Thermally Cross-Linked Superparamagnetic Iron Oxide Nanoparticles:  Synthesis and Application as a Dual Imaging Probe for Cancer in Vivo

Abstract

We report the fabrication and characterization of thermally cross-linked superparamagnetic iron oxide nanoparticles (TCL-SPION) and their application to the dual imaging of cancer in vivo. Unlike dextran-coated cross-linked iron oxide nanoparticles, which are prepared by a chemical cross-linking method, TCL-SPION are prepared by a simple, thermal cross-linking method using a Si-OH-containing copolymer. The copolymer, poly(3-(trimethoxysilyl)propyl methacrylate-r-PEG methyl ether methacrylate-r-N-acryloxysuccinimide), was synthesized by radical polymerization and used as a coating material for as-synthesized magnetite (Fe3O4) SPION. The polymer-coated SPION was further heated at 80 degrees C to induce cross-linking between the -Si(OH)3 groups in the polymer chains, which finally generated TCL-SPION bearing a carboxyl group as a surface functional group. The particle size, surface charge, presence of polymer-coating layers, and the extent of thermal cross-linking were characterized and confirmed by various measurements, including dynamic light scattering, Fourier transform infrared spectroscopy, and X-ray photoelectron spectroscopy. The carboxyl TCL-SPION was converted to amine-modified TCL-SPION and then finally to Cy5.5 dye-conjugated TCL-SPION for use in dual (magnetic resonance/optical) in vivo cancer imaging. When the Cy5.5 TCL-SPION was administered to Lewis lung carcinoma tumor allograft mice by intravenous injection, the tumor was unambiguously detected in T2-weighted magnetic resonance images as a 68% signal drop as well as in optical fluorescence images within 4 h, indicating a high level of accumulation of the nanomagnets within the tumor site. In addition, ex vivo fluorescence images of the harvested tumor and other major organs further confirmed the highest accumulation of the Cy5.5 TCL-SPION within the tumor. It is noteworthy that, despite the fact that TCL-SPION does not bear any targeting ligands on its surface, it was highly effective for tumor detection in vivo by dual imaging.

The design and utility of polymer-stabilized iron-oxide nanoparticles for nanomedicine applications

“…Silane can be covalently attached onto IONP surfaces by reaction of the surface Fe-OH group with the Si-OCH 3 moiety [11]. Further cross-linking events produce a thin inorganic silica layer around the particles [12].…”

“…Using this multi-interaction approach, many different types of functionalities have been used, such as dopamine [29], carboxylic acid [30] and trimethyl silane [31], yielding stable nanoparticles. Th e acid groups, not used for IONP stabilization, were exploited for the attachment of Cy5.5 dye [11] and small-molecule drugs such as doxorubicin [32].…”

Nonpolymeric Surface–Coated Iron Oxide Nanoparticles for In Vivo Molecular Imaging: Biodegradation, Biocompatibility, and Multiplatform

“…ATP@SPIONs were prepared simply by an alkali-mediated coprecipitation method as described previously (14). It is well recognized that phosphate molecules are stably anchored on the surface of SPIONs (25,26).…”

“…In particular, it is essential to engineer the surface of SPIONs to prevent aggregation between magnetic particles by van der Waals attraction and to improve their colloidal stability in biologic solutions (5)(6)(7). Although various coating materials such as bovine serum albumin, polysaccharide-based materials (dextran, chitosan, and curdlan), polyethylene glycol, polyvinyl alcohol, and polyacrylamide have recently been used for the surface engineering of SPIONs, there are many problems associated with their use in biomedical applications (8)(9)(10)(11)(12)(13)(14). The fate of these polymeric materials in the body after intravenous injection has not yet been completely evaluated (15)(16)(17).…”

Distribution and accumulation of ¹⁷⁷Lu-labeled thermally cross-linked superparamagnetic iron oxide nanoparticles in the tissues of ICR mice

“…More importantly, iron oxide nanoparticles have a long blood retention time, biodegradability and low toxicity [6,7]. Recently, anti-biofouling polymer-coated TCL-SPION was reported as a novel diagnostic probe for in vivo cancer imaging [9,10].…”