Sarah Nanoparticles (SaNPs) are unique multicore iron oxide-based nanoparticles, developed for the treatment of advanced cancer, following standard care, through the selective delivery of thermal energy to malignant cells upon exposure to an alternating magnetic field. For their therapeutic effect, SaNPs need to accumulate in the tumor. Since the potential accumulation and associated toxicity in normal tissues are an important risk consideration, biodistribution and toxicity were assessed in naïve BALB/c mice. Therapeutic efficacy and the effect on survival were investigated in the 4T1 murine model of metastatic breast cancer. Toxicity evaluation at various timepoints did not reveal any abnormal clinical signs, evidence of alterations in organ function, nor histopathologic adverse target organ toxicity, even after a follow up period of 25 weeks, confirming the safety of SaNP use. The biodistribution evaluation, following SaNP administration, indicated that SaNPs accumulate mainly in the liver and spleen. A comprehensive pharmacokinetics evaluation, demonstrated that the total percentage of SaNPs that accumulated in the blood and vital organs was ~78%, 46%, and 36% after 4, 13, and 25 weeks, respectively, suggesting a time-dependent clearance from the body. Efficacy