FeNi nanotubes: perspective tool for targeted delivery
Egor Kaniukov, Alena Shumskaya, Dzmitry Yakimchuk, Artem Kozlovskiy, Ilya Korolkov, Milana Ibragimova, Maxim Zdorovets, et al. Applied Nanoscience ISSN 2190-5509 Appl Nanosci DOI 10.1007/s13204-018-0762-4
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Author's personal copy Applied Nanoscience https://doi.org/10.1007/s13204-018-0762-4
ORIGINAL ARTICLE
FeNi nanotubes: perspective tool for targeted delivery Egor Kaniukov1 · Alena Shumskaya1 · Dzmitry Yakimchuk1 · Artem Kozlovskiy2 · Ilya Korolkov2 · Milana Ibragimova2 · Maxim Zdorovets2,4,5 · Kairat Kadyrzhanov2,3 · Vyacheslav Rusakov6 · Maxim Fadeev6 · Eugenia Lobko7 · Кristina Saunina8 · Larisa Nikolaevich8 Received: 30 December 2017 / Accepted: 1 April 2018 © Springer-Verlag GmbH Germany, part of Springer Nature 2018
Abstract Targeted delivery of drugs and proteins by magnetic field is a promising method to treat cancer that reduces undesired systemic toxicity of drugs. In this method, the therapeutic agent is attached through links to functional groups with magnetic nanostructure and injected into the blood to be transported to the problem area. To provide a local effect of drug treatment, nanostructures are concentrated and fixed in the selected area by the external magnetic field (magnet). After the exposure, carriers are removed from the circulatory system by magnetic field. In this study, F e20Ni80 nanotubes are considered as carriers for targeted delivery of drugs and proteins. A simple synthesis method is proposed to form these structures by electrodeposition in PET template pores, and structural and magnetic properties are studied in detail. Nanotubes have polycrystalline walls providing mechanical strength of carriers and magnetic anisotropy that allow controlling the nanostructure movement under the exposure of by magnetic field. Moreover, potential advantages of magnetic nanotubes are discussed in comparison with other carrier types. Most sufficient of them is predictable behavior in magnetic field due to the absence of magnetic core, low specific density that allows floating in biological media, and large specific surface area providing the attachment of a larger number of payloads for the targeted delivery. A method of coating nanotube surfaces with PMMA is proposed to exclude possible negative impact of the carrier material and to form functional bonds for the payload connection. Cytotoxicity studies of coated and uncoated nanotubes are carried out to understand their influence on the biological media. Keywords Magnetic nanostructures · FeNi nanotubes · Targeted delivery · Functionalization of nanostructures · Cytotoxicity
Introduction * Alena Shumskaya
[email protected] 1
Cryogenic Research Division, Scientific-Practical Materials Research Centre NAS of Belarus, Minsk, Belarus
2
The Astana Branch of the Institute of Nuclear Physics of Republic of Kazakhstan, Astana, Kazakhstan
3
L.N. Gumilyov Eurasian National University, Astana, Kazakhstan
4
Ural Federal University named after the First President of Russia B.N. Yeltsin, Yekaterinburg, Russia
5
National Research Nuclear University «MEPhI», Moscow, Russia
6
M.V. Lomonosov Moscow State University, Moscow, Russia
7
Institute of Macromolecular Chemistry of the National Academy of Sciences of Ukraine, Kiev, Ukraine
8
Cell Technology Laboratory, Institute of Physiology National Academy of Sciences of Belarus, Minsk, Belarus
In recent decade, nanomedicine is an actively developing direction, including methods of prevention, diagnosis, and treatment of wide range of diseases using different types of nanostructures (NSs), for example, nanoparticles (NPs) (Yen et al. 2013; Karimi et al. 2013), nanowires (NWs) (Salem et al. 2003; Safi et al. 2011), or nanotubes (NTs) (Eisenstein 2005; Son et al. 2005). Control of shape, sizes, and chemical composition of NSs allows setting their physical properties at the stage of synthesis that opens new opportunities for bioapplication (Yen et al. 2013; Salem et al. 2003; Safi et al. 2011; Eisenstein 2005; Son et al. 2005; Dave and Gao 2009; Zhang et al. 2012). Noteworthy, possibilities of NSs’ application are the targeted delivery of payloads (drugs or proteins) by magnetic field. Drug or protein is associated to the magnetic NS by functional groups, injected to circulatory system and transported towards the problem area by
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magnetic field. Perspectives of this method were shown in modelling studies (Alexiou et al. 2000; Goodwin et al. 1999) and tests on animals (Hirota et al. 2009; Yoshida et al. 2007), but results of clinical tests have not been reported yet. In most cases, spherical magnetic NPs are considered as carriers of drugs and proteins (Dave and Gao 2009; Tartaj et al. 2003). However, the small magnetic moment of these particles makes it difficult to focus magnetic field on them. This problem does not allow to make a sufficient force for the resistance of the blood flow. NWs and NTs with their elongated form and anisotropy of magnetic properties overcome typical limitations for NPs (Zhang et al. 2012; Hillebrenner et al. 2006; Prina-Mello et al. 2006; Torati et al. 2015; Pondman et al. 2015; Fung et al. 2008). In comparison with NWs and NTs, some potential advantages have been discovered revealed for the NTs, such as the absence of magnetic core. This allows creating NSs with uniform magnetic