPs for the least toxic and biodegradable [4–10]. Nanomaterials con- efective removal of dyes and heavy metals during waste- taining iron are derived from iron nanoalloys, zero valent water treatment [19]. iron and oxides like ferrites, etc. Iron naturally exists in the environment as Fe(II) and Fe(III) oxides. Iron oxides General structural properties of iron oxides refer to oxides, hydroxides and oxy-hydroxides contains Tere are eight diferent iron oxides that are well known 2− − both Fe(II)/Fe(III) cations and O /OH anions. Sixteen in nature [20], among them magnetite (Fe 3O4), magh- pure phases of iron oxides are known till date. Tese emite (γ-Fe2O3) and hematite (α-Fe2O3) shows the unique includes Fe(OH)2, Fe(OH)3, Fe3O4, Fe5HO8.4H2O, FeO, magnetic properties and they have diferent polymorphic four polymorphs of Fe 2O3 and fve of FeOOH [11, 12]. forms and undergo temperature induced phase transi- Characteristics of these oxide compounds are inclusive tion. Magnetite and maghemite are ideal materials for of divalent and trivalent states of the iron, relatively low industrial and biomedical applications. Both have reus- solubility and their brilliant colours. Among the iron able advantage over other iron oxides due to their unique oxides, Fe3O4 and γ-Fe2O3 have received wide attention magnetic, catalytic and biochemical properties. Te and acceptance due to their tunable size-dependent mag- physical properties of Fe3O4, γ-Fe2O3 and α-Fe2O3 are netic properties [13, 14]. presented in Table 1 [20–22]. During the last decade, researchers have focused their priority towards developing efcient methods for the Magnetite synthesis of MIONPs to address their growing demands Fe3O4 is derived from various sources such as black iron with desired physical and chemical properties. Tis oxide, magnetic iron ore, loadstone, ferrous ferrite and clearly refects the increasing need for various synthetic Hercules stone. Fe3O4 has face centered cubic spinel approaches to obtain well-crystallized and well-defned structure with both divalent and trivalent iron in it. All of MIONPs [15, 16]. After synthesis, MIONPs need appro- the Fe2+ ions reside in half of the octahedral sites whereas priate surface modifcations to make them more com- the Fe3+ ions are divided evenly across the remaining patible for their respective applications with suitable available octahedral and the tetrahedral sites [20, 21]. It molecular conjugation and functionalization methods reveals strong magnetism when compared to other tran- [17]. Terefore, surface modifcation becomes a critical sition metal oxides. Te saturation magnetization value post-synthetic step for preparing compatible and stable for bulk material is 92 emu/g. It ofers a high surface area MIONPs. A schematic representation that summarizes for adsorption and immobilization of molecules or drugs the development of MIONPs is presented in Fig. 1. for our interest. It can be controlled and easily separated At present, MIONPs are widely used in biomedical by a magnetic feld and further applicable for subsequent applications such as magnetic bio-separation and detec- reuse. tion of biological entities (for example cells, proteins, nucleic acids, enzymes, bacteria, virus, etc.). Further Maghemite MIONPs are implicated in clinical diagnosis like mag- γ-Fe2O3 is present in soils as a weathering product of netic resonance imaging and therapy such as targeted Fe3O4. γ-Fe2O3 has a cubic spinel crystal structure with drug delivery, magnetic fuid hyperthermia, and biologi- each unit contains 32 O2− and 21½ Fe3+ ions with 2½ cal labels for anticancer therapy, catalysis, wastewater vacancies. Oxygen anions lead to a cubic close-packed treatment and oil recovery. Te main reasons for the spe- arrangement whereas ferric ions are spread over tetra- cifc choice of these nanoparticles in such applications are hedral and octahedral sites [21, 23]. Since, the atomic due to the controllable size ranging from few nanometers radii of Fe3+ ion is smaller than the Fe2+ ion, the unit cell to tens of nanometers thereby providing the dimensions parameter of γ-Fe2O3 is smaller than Fe 3O4. It also shows that are either comparable or closer to those of a protein strong magnetism with the saturation magnetization (5–50 nm), a virus (20–450 nm), or even a gene (10– value of 78 emu/g for the bulk material. 100 nm long and 2 nm wide). So that it could efciently get into the close vicinity of a biological entity as well as the therapeutic target of interest [18]. In addition to that, Natarajan et al. BMC Mat (2019) 1:2 Page 3 of 22 Fig. 1 A schematic representation of the development of MIONPs Hematite Magnetic