Magnetic nanoparticles: an emerging technology for malignant brain tumor imaging and therapy

Abstract

Magnetic nanoparticles (MNPs) represent a promising nanomaterial for the targeted therapy and imaging of malignant brain tumors. Conjugation of peptides or antibodies to the surface of MNPs allows direct targeting of the tumor cell surface and potential disruption of active signaling pathways present in tumor cells. Delivery of nanoparticles to malignant brain tumors represents a formidable challenge due to the presence of the blood-brain barrier and infiltrating cancer cells in the normal brain. Newer strategies permit better delivery of MNPs systemically and by direct convection-enhanced delivery to the brain. Completion of a human clinical trial involving direct injection of MNPs into recurrent malignant brain tumors for thermotherapy has established their feasibility, safety and efficacy in patients. Future translational studies are in progress to understand the promising impact of MNPs in the treatment of malignant brain tumors.

Figure 1. Illustration of a magnetic iron oxide nanoparticle

A typical magnetic nanoparticle is depicted by a core-shell morphology with an iron oxide core (usually magnetite Fe₃O₄) coated with a biocompatible material (e.g., polysaccharide, synthetic polymer, lipid, protein or small silane linker). The coating can be easily modified to make the particles tumor specific while also imparting stability in physiologic settings.

Figure 2. Illustration of an EGF receptor vIII-expressing glioblastoma cell bound by an EGF receptor vIII antibody-conjugated magnetic nanoparticle construct

The wt EGFR dimerizes upon ligand binding. The truncated EGFRvIII deletion mutant, which does not require a ligand for activation, is bound by an EGFRvIII antibody-conjugated magnetic nanoparticle conjugate (EGFRvIIIAb-iron oxide nanoparticle). The EGFRvIIIAb-iron oxide nanoparticle is comprised of a 10-nm iron oxide core surrounded by an amphiphilic triblock copolymer, which is covalently conjugated to the EGFRvIIIAb. Ab: Antibody; EGFR: EGF receptor; GBM: Glioblastoma; IONP: Iron oxide nanoparticle; wt: Wild-type.

Figure 3. Transmission electron microscopy of an EGF receptor vIII-expressing glioblastoma cell bound by magnetic nanoparticles

Transmission electron microscopy confirms glioblastoma cell binding and internalization of the magnetic nanoparticles (shown by black arrows; magnification 10,000×). Reproduced from [1].

Figure 4. Targeting of glioblastoma tumor and infiltrating cancer cells by magnetic nanoparticle contrast-enhanced delivery

Coronal depiction of the brain with placement of two intratumoral catheters and magnetic nanoparticle convection-enhanced delivery. The glioblastoma tumor and its infiltrating margins are shown. Intra- and peri-tumoral magnetic nanoparticle distribution is shown after convection-enhanced delivery. A magnified view of EGF receptor-expressing GBM cells adjacent to normal brain cells is shown at the tumor margin. Targeting of the EGF receptor-expressing GBM cells with antibody-conjugated magnetic nanoparticles is shown. GBM: Glioblastoma.

Figure 5. Contrast-enhanced delivery of EGFRvIIIAb-iron oxide nanoparticles in a mouse glioblastoma model

(A) T₂ -weighted MRI showing a tumor xenograft with bright signal 7 days post-tumor implantation (arrow); (B) Tumor shown (arrow) by contrast enhancement after injection of the gadolinium contrast agent (Gd-DTPA); (C) MRI signal drop (arrow) after convection-enhanced delivery of EGFRvIIIAb-iron oxide nanoparticles; (D) EGFRvIIIAb-iron oxide nanoparticle dispersion and T₂ signal drop (arrow) on MRI 4 days after convection-enhanced delivery. Reproduced from [1].

Figure 6. Intratumoral thermotherapy of a malignant brain tumor with magnetic nanoparticles

A patient who has undergone intratumoral implantation of magnetic nanoparticles is depicted undergoing an alternating magnetic field session for treatment of his malignant brain tumor by thermotherapy.