field. A lower specific density enables them to float swim in liquids (including the biological ones). The large specific surface area of NTs facilitates carriage of more cargo by more functional groups to the targeted delivery. One of the most promising materials to create magnetic NSs is iron and nickel alloy due to its higher saturation magnetization compared with the value for pure ferromagnetic metals as Co, Ni, and Fe (Kalska-Szostko et al. 2015). Low coercivity of FeNi alloy (permalloy as well) prevents agglomeration of NSs. At present, the properties of FeNi NWs have been well studied (Kalska-Szostko et al. 2015; Zhang et al. 2013; Yang et al. 2016; Kashi et al. 2013; Sellmyer et al. 2001), but special aspect features of NTs have not been investigated enough. Methods of NTs’ synthesis, which have been suggested just in limited a few works (Hua et al. 2006), lead to the production of fragile NSs (the wall thickness around dozen nm and walls of NTs consist of individual granules Xue et al. 2005; Zhou et al. 2007). This fact limits the possibility of NTs’ application applying of the NTs. Development of reliable synthesis method of FeNi NTs with crystalline wall structure provides an opportunity to obtain NSs, which would become perfect tool for bioapplication. Use of FeNi NTs in biological media is impossible without understanding the NTs’ effect on living cells. For example, on the one hand, the presence of Ni in the alloy can induce death of tumor cells (Ma et al. 2014), and on the other hand, it is toxic for healthy cells (Kasprzak 2003). In general, evaluation of NTs’ cytotoxicity is a key research setting the limits of their applicability in biomedicine. It should be noted that it is essential to expand that the field of applying magnetic NTs is possible by covering them with a layer of a biologically neutral substance, for example, with a polymer (PMMA, PEG, etc.), silane, gold, etc. (Tran et al. 2012; Kalska-Szostko et al. 2013; Gao et al. 2010; Pinheiro et al. 2013; Silvestrini et al. 2013; Kozlovskiy et al. 2017). To a large extent, the choice of coverage mostly depends on
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the further use of NSs and is necessitated of the presence of specific functional groups on the surface, which useful load (proteins or drugs) will be joined to. Taking into account that producing of NTs with crystal structure of walls, which would guarantee their mechanical strength, allows one to design a perspective tool for drugs and proteins delivery, in this work, we suggest and propose a simple technique of FeNi NTs’ formation by template synthesis via electrochemical deposition in pores of ion-track polymer membranes. Based on NTs’ morphology and magnetic properties analysis, we show the advantages of these structures for bioapplications. Moreover, we consider aspects of NTs’ applications as targeted delivery carriers through cytotoxicity investigation of NTs coated and uncoated with PMMA FeNi.
Results and discussion Structural features The growth features of magnetic NTs in PET template pores, as well as the dependence of their structural parameters on the electrodeposition regimes, are considered in detail in (Kozlovskiy et al. 2015, 2016, 2017; Shumskaya et al. 2017). The SEM image obtained after removal NSs from PET (Fig. 1a, b) shows that the NSs have the hollow tubes shape. Analysis of the SEM images allows determining the length of NTs and their outer diameters. Their length corresponds to the thickness (12 µm) and their diameters—to the ones of templates pores (400 nm). Due to the insufficient resolution of SEM and small dimension of FeNi NTs’ the inner NTs’ diameter d was estimated by gas permeability method, described in detail in (Kaniukov et al. 2016), and established as 160 ± 5 nm along the whole length of NTs; consequently, the NTs’ wall thickness is 120 ± 5 nm. Based on the results of EDS spectra analysis, the atomic metal ratio was determined as 20% Fe and 80% Ni. Analysis of TEM images (Fig. 1c, d) allows evaluating NTs’ geometric dimensions, and also indicates the compacted structure of the walls. Analysis shows that along the entire length (Fig. 1c) FeNi NTs’ external diameters D are ~ 400 nm, with minor deviations (within 5–8%) from the mean value. Considering the fact that pores in PET film are rough (Toimil-Molares 2012), the NTs have uneven surface. Taking into account that the obtained NSs have a hollow shape, it provides almost two times more surface area and almost 1.7 times lower specific density than NWs with the same size. In normal orientation, NTs’ dimensions allow passing not only through small vessels and veins (~ 500–700 μm), but even through capillaries (~ 8–10 μm).
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Fig. 1 Analysis of the morphological and structural features. SEM images of FeNi NSs after PET dissolution: NTs array (a) and individual NT with extended fragment (b). TEM images (c, d) with SAED (inset to d). X-ray diffraction spectra of NTs array inside of PET template (e)
The crystal structure of FeNi NTs was studied on the basis of the analysis of SAED for individual NTs (insert in Fig. 1d) and the X-ray diffraction spectra (Fig. 1e) of NTs’ arrays into PET template. NTs have preferred direction of
growth (111), which is also confirmed by the large ratio of the peaks Ni (111) and Fe (110) on X-ray diffraction spectra. The XRD pattern recorded at diffraction angles 2θ
