Superparamagnetic Iron Oxide Nanoparticles (SPION): From Fundamentals to State-of-the-Art Innovative Applications for Cancer Therapy

Abstract

Despite significant advances in cancer therapy over the years, its complex pathological process still represents a major health challenge when seeking effective treatment and improved healthcare. With the advent of nanotechnologies, nanomedicine-based cancer therapy has been widely explored as a promising technology able to handle the requirements of the clinical sector. Superparamagnetic iron oxide nanoparticles (SPION) have been at the forefront of nanotechnology development since the mid-1990s, thanks to their former role as contrast agents for magnetic resonance imaging. Though their use as MRI probes has been discontinued due to an unfavorable cost/benefit ratio, several innovative applications as therapeutic tools have prompted a renewal of interest. The unique characteristics of SPION, i.e., their magnetic properties enabling specific response when submitted to high frequency (magnetic hyperthermia) or low frequency (magneto-mechanical therapy) alternating magnetic field, and their ability to generate reactive oxygen species (either intrinsically or when activated using various stimuli), make them particularly adapted for cancer therapy. This review provides a comprehensive description of the fundamental aspects of SPION formulation and highlights various recent approaches regarding in vivo applications in the field of cancer therapy.

Keywords: SPION; cancer therapy; drug delivery; iron oxide nanoparticles; macrophage polarization; magnetic hyperthermia; reactive oxygen species; theranostics.

Figure 3

Examples of particle morphologies: (A) nanospheres; (B) plates; (C) tetrahedrons; (D) cubes; (E) truncated octahedrons; (F) octahedrons; (G) concaves; (H) octapods; (I) multibranches. Reprinted from [26].

Figure 5

Schematic comparison of the main differences between the “hard” corona and the “soft” corona. Reprinted from [60].

Figure 6

Schematic illustration of the abilities of magnetic microspheres with different sharpness to pierce the cancer cell membrane. Fe₃O₄/BSA, Fe₃O₄/BSA/SrSiO₂, Fe₃O₄/BSA/MrSiO₂, Fe₃O₄/BSA/LrSiO₂, and Fe₃O₄/BSA/CrSiO₂ are numbered ➀, ➁, ➂, ➃, and ➄, respectively. Reprinted from [104].

Figure 7

Binary categorization of proinflammatory (M1-like) and anti-inflammatory (M2-like) macrophages in the tumor microenvironment. Reprinted from [126].

Figure 8

Illustration of (A) SPION-based RNAi platforms (AIO: amorphous iron oxide) and (B) their interaction with tumor cells. Upon i.v. administration, nanoparticles accumulate in tumor cells through the EPR effect. Internalization of the nanoparticles within the endosome and subsequent release of iron ions leads to osmotic pressure and/or endosomal membrane oxidation. The resulting endosomal escape induces the release of RNAi and iron ions, resulting in MCT4 silencing and oxidative stress via the Fenton-like reaction. Reprinted from [151].

Figure 9

Illustration of (a) photodynamic therapy mechanism and (b) photothermal therapy mechanism. Reprinted from [155].

Figure 1

(a) Illustration of the face-centered cubic arrangement of O²⁻ anions and location of ferric and ferrous ions in octahedral and tetrahedral sites; (b) illustration of the ferrimagnetic network formed by ferrous and ferric ions in magnetite; (c) illustration of domain formation in ferrimagnetic material and resulting magnetization behavior; (d) illustration of a single-domain nanoparticle and resulting superparamagnetic curve.

Figure 2

Lamer diagram schematic showing an increase in monomer concentration (Step 1), the nucleation (Step 2), and growth phenomenon (Step 3) in function of monomer concentration and time.

Figure 4

(a) Anchoring groups grafted on an iron oxide surface, from left to right, dopamine, siloxane, hydroxyamate, 2,3-dihydroxybenzamide, mono- and bis-phosphonate, and carboxylate; (b) examples of capping agents providing electrostatic stabilization; (c) polymer coatings providing steric stabilization.