Magnetic Micellar Nanovehicles: Prospects of Multifunctional Hybrid Systems for Precision Theranostics

Abstract

Hybrid nanoarchitectures such as magnetic polymeric micelles (MPMs) are among the most promising nanotechnology-enabled materials for biomedical applications combining the benefits of polymeric micelles and magnetic nanoparticles within a single bioinstructive system. MPMs are formed by the self-assembly of polymer amphiphiles above the critical micelle concentration, generating a colloidal structure with a hydrophobic core and a hydrophilic shell incorporating magnetic particles (MNPs) in one of the segments. MPMs have been investigated most prominently as contrast agents for magnetic resonance imaging (MRI), as heat generators in hyperthermia treatments, and as magnetic-susceptible nanocarriers for the delivery and release of therapeutic agents. The versatility of MPMs constitutes a powerful route to ultrasensitive, precise, and multifunctional diagnostic and therapeutic vehicles for the treatment of a wide range of pathologies. Although MPMs have been significantly explored for MRI and cancer therapy, MPMs are multipurpose functional units, widening their applicability into less expected fields of research such as bioengineering and regenerative medicine. Herein, we aim to review published reports of the last five years about MPMs concerning their structure and fabrication methods as well as their current and foreseen expectations for advanced biomedical applications.

Keywords: drug delivery; hybrid nanosystems; hyperthermia; imaging; magnetic nanoparticles; magnetic polymeric micelles; magnetically assisted technologies; nanotherapeutics; polymeric micelles; target delivery.

Figure 1

Schematic representation of a magnetic polymeric micelle (MPM). MPMs are formed by self-assembly of amphiphilic copolymers in the presence of multiple magnetic nanoparticle (MNPs) units. MNPs can have a hydrophilic (light green) or hydrophobic (light orange) coating to be incorporated into the hydrophilic (green) or hydrophobic (orange) segment of the polymeric micelle, respectively.

Figure 2

The influence of the shape in the magnetization of magnetic polymeric micelles. (A) TEM images of micelles produced with PBA-PEG-PCL@Fe₃O₄ with spherical (a,b) or rod-like (c,d) morphology. Images in (a,c) represent micelles without Fe₃O₄ while (b,d) refer to magnetic polymeric micelles. In panels (a,c), the inserted images indicate the nanoparticle size distribution. (B) The magnetization loop was performed on the magnetic particles (Fe₃O₄) and the spherical (S₂@Fe₃O₄,) and rod-like (R₂@Fe₃O₄) micelles at room temperature by vibrating sample magnetometry. Adapted with permission from Ref. [85]. Copyright 2022, The Royal Society of Chemistry.

Figure 3

Methods for the production of magnetic polymeric micelles.

Figure 4

Imaging features of magnetic micelles. T₂-weight MRI images of SPIONs and SPION@micelles in vitro (A,B) and in vivo (C–F): (A) T₂ relaxation rates as a function of iron (Fe) concentrations; (B) T₂-weight MRI images of SPIONs (I) and SPION@ micelles (II) recorded on a 1.5 T clinical MRI instrument at different Fe concentrations (mM): a, 0; b, 0.05; c, 0.1; d, 0.2; e, 0.3; f, 0.4; g, 0.5; (C–F) In vivo T₂-weighed MR images of HeLa tumor-bearing mice before (C) and after intravascular injection of SPION loaded micelles for (D) 1 h, (E) 3 h and (F) 7 h acquired on a 7.0 T MRI instrument. The tumors in the left and right flanks are identified by green dots and red circles, respectively. The magnetic field was applied to the right tumor while the left was not. (G) Photos showing the magnetic responses of polymeric micelles incorporating magnetic nanoparticles and quantum dots (HyMNS-M/Q), and magnetic nanoparticles coated with poly(maleic anhydride-alt-1-octadecene)-poly(ethylene glycol) (MNPs-PP) after applying an external magnetic field; (H) Real-time image of HyMNS-M/Q migration (yellow arrows) in the cytoplasm of a living cell under the external magnetic stimulus. Scale bar: 3 µm. Adapted with permission from Refs. [38, 89]. Copyright 2022, Elsevier.

Figure 5

The multi-responsive potential of magnetic polymeric micelles. (A-C) DOX-Fe₃O₄@PAAP micelles produced from P(AAm-co-AN)-g-PEG, SPIONs and DOX, evidenced a pH and NIR irradiation controlled release of DOX: (A) Thermographic images of Fe₃O₄@PAAP micelles after exposure to NIR radiation (808 nm laser at 2 W cm⁻²); (B) Cumulative release curves of DOX in PBS (pH 5.5, 6.5 and 7.4) with or without serum at pH 7.4; (C) Cumulative release curves of DOX in PBS (pH 5.5, 6.5, and 7.4) upon irradiation with a NIR laser for 3 min. (D) Cumulative release curves of DOX from PPI-b-TEGME, SPIONs and DOX micelles at 37 °C, 45 °C, and after a 5 min exposure to an AMF. Adapted with permission from Refs. [8, 32]. Copyright 2022, The Royal Society of Chemistry.

Figure 6

Magnetic polymeric micelles for hyperthermia treatment. (A) Schematic illustration of the magnetic hyperthermia in vitro assay; (B) Time-dependent temperature curves with different AMF intensities; (C) The release curves of emodin from emodin-magnetic micelles (EMM) after a 10 min treatment at 37 °C and 45 °C, and in response to an AMF; (D) T₂-weighted image map of EMMs; (E) The in vivo T₂-weighted images of the tumor after intravenous injection of non-loaded emodin-magnetic micelles (MM) in the absence and presence (MM + Magnet) of magnetic targeting; (F) Schematic illustration of EMM mediated magnetic hyperthermia (MHT) and chemotherapy (CHT) in vivo study with 4T1 tumor-bearing mice; (G) The tumor growth curves (statistical analyses were performed using Student’s t-test; ∗∗∗ P < 0.001). Adapted from reference [31].