(672g) Engineering Theranostic Superparamagnetic Nanoparticles for Hyperthermia and Magnetic Particle Imaging Using a Quality-By-Design Approach

Image guided therapy integrating magnetic particle imaging (MPI) and magnetic hyperthermia (MH) is of great potential interest as it enables personalized and precise treatment.¹ The properties of superparamagnetic iron oxide nanoparticles (SPIONs) to release heat in an alternating magnetic field (AMF) and to act as contrast agents make them an excellent theranostic modality. The development of tailored SPIONs is paramount to achieve high sensitivity and good resolution for imaging, and efficient and controlled hyperthermia.² Therefore, to support the clinical translation of SPIONs, here we apply a quality-by-design (QbD) approach to systematically investigate the effect of SPION particle properties on their MPI and MH performance.

SPIONs were produced by scalable flame spray pyrolysis (FSP)³ technique. The QbD approach, implemented risk analysis and design of experiments (DoE) to link the SPION properties with MPI and MH performance. First, the effects of FSP process parameters were correlated with the SPION crystal size using a factorial design. This DoE was modelled using multiple linear regression (R² 0.98, Q² 0.95). The nanoparticle crystal size was strongly affected by the precursor concentration and flow rate, and the dispersion gas flow rate. Based on this DoE model, the nanoparticle size and surface area can be fine-tuned during their manufacturing. Then, a subsequent DoE linked the crystal size and composition of SPIONs with their saturation magnetization (M_s), intrinsic loss power (ILP) and MPI performance. The crystal size was varied between 6 to 30 nm (to yield superparamagnetic particles) and the SPION composition (M_xFe_3-xO₄) was modified using four dopants (M = Zn, Co, Mn, Mg) at three doping concentrations (x = 0.25, 0.5, 0.75).

Modelling of the DoE showed that the choice of dopant has a significant effect on the M_s. Doping with Co, Mn and Zn increased the M_s, whereas Mg doping significantly decreased it. Furthermore, larger crystal size and lower doping content was strongly linked to an increase in M_s. Preliminary studies of the hyperthermia performance, as assessed by ILP, also indicated a strong correlation with the dopant. Manganese showed the highest ILP amongst all the dopants. Moreover, the ILP was found to be higher in SPIONs > 13 nm compared to smaller ones.

Overall, MPI and MH performance of SPIONs show strong relationship with their size and composition. This study demonstrates a systematic QbD approach to develop theranostic SPION-based drug delivery system and supports their early development towards clinical applications.

Acknowledgement: This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No. 101002582). The authors also acknowledge financial support from the Science for Life Laboratory.

References:

(1) Dadfar, S. M.; Roemhild, K.; Drude, N. I.; von Stillfried, S.; Knüchel, R.; Kiessling, F.; Lammers, T. Iron Oxide Nanoparticles: Diagnostic, Therapeutic and Theranostic Applications. Adv. Drug Deliv. Rev. 2019, 138, 302–325.

(2) Du, Y.; Liu, X.; Liang, Q.; Liang, X.-J.; Tian, J. Optimization and Design of Magnetic Ferrite Nanoparticles with Uniform Tumor Distribution for Highly Sensitive MRI/MPI Performance and Improved Magnetic Hyperthermia Therapy. Nano Lett. 2019, 19 (6), 3618–3626.

(3) Mueller, R.; Mädler, L.; Pratsinis, S. E. Nanoparticle Synthesis at High Production Rates by Flame Spray Pyrolysis. Chem. Eng. Sci. 2003, 58 (10), 1969–1976.