Stimuli-Responsive Iron Oxide Nanotheranostics: A Versatile and Powerful Approach for Cancer Therapy

Abstract

Recent advancements in unravelling elements of cancer biology involved in disease progression and treatment resistance have highlighted the need for a holistic approach to effectively tackle cancer. Stimuli-responsive nanotheranostics based on iron oxide nanoparticles are an emerging class of versatile nanomedicines with powerful capabilities to "seek, sense, and attack" multiple components of solid tumors. In this work, the rationale for using iron oxide nanoparticles and the basic physical principles that impact their function in biomedical applications are reviewed. Subsequently, recent advances in the integration of iron oxide nanoparticles with various stimulus mechanisms to facilitate the development of stimuli-responsive nanotheranostics for application in cancer therapy are summarized. The integration of an iron oxide core with various surface coating mechanisms results in the generation of hybrid nanoconstructs with capabilities to codeliver a wide variety of highly potent anticancer therapeutics and immune modulators. Finally, emerging future directions and considerations for their clinical translation are touched upon.

Keywords: cancer; iron oxide nanoparticles; medical imaging; stimuli-responsive; theranostics.

Figure 1.

Mechanisms of heat generation in magnetic nanoparticles (MNPs) upon exposure to an alternating magnetic field (AMF). Gray circles represent MNPs, blue arrows indicate direction of magnetic moment, and dotted lines delineate boundaries of domains within multi-domain MNPs. In the case of single domain MNPs, magnetic relaxation occurs in the form of internal changes in the magnetic moment direction (Néelian, dashed red arrows) or physical movement (Brownian, solid red arrows) as the particles attempt to align with the applied magnetic field. Reproduced under the terms of the Creative Commons license.^[37]

Figure 2.

Magnetic properties of a nanoparticle can be tuned by changing particle size, shape or composition. (a) Varying the particle diameter, shape or core-shell can affect the size, surface anisotropy, and exchange anisotropy, respectively. (b) The standard loss of power (SLP) of cubic NPs is closely related to the particle size. (c) SLP of various nanoparticles is influenced by the size, shape and composition. (d,e) Simulated magnetic spin states show that more spins are directed in the direction of cube (d) than in spherical NPs (e). Reproduced after minor modification with permission.^[81] Copyright 2012, American Chemical Society.

Figure 3.

Mesoporous silica-iron oxide nanoparticles (ms-IONPs) for controlled hyperthermia and MR visualization. (a) Synthesis of ms-IONPs standard sol-gel chemistry stabilizes the parent IONPs to prevent bulk aggregation. (b) Comparison of uncoated IONPs to ms-IONPs highlights the influence of surface modification on magnetic properties, such as stable heat production in magnetic hyperthermia and contrast enhancement using T1 or T2-weighted MRI. Reproduced with permission.^[83] Copyright 2016, American Chemical Society.

Figure 4.

Magnetic nanoparticles for multimodal imaging in combination with magnetic hyperthermia and photodynamic therapy. (a) Acetylated hyaluronic acid (AHP) conjugated to fluorescent pheophorbide-a (PheoA) is used to coat magnetic Fe₃O₄ nanoparticles (AHP@MNPs). (b) Magnetic exposure induces hyperthermia and MR imaging (left) while near infrared (NIR) laser irradiation facilitates photodynamic therapy (PDT) and fluorescence optical imaging through excitement of pheoA (right). Reproduced with permission.^[91] Copyright 2016, Royal Society of Chemistry.

Figure 5.

Top, Synthesis of Fe₃O₄/Au dendrimer-stabilized nanoflowers (DSNFs) using thermal decomposition. Ultrasmall IONPs produce high T1-weighted MRI contrast while the gold molecules result in visualization with computed tomography (CT) imaging. Application of an external NIR laser also can facilitate photothermal therapy (PTT) and photoacoustic imaging (PA). Reproduced under the terms of the Creative Commons license.^[95]

Figure 6.

Remotely controlled drug release using an alternating magnetic field (AMF) from stealth liposomes. Upon AMF exposure, palmityl-nitroDOPA-stabilized SPIONs within the lipid bilayer transiently destabilize the liposomal membrane, allowing drug to escape. Reproduced with permission.^[107c] Copyright 2011, American Chemical Society.

Figure 7.

Ultra magnetic liposomes encapsulate iron oxide particles for use in magnetic hyperthermia and MRI. Left, TEM of magnetic liposomes. Right, cartoon depiction of lipid bilayer (blue) surrounding hydrophilic SPIONs (red) within the interior of the liposome. Reproduced with permission.^[114a] Copyright 2012, American Chemical Society.

Figure 8.

Heat-labile gatekeeper mechanism for uncapping of MSN pores using thermo-degradable azo-containing PEG chains. Following exposure to an alternating magnetic field, local temperature increase causes irreversible cleavage of N-N bonds (highlighted in red as triangles (A) and bonds (B)). Removal of the gatekeeping polymer results in release of encapsulated drug. Reproduced with permission.^[116] Copyright 2015, Royal Society of Chemistry.

Figure 9.

Use of a thermoresponsive polymer coating for reversible, heat-mediated pore-uncapping of magnetic iron oxide core mesoporous silica nanoparticles. At normal body temperature, the polymer maintains a hydrophilic extended coil conformation, preventing premature drug leakage in circulation. Upon temperature elevation (above 40°C), the polymer contracts into a more hydrophobic globular conformation, allowing drug to escape the MSN pores. Reproduced with permission.^[118c] Copyright 2019, Elsevier.

Figure 10.

Multicomponent liposome-IO nanochains for radiofrequency-triggered drug release. (a) Cartoon depiction of liposome-IO nanochain, comprised of a chain of iron oxide spheres attached to a drug-loaded liposome. (b) TEM images of the liposome-IO nanochain, scale bar 50 nm. (c) Schematic of ligand-directed vascular targeting drug delivery approach using RGD-targeted nanochains and application of an external RF-triggered release mechanism. Reproduced with permission.^[36d] Copyright 2014, Elsevier.

Figure 11.

Remote drug delivery stimulated by radiofrequency (RF) field. (a) Illustration of a multicomponent nanoparticle (Fe@MSN) containing an iron oxide core encompassed by a mesoporous silica shell. The surface of the particle is easily modified for drug loading and inclusion of targeting ligands. (b) Application of an external low-power (50 kHz, 5 mT) RF field induces mechanical vibration of the iron core, dislodging drug from the MSN pores and allowing the drug to escape. (c) The treatment strategy involves active targeting of the endothelium of glioma sites, and rapid RF-triggered drug release from the Fe@MSNs, causing delivery of potent chemotherapeutics to brain tumor cells across the blood-brain-barrier. Reproduced with permission.^[36b] Copyright 2019, The Royal Society of Chemistry.

Figure 12.

Comparison of targeting mechanisms for delivery of magnetic nanoparticles. (a) Passive targeting relies solely on nanoparticle accumulation non-targeted iron oxide (Fe₃O₄@PEG) due to the enhanced permeation and retention (EPR) effect of tumors. (b) For active targeting, IONPs containing cyclic-RGD and a glucose transporter molecule (Fe₃O₄@RGD@GLU) are used for ligand-specific binding and uptake by cancer cells. (c) The combination of magnetic targeting with active targeting (right) dramatically increases the intratumoral delivery of magnetic IONPs. Reproduced with permission.^[124f] Copyright 2019, Elsevier.