This is the submitted version of the following article: Roca A.G., Gutiérrez L., Gavilán H., Fortes Brollo M.E., Veintemillas-Verdaguer S., Morales M.D.P.. Design strategies for shape-controlled magnetic iron oxide nanoparticles. Advanced Drug Delivery Reviews, (2019). 138. : 68 - . 10.1016/j.addr.2018.12.008, which has been published in final form at https://dx.doi.org/10.1016/j.addr.2018.12.008 © https://dx.doi.org/10.1016/j.addr.2018.12.008. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/ Design Strategies for Shape-Controlled Magnetic Iron Oxide Nanoparticles Alejandro G. Rocaa,b,*, Lucía Gutiérreza,c,*, Helena Gavilána, María Eugênia Fortes Brolloa, Sabino Veintemillas-Verdaguera, María del Puerto Moralesa a, Instituto de Ciencia de Materiales de Madrid, Consejo Superior de Investigaciones Científicas, Cantoblanco, E-28049 Madrid, Spain b Catalan Institute of Nanoscience and Nanotechnology (ICN2), CSIC and BIST, Campus UAB, Bellaterra, E-08193 Barcelona, Spain cDept. Química Analítica, Instituto de Nanociencia de Aragón, Universidad de Zaragoza and CIBER-BBN, E-50018 Zaragoza, Spain Corresponding author: E-mail: [email protected]; [email protected] Keywords: Magnetic nanoparticles; anisometry; shape anisotropy; nanocubes; elongated nanoparticles; disks; hollow nanoparticles; nanocitotoxicity; biomedical applications Abstract: Ferrimagnetic iron oxide nanoparticles (magnetite or maghemite) have been the subject of an intense research since ancient times, not only for fundamental research but also for their potentiality in a widespread number of practical applications. Most of these studies were focused on nanoparticles with spherical morphology but recently there is an emerging interest on anisometric nanoparticles. This review is focused on the synthesis routes for the production of uniform anisometric magnetite/maghemite nanoparticles with different morphologies like cubes, rods, disks, flowers and many others, such as hollow spheres, worms, stars or tetrapods. We analyse key parameters governing the production of these nanoparticles and, in particular, the role of the ligands in the final nanoparticle morphology. The main structural and magnetic features as well as the nanotoxicity as a function of the nanoparticle morphology are also described. Finally, the impact of 1 each morphology on the different biomedical applications (hyperthermia, magnetic resonance imaging and drug delivery) are analysed in detail but other applications such as spintronics, magnetic recording media, microwave absorption or environmental remediation are also discussed. We would like to dedicate this work to Professor Carlos J. Serna, Instituto de Ciencia de Materiales de Madrid, ICMM/CSIC, for his outstanding contribution in the field of monodispersed colloids and iron oxide nanoparticles. We would like to express our gratitude for all these years of support and inspiration on the occasion of his retirement. Contents 1. Introduction ................................................................................................................................................ 3 2. Synthesis of anisometric magnetic nanoparticles ....................................................................................... 5 2.1. Cubic-shaped nanoparticles ................................................................................................................ 7 2.2. Elongated nanoparticles .................................................................................................................... 12 2.3. Disk-shaped nanoparticles ................................................................................................................ 16 2.4. Flower-like nanoparticles ................................................................................................................. 18 2.5. Other shapes ...................................................................................................................................... 20 3. Ligands ..................................................................................................................................................... 25 3.1. Tips for cubic-shaped nanoparticles ................................................................................................. 28 3.2. Tips for elongated nanoparticles ....................................................................................................... 29 3.3. Tips for disk-shaped nanoparticles ................................................................................................... 31 3.4. Tips for flower-like nanoparticles ..................................................................................................... 31 3.5. Tips for other morphologies ............................................................................................................. 32 4. Properties .................................................................................................................................................. 33 4.1. Structural properties .......................................................................................................................... 33 4.2. Magnetic properties .......................................................................................................................... 38 4.3. Nanotoxicity ...................................................................................................................................... 44 5. Applications ............................................................................................................................................. 46 5.1. Hyperthermia .................................................................................................................................... 46 5.2. Magnetic Resonance Imaging ........................................................................................................... 52 5.3. Drug delivery .................................................................................................................................... 55 2 5.5. Others ................................................................................................................................................ 57 5.5.1. Magnetic recording media ...................................................................................................... 57 5.5.2. Water treatment ...................................................................................................................... 58 5.5.3. Spintronics .............................................................................................................................. 59 5.5.4. Microwave absorption ............................................................................................................ 59 5.5.5. Li-ion batteries ........................................................................................................................ 60 6. Conclusions and future remarks ............................................................................................................... 61 Acknowledgements .......................................................................................................................................... 63 References ........................................................................................................................................................ 63 1. Introduction In the last decades, nanocrystals have gained attention due to their unique properties at the nanoscale and have been used in different technological applications such as energy storage, catalysis, photonics, electronics or biomedicine.[1–10] The improvement of their performance has required innovative and continuous upgrades of the nanofabrication processes to yield “monodispersed colloids’ consisting on uniform nanoparticles in both size and shape (e.g. size and shape distribution less than 10%).[11–16] In these systems, the overall physicochemical properties reflect the properties of each constituent, leading to size/shape-dependent performance materials. Apart of size and shape, aggregation and the internal structure, are important parameters that control the materials properties. The control of these parameters is linked to the synthesis route used for their preparation or the post-synthesis treatments. Recently, different efforts have been made in developing new routes for the synthesis of anisometric nanocrystals (i.e. nanocrystals which differ from spherical shape) like nanocubes, nanorods, nanowires, nanodisks, and nanoflowers among others.[17–23] These materials possess direction-dependent properties, high surface-to-volume ratio and also particular crystal facets at the surface that can confer different reactivity.[24] The final shape of the nanocrystals is determined during the growth stage in the synthesis procedure, where thermodynamic and kinetic aspects control the reaction (see Fig.1).[25–29] In many cases, a general mechanism for the formation of these morphologies has not been fully described yet because of the difficulty in characterising the nanoparticle formation from the first stages. Those mechanisms include a complex combination of chemical reactions leading to the growth units, nucleation of first clusters, and final crystal growth by diffusion or self-assembly into aggregates.[30–32] In some cases, preferential adsorption of capping molecules to specific facets