(536j) Magnetic Hyperthermia in Biosimilar Colonic Tumor Environment Using Silica-Coated Superparamagnetic Iron Oxide Nanoparticles

Colorectal cancer (CRC) is the fourth most deadly cancer in the world. Standard treatment options include surgery, chemotherapy and radiotherapy. In the clinic, those treatments are often combined or used with other alternative therapies to improve the treatment outcome. Magnetic nanoparticle hyperthermia has attracted clinical interest as an alternative treatment option for chemo-resistant cancer due to its advantages in deep tumor penetration, local tumor heating, and targeted tumor killing when functionalized with specific targeting moieties. This therapy relies on delivering superparamagnetic iron oxide nanoparticles (SPIONs) to the tumor site where they can generate heat in the presence of an alternating magnetic field (AMF). The local temperature increase causes cancer cell death by apoptosis. Current challenges of magnetic hyperthermia are to improve hyperthermia efficacy while minimizing any toxic off-target effects of the SPIONs. The former can be achieved by increasing the heat dissipation rate of SPIONs which is controlled by SPION size, composition and shape. Furthermore, the SPION heating efficiency also strongly depends on the composition and viscosity of the surrounding biological environment and will vary due to the dynamic biotransformations of SPIONs in vivo. In this study, we aim to optimize the hyperthermia effiency of orally administered SPIONs for local treatment of CRC. We study the hyperthermia efficiency of SPIONs in vitro in biosimilar colonic environments in order to predict the optimal subcellular environment for hyperthermia therapy of CRC. SPIONs were synthesized using a flame aerosol reactor that allows scalable manufacture of functional nanoparticles. We varied the SPION composition by addition of dopants (zinc, cobalt, manganese, gadolinium) that are known to enhance the saturation magnetization and hypethermia efficiency of SPIONs. The particles were characterized by nitrogen adsorption, X-ray diffraction, and their hydrodynamic diameter by dynamic light scattering. The crystallite size of particles was finely tuned to 15 nm by controlling flame process parameters to render them superparamagnetic. The particles were hermetically encapsulated by nanothin SiO₂ by in-situ flame coating to facilitate subsequent surface functionalization [1, 2]. Methoxy polyethylene glycol (mPEG) was successfully conjugated to the nanoparticle surface post-synthesis to improve nanoparticle suspension stability in biologically relevant media. The successful pegylation was confirmed by C-H stretching (2871 cm^-1) and bending (1454 and 1349 cm^-1) bands appearing in Fourier transform infrared spectra. The hydrodynamic diameter of mPEG-SPIONs in cell culture media decreased compared to the bare particles (e.g. the hydrodynamic diameter of SiO₂-coated Mn_0.6Zn_0.4Fe₂O₄ in cell culture media was 800 nm and 200 nm before and after pegylation, respectively). The mPEG-SPION suspensions were stable in cell culture media with minimal sedimentation even after 1 hour of AMF exposure. The heating efficiency of nanoparticles was characterized in biosimilar colonic tumor environments (biosimilar mucus, agar tumor phantom, and artificial colonic fluid) to study the outcome of CRC hyperthermia therapy in vitro. Preliminary data suggests that the hyperthermia efficiency is lower in highly viscous environments (e.g. biosimilar mucus and agar tumor phantom) compared to water. Overall, this study will allow the systematic development of surface-modified SPIONs for targeted and efficient hyperthermia therapy of CRC.

1. Teleki, A., et al., Hermetically Coated Superparamagnetic Fe2O3 Particles with SiO2 Nanofilms. Chemistry of Materials, 2009. 21(10): p. 2094-2100.

2. Teleki, A., et al., Highly scalable production of uniformly-coated superparamagnetic nanoparticles for triggered drug release from alginate hydrogels. RSC Advances, 2016. 6(26): p. 21503-21510.