Iron Oxide Nanoparticle Developments for Biomedical Nano-Heating

Abstract

This work describes iron oxide nanoparticle formulations and heating capabilities for biomedical applications. The coating of iron oxide nanoparticles is key to their dispersion in solution. The heating that results is important for applications including tumor ablation and organ cryopreservation. We propose an iron oxide nanoparticle (IONP)-enhanced precipitating hydrophobic injectable liquid (PHIL, MicroVention Inc.) embolic agent as a localized dual treatment implant for nutrient deprivation and multiple repeatable thermal ablations of deep-seated tumors. Following a single injection, multiple thermal treatments can be repeated as needed based on tumor growth/recurrence. Herein we show the ability to create an injectable solution of stable colloidal dispersion of IONPs with PHIL dissolved in DMSO and monitor deposition of PHIL-IONP precipitate dispersion by µCT and magnetic resonance imaging. Once precipitated, the PHIL-IONP implant can heat to therapeutic temperatures >8 °C for thermal ablation (clinical temperature of +45 °C) in multiple models and in postmortem mouse tissue models. IONPs in other formulations can be used in regenerative medicine such as with “nanowarming” cryopreserved organs. Radiofrequency excited IONPs dispersed in cryoprotectant agents (CPAs) can uniformly rewarm cryopreserved biological samples such as rat kidneys and hearts. To reliably produce IONPs at a scale needed to nanowarm whole human kidneys, a simpler, biocompatible PEG-coated IONP is needed. The IONP needs 1) to be stable in CPAs, 2) have a low volume fraction, and 3) be inexpensive and easy to produce in 10 g batches. We designed a small-molecule phosphonate linker (PLink) which contains a phosphonate “anchor” for high irreversible binding to iron oxide and a carboxyl “handle” for ligand attachment. PLink-PEG removes and replaces the initial coating layer of commercially available IONPs (EMG1200 (hydrophobic) and EMG308 (hydrophilic), Ferrotec, Inc.) allowing for colloidal stability in both water and CPAs (verified with dynamic light scattering) from minutes (uncoated) to up to 4 weeks. Herein concentrations of IONP in VS55 (common CPA) of 60 mg Fe/mL was reached significantly above our previous capabilities of 10 mg Fe/ mL. These IONPs were successful at nanowarming cryopreserved human dermal fibroblast cells with higher viability as compared to convective rewarming in a water bath and heating rate close to 200 °C/min, 2.5 times faster than our current system. Additionally, initial scale up formulations resulted in 10 g of CPA stable IONPs, which will allow us to significantly accelerate the development of actual kidney cryopreservation and nanowarming for transplantation.