Theranostic Magnetic Nanostructures (MNS) for Cancer

Abstract

Despite the complexities of cancer, remarkable diagnostic and therapeutic advances have been made during the past decade, which include improved genetic, molecular, and nanoscale understanding of the disease. Physical science and engineering, and nanotechnology in particular, have contributed to these developments through out-of-the-box ideas and initiatives from perspectives that are far removed from classical biological and medicinal aspects of cancer. Nanostructures, in particular, are being effectively utilized in sensing/diagnostics of cancer while nanoscale carriers are able to deliver therapeutic cargo for timed and controlled release at localized tumor sites. Magnetic nanostructures (MNS) have especially attracted considerable attention of researchers to address cancer diagnostics and therapy. A significant part of the promise of MNS lies in their potential for "theranostic" applications, wherein diagnostics makes use of the enhanced localized contrast in magnetic resonance imaging (MRI) while therapy leverages the ability of MNS to heat under external radio frequency (RF) field for thermal therapy or use of thermal activation for release of therapy cargo. In this chapter, we report some of the key developments in recent years in regard to MNS as potential theranostic carriers. We describe that the r₂relaxivity of MNS can be maximized by allowing water (proton) diffusion in the vicinity of MNS by polyethylene glycol (PEG) anchoring, which also facilitates excellent fluidic stability in various media and extended in vivo circulation while maintaining high r₂values needed for T₂-weighted MRI contrast. Further, the specific absorption rate (SAR) required for thermal activation of MNS can be tailored by controlling composition and size of MNS. Together, emerging MNS show considerable promise to realize theranostic potential. We discuss that properly functionalized MNS can be designed to provide remarkable in vivo stability and accompanying pharmacokinetics exhibit organ localization that can be tailored for specific applications. In this context, even iron-based MNS show extended circulation as well as diverse organ accumulation beyond liver, which otherwise renders MNS potentially toxic to liver function. We believe that MNS, including those based on iron oxides, have entered a renaissance era where intelligent synthesis, functionalization, stabilization, and targeting provide ample evidence for applications in localized cancer theranostics.

Fig. 1

Size scale of MNS as compared to biomolecules. MNS can be adapted to include biomolecules, drugs, or targeting and imaging molecules to form targeted MNS theranostic agents

Fig. 2

Functional architecture of MNS and theranostic modalities. MNS are comprised of thermally active magnetic core and biocompatible coating and/or functionalization that allows integration of targeting agents and bio/chemotherapeutics

Fig. 3

T₂ contrast enhancement in water due to MNS. When water molecules diffuse into the periphery of the induced dipole moment by MNS, the T₂ relaxation time of the water protons is shortened which enhances the negative contrast

Fig. 4

MFe₂O₄ (where M = Mn, Fe, Co, Ni) MNS with inverse spinel structure and its magnetic spin alignments. The mass magnetization values and r₂ relaxivity values of MFe₂O₄ MNS are proportional to the magnetic moments of the divalent ions (M²⁺) [38]

Fig. 5

Saturation magnetization and r₂ relaxivity (at 4.5 T) of (Zn_xMn_1–x)Fe₂O₄ MNS at different Zn²⁺ doping levels. The (Zn_xMn_1–x)Fe₂O₄ MNS showed significantly high r₂ relaxivities compared to conventional iron oxide MNS [42]

Fig. 6

Schematic illustration of RES clearance of MNS. MNS larger than 100 nm are absorbed by circulating opsonin proteins that are recognized by macrophages and removed from the bloodstream

Fig. 7

Passive targeting of MNS via enhanced permeability and retention (EPR) effect. The compromised vasculature of a solid tumor facilitates extravasation of MNS of size less than 200 nm from the circulation into the tumor interstitium, while endothelial cells are closely packed and present a barrier for MNS penetration

Fig. 8

Size effects of Fe₃O₄ MNS on r₂ relaxivity. a TEM images, b saturation magnetization values, c T₂-weighted MR images (top black and white, bottom color), and d the r₂ relaxivity values of 4, 6, 9, and 12 nm sized Fe₃O₄ MNS. The r₂ relaxivity value increased with size of Fe₃O₄ MNS which resulted in the T₂ contrast change from light gray to black in T₂ weighted MR images or from red to blue in the corresponding color-coded images. Reprinted with permission from [27]. Copyright 2005 American Chemical Society

Fig. 9

In vivo MR detection of cancer in a mouse implanted with the cancer cell line NIH3T6.7 using 12 nm MnFe₂O₄, 12 nm Fe₃O₄ and dextran coated cross-linked 4 nm Fe₃O₄ (CLIO) MNS. T₂-weighted MR images of the mouse (a) before injection, (b) after 1 h injection, and (c) after 2 h injection of MnFe₂O₄ in comparison to (d) after 2 h injection of CLIO. MnFe₂O₄-Herceptin conjugates produced higher contrast than CLIO-Herceptin conjugates at the tumor site after 2 h. e Plot of R₂ change versus time. Increase in R₂ up to 34 % was observed for MnFe₂O₄-Herceptin conjugates in comparison to 5 and 13 % for CLIO-Herceptin conjugate (dots) and 12 nm Fe₃O₄-Herceptin conjugates, respectively. f Change in R₂ values was confirmed in the ex vivo MR images of explanted tumors (8 h). Reprinted with permission from [38]. Copyright 2007 Nature Publishing Group

Fig. 10

MR signal enhancement by assembly of Fe₃O₄ on SiO₂ nanoparticles. a Schematic illustration of the synthetic procedure for Fe₃O₄ decorated mesoporous silica nanoparticles. b Relaxivity values and T₂ weighted MR image of Fe₃O₄ decorated SiO₂ nanoparticles (Fe₃O₄-MSN) and free Fe₃O₄ nanoparticles. The r₂ relaxivity of Fe₃O₄ decorated SiO₂ nanoparticles was increased by 2.8 times as compared to free Fe₃O₄ nanoparticles, hence darker signal was observed in T₂ weighted MR image at the same concentration of Fe. Reprinted with permission from Ref. [150]. Copyright 2010 American Chemical Society

Fig. 11

r₂ relaxivity values of 12 nm nitrodopamine-PEG functionalized Fe₃O₄ MNS with molecular weight of PEG 200 (EG2), 400 (EG4), 500 (EG5), and 600 Da (EG6) in comparison to Ferumoxytol and Ferumoxides (unpublished). It was found that the PEG coating not only provides stability but the thickness of PEG coating also affects the r₂ relaxivity of Fe₃O₄ MNS. The highest r value of 396 mM⁻¹ s⁻¹ with PEG 600 (EG6) was almost four times that of Feridex (Ferumoxide)

Fig. 12

SAR values and percentage of HeLa cells killed after treatment with (Zn_0.4Mn_0.6)Fe₂O₄ MNS or Feridex in AMF. Fluorescence microscopy images of HeLa cells treated with (Zn_0.4Mn_0.6) Fe₂O₄ nanoparticles (or Feridex) and stained with calcein show live cells as green fluorescence. (Zn_0.4Mn_0.6)Fe₂O₄ MNS have shown SAR value of 432 W/g, ~4 times higher than SAR of Feridex (115 W/g) which resulted in 84.4 % death of HeLa cancer cells in comparison to 13.5 % from Feridex. Reprinted with permission from Ref. [42] Copyright © 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Fig. 13

a Schematic illustration of drug (DOX) release from thermoresponsive hydrogel-MNS composite. b Percent DOX release and cell viability of HeLa cell lines treated with the hydrogel-MNS composite with and without external RF field [83]