(266a) Preparation and Evaluation of Hafnium Oxide Nanoparticle CT Contrast Agents

The high atomic number (Z = 72), high electron density, and chemical stability of hafnium oxide (hafnia, HfO₂) makes its nanoparticles good candidates for biomedical applications as x-ray contrast agents in computed tomography (CT) and as radiotherapy enhancers. Currently, iodine x-ray contrast agents are commonly used clinically. However, studies suggest that hafnia has better overall performance compared to iodine at clinical CT tube potentials. In addition, iodine-based CT contrast agents show increase in retention in the kidneys and can leads to low tolerance to patients with chronic kidney disease. Gold nanoparticles are also of interest as x-ray contrast agents and radiotherapy enhancers. Hafnia nanoparticles could be a lower-cost alternative to gold nanoparticles ($8/g Hf vs. $56/g Au).

Previous studies describing preparation of hafnia nanoparticles for use as CT contrast agents used particles synthesized using sol-gel and direct precipitation methods. However, these approaches have limited size and shape control and can result in contamination leading to cytotoxicity. Although thermal decomposition synthesis methods could provide for improved size control, they remain poorly investigated for synthesis of hafnia nanoparticles. Additionally, thermal decomposition methods result in particles coated with an organic layer and require phase transfer to aqueous media to enable biomedical applications.

Flash nanoprecipitation (FNP) is a simple and scalable method to formulate nanoparticles consisting of a hydrophobic core and an outer hydrophilic layer through rapid mixing and diffusion limited aggregation of hydrophobic compounds and particles and amphiphilic block copolymers. FNP has been widely used to formulate organic drug carriers and, to a lesser extent, composite nanoparticles consisting of inorganic nanocrystals and co-core organic excipients such as fluorophores and drugs.

Here, we report the preparation of hafnia nanoparticle clusters (HNCs) using hafnia nanoparticles synthesized through thermal decomposition of hafnium trifluoroacetate in oleylamine. Hafnia nanoparticles and hydrophobic green fluorophore (3,3′-Dioctadecyloxacarbocyanine perchlorate) with polylactic acid (PLA) as co-core polymer were encapsulated in poly(lactic acid)-b-poly(ethylene glycol) (PLA-b-PEG) by FNP using a new 3D printed multi-inlet vortex mixer. HNCs of hydrodynamic size ranging from 100 to 200 nm were prepared by adjusting FNP conditions. The CT contrast performance of HNCs was compared to the clinical CT contrast agent OMNIPAQUE (active ingredient, iohexol), suggesting better CT contrast for the HNCs. The HNCs were found to be colloidally stable in cell culture media, with negligible change in hydrodynamic diameter over a period of 24 hours. Results for in vitro cytotoxicity and pharmacokinetics of the HNCs in mice will also be presented. This study will be the first to investigate the CT performance, cytotoxicity, and pharmacokinetic of hafnia nanoparticles synthesized from thermal decomposition. We aim to find an excellent candidate to substitute current blood pool imaging agents for CT with lower cost, better biocompatibility, and higher tolerance to patients with chronic kidney disease.