Multifunctional doped ferrite nanoparticles for cancer therapy: innovations in magnetic fluid hyperthermia and imaging technologies

This PhD thesis investigates the development and application of multifunctional magnetic nanoparticles (MNPs) to advance cancer therapy, particularly through the integration of magnetic fluid hyperthermia (MFH) with diagnostic imaging techniques such as magnetic resonance imaging (MRI) and magnetic particle imaging (MPI). This work addresses some critical challenges in hyperthermia-based cancer treatment by introducing a novel class of doped ferrite nanoparticles engineered with self-regulating temperature capabilities. These self-regulating nanoparticles were designed to heat precisely up to their Curie temperature, ceasing further heat generation to protect surrounding healthy tissues, thereby improving the safety and effectiveness of hyperthermia treatments. A key component of the project was the functionalization of these nanoparticles with biocompatible coatings, including glucose (GM55), chitosan (CM55), and polyethylene glycol (PM55). Each coating imparted unique properties, enabling the nanoparticles to be tailored for specific therapeutic and diagnostic applications. Glucose-coated nanoparticles (GM55) emerged as the most effective variant for intracellular hyperthermia, demonstrating enhanced cellular uptake, superior heating efficiency, and excellent biocompatibility in cellular models. These nanoparticles achieved therapeutic hyperthermic temperatures under an alternating magnetic field, inducing significant cancer cell death after single and repeated treatments. The self-regulating mechanism of these nanoparticles further ensured that therapeutic heating was achieved without exceeding safe temperature thresholds, minimizing risks of collateral damage. In addition to their therapeutic potential, the nanoparticles exhibited robust dual imaging capabilities, providing a comprehensive theranostic platform. MRI studies showed significant contrast enhancement in T2-weighted imaging, facilitating precise localization. MPI, a relatively new imaging modality, allowed direct, quantitative tracking of nanoparticle with promising sensitivity. These complementary imaging techniques enabled real-time monitoring of treatment delivery and tumor response, significantly improving the ability to tailor and optimize therapy protocols dynamically. A critical barrier to hyperthermia’s efficacy, cellular resistance mediated by the heat shock response (HSR), was also addressed in this study. Proteomic analyses revealed the upregulation of heat shock proteins (HSPs), which act as molecular chaperones to protect cancer cells from hyperthermic stress. The research explored combination therapies involving MFH and HSR inhibitors, demonstrating that such strategies could effectively enhance hyperthermia-induced cell death in vitro. This approach highlighted the potential to achieve synergistic effects when combining MFH with adjunct therapies such as chemotherapy or immunotherapy. In vivo studies further validated the efficacy of these nanoparticles in a mouse model of aggressive breast cancer. GM55 nanoparticles reduced tumor growth, confirming their suitability as therapeutic agents and imaging tracers. The findings pave the way for potential clinical translation, especially for treating aggressive cancers such as triple-negative breast cancer, which are often resistant to conventional therapies. This work represents an advancement in the field of nanomedicine, showcasing the potential of multifunctional nanoparticles to integrate therapeutic and diagnostic roles into a single platform. By addressing safety concerns, overcoming treatment resistance, and enhancing treatment monitoring, these self-regulating nanoparticles provide a new avenue for more targeted, efficient, and minimally invasive cancer therapies. The results also open pathways for future research into optimizing nanoparticle formulations, improving circulation times, and exploring the efficacy of MFH in combination with other therapeutic modalities. This PhD research lays a robust foundation for the clinical application of theranostic nanoparticles, offering transformative potential in the fight against cancer.