Shape-, size- and structure-controlled synthesis and biocompatibility of iron oxide nanoparticles for magnetic theranostics

Abstract

In the past decade, iron oxide nanoparticles (IONPs) have attracted more and more attention for their excellent physicochemical properties and promising biomedical applications. In this review, we summarize and highlight recent progress in the design, synthesis, biocompatibility evaluation and magnetic theranostic applications of IONPs, with a special focus on cancer treatment. Firstly, we provide an overview of the controlling synthesis strategies for fabricating zero-, one- and three-dimensional IONPs with different shapes, sizes and structures. Then, the in vitro and in vivo biocompatibility evaluation and biotranslocation of IONPs are discussed in relation to their chemo-physical properties including particle size, surface properties, shape and structure. Finally, we also highlight significant achievements in magnetic theranostic applications including magnetic resonance imaging (MRI), magnetic hyperthermia and targeted drug delivery. This review provides a background on the controlled synthesis, biocompatibility evaluation and applications of IONPs as cancer theranostic agents and an overview of the most up-to-date developments in this area.

Keywords: biocompatibility; controlled synthesis; iron oxide; magnetic theranostics.

Figure 1

Example morphologies of 0-dimensional IONPs: (A) nanospheres, (B) plates, (C) tetrahedrons, (D) cubes, (E) truncated octahedrons, (F) octahedrons, (G) concaves, (H) Octapods, and (I) multibranches. (A) Reproduced with permission from , copyright 2004. (B-C, E, G, I) Reproduced with permission from , copyright 2015. (D) Reproduced with permission from , copyright 2007. (F) Reproduced with permission from , copyright 2010. (H) Reproduced with permission from , copyright 2013.

Figure 2

Example morphologies of 1-dimensional and 3-dimensional IONPs: (A) nanowires, (B) long nanotubes, (C) nanoneedles, (D) nanorods, (E) short nanotubes, (F) tube-in-tubes, and (G) nanorings. (A) Reproduced with permission from , copyright 2007. (B) Reproduced with permission from , copyright 2005. (C) Reproduced with permission from , copyright 2015. (D) Reproduced with permission from , copyright 2005. (E) Reproduced with permission from , copyright 2005. (F) Reproduced with permission from , copyright 2007. (G) Reproduced with permission from , copyright 2016.

Figure 3

Controlled synthesis of different shapes of IONPs via varying the reaction conditions. (A) Varying the solvent component ratio. Reproduced with permission from , copyright 2010. (B) Controlling the alkaline reaction environment via different concentration of TBAB. Reproduced with permission from , copyright 2011. (C) Controlling the reaction temperature and time. Reproduced with permission from , copyright 2010.

Figure 4

Example morphologies of aggregates of IONPs: (A) clusters, (B) porous core-shell spheres, (C) hollow spheres with a smooth surface, (D) hollow spheres with a rough surface, and (E) nanoflowers. (A) Reproduced with permission from , copyright 2017. (B) Reproduced with permission from , copyright 2010. (C) Reproduced with permission from , copyright 2008. (D) Reproduced with permission from , copyright 2015. (E) Reproduced with permission from , copyright 2011.

Figure 5

Size-controlled synthesis of IONPs via using various solvents with different boiling points (b.p.). (A1, A2) 5 nm with 1-hexadecene (b.p. 274 °C), (B1, B2) 9 nm with octyl ether (b.p. 287 °C), (C1, C2) 12 nm with 1-octadecene (b.p. 317 °C), (D1, D2) 16 nm with 1-eicosene (b.p. 330 °C), (E1, E2) 22 nm with trioctylamine (b.p. 365 °C). Reproduced with the permission from , copyright 200.

Figure 6

TEM images of various Fe-Fe₃O₄ (A) and hollow IONPs (B-E) after heating the seed Fe-Fe₃O₄ nanoparticles. (B) 130 °C for 1 h, (C)130 °C for 2 h, (D) 210 °C for 40 min, (E) 210 °C for 80 min, (F) 210 °C for 120 min. Reproduced with permission from , copyright 2007.

Figure 7

Modification of IONPs with (A) poly(ethylene glycol) saline, (B) poly(vinyl pyrrolidone)-catechol, (C) polylactice acid, (D) polyacrylic acid, (E) poly(lactic-co-glycolic acid), (F) dextran, (G) polyvinyl alcohol, (H) chitosan and (I) polyethyleneimine. (A) Reproduced with permission from , copyright 2004. (B) Reproduced with permission from , copyright 2013. (C) Reproduced with permission from , copyright 2008. (D) Reproduced with permission from , copyright 2009. (E) Reproduced with permission from , copyright 2012. (F) Reproduced with permission from , copyright 2008. (G) Reproduced with permission from , copyright 2008. (H) Reproduced with permission from , copyright 2010. (I) Reproduced with permission from , copyright 2007.

Figure 8

Functionalization of IONPs with silica. (A) General procedures for coating silica on IONPs. Reprinted with permission from , copyright 2006. (B) La Mer-like diagram: hydrolyzed TEOS (monomers) concentration against time for homogeneous nucleation and heterogeneous nucleation and TEM images of different Fe₃O₄@SiO₂ NPs. Reprinted with permission from , copyright 2012. (C) TEM images and magnetization curves of Fe₃O₄@SiO₂ hollow mesoporous spheres with varying Fe₃O₄ content. Reprinted with permission from , copyright 2010. (D) Schematic illustration of the preparation of IOMSN@uIO(DOX)-FA NPs and its application as a MRI-guided stimuli-responsive theranostic platform for effective targeted chemotherapy of cancer. Reprinted with permission from , copyright 2018.

Figure 9

T₂-weighted contrast MR images of various IONPs. (A) Schematic illustration of the ball models of octapod and spherical IONPs with the same geometric volume, smooth M-H curves, T₂-weighted MR images, and comparison of r₂ values of IONPs with different diameters: Octapod-30 (~58 nm), Octapod-20 (~49 nm), Spherical-16 (~30 nm) and Spherical-10 (22 nm). Reproduced with permission from , copyright 2013. (B) TEM images, r₂ values and T₂-weighted MR images of different IO clusters C1-C3 (C1: ~115.5nm; C2: ~127.8 nm; C3: ~129.2 nm), as well as the single IO-5 (~5.2 nm) and IO-15 (~15.1 nm) NPs. Reproduced with permission from , copyright 2017. (C) The MR contrast effect of Fe₃O₄ NRs of different lengths and NPs of different diameters. Reproduced with permission from , copyright 2015.

Figure 10

T₁-weighted MR images of different IONPs. (A) r₁ value and r₂/r₁ ratio of ES-MIONs as a function of particle size.. (B) T₁-weighted MR images of a mouse injected with ZDS-coated exceedingly small SPIONs (ZES-SPIONs) at 7 T. (C) T₁-weighted MRA of a mouse injected with ZES-SPIONs at 7 T. (A, B) Reproduced with permission from , copyright 2017. (C) Reproduced with permission from , copyright 2017.

Figure 11

Various T₁/T₂ dual-modal MRI contrast agents based on IONPs. (A) Magnetic coupling between T₁ and T₂ contrast materials and the structures for a dual-modal nanoparticle contrast agent. Reproduced with permission from , copyright 2010. (B) T₁ and T₂ images of phantoms were post processed using the AND logic algorithm. Reproduced with permission from , copyright 2014. (C) T₁- and T₂-weighted phantom imaging of GdIOPs (Gd₂O₃-embedded iron oxide nanoplates) under four different magnetic fields (0.5, 3.0, 7.0, and 9.4 T) and a comparison of r₁ values of GdIOPs, IO cubes, and GdIO spheres in 0.5 T. Reproduced with permission from , copyright 2015. (D) Phenomenon of proton interaction with a spherical magnetic nanoparticle system: molecular water diffusion and chemical exchange with surface magnetic metals are related to their T₂ and T₁ contrast enhancements, respectively. Reproduced with permission from , copyright 2014. (E) Engineering heterogeneous nanostructures for magnetic coupling of T₁ and T₂ contrast agents with (left) core/shell structures or (right) dumbbell structures and the design of dumbbell heterostructures for dual T₁- and T₂-weighted MRI. Reproduced with permission from , copyright 2014.

Figure 12

Schematic illustration of a mechanism to enhance the EPR effect and tumor accumulation by ultrafine iron oxide nanoparticles (uIONPs) with bright-to-dark T₁-T₂ MRI contrast switching. uIONPs could extravasate faster and easier from the leaky tumor vessels into a tumor with favorable kinetics and then self-assemble to clusters in the tumor interstitial space with relatively low pH (~6.5), thus restricting clustered uIONPs intravasation back into blood circulation. Reproduced with permission from , copyright 2017.

Figure 13

Magnetic hyperthermia properties of various IONPs. (A) A homemade device for magnetically induced hyperthermia. The magnetic hyperthermia properties (SAR or SLP value) of IONPs influenced by (B) size, (C) the value of Hf, (D) the frequency of the magnetic field, (E) the shape of the particles, and (F) their concentration. (A, B) Reproduced with permission from , copyright 2007. (C) Reproduced with permission from , copyright 2012. (D) Reproduced with permission from , copyright 2011. (E, F) Reproduced with permission from , copyright 2013.

Figure 14

Various IONPs as agents for targeted drug delivery. (A) Diagram showing the proposed synthesis of surface-modified IONPs using citric acid and the preparation of DOX-loaded magnetic liposomes and their interaction with high frequency magnetic field. Reproduced with permission from , copyright 2014. (B) Schematic illustrating the intracellular uptake, extracellular trafficking and processing of NP-PEIb-siRNA-CTX (NP: iron oxide nanovector; PEIb: highly amine blocked polyetherimide; CTX: chlorotoxin) in tumor cells. Reproduced with permission from , copyright 2010. (C) Stimulus-responsive magnetic triggering induced heating in vitro based on IONPs. Reproduced with permission from , copyright 2009. (D) Gamma camera images of the abdominal region of a swine after administration of ^99mTc-MTC based on magnetic targeting. Reproduced with permission from , copyright 1999.

Figure 15

Schematic illustration of IONPs for magnetic theranostics. Reproduced with permission from , copyright 2015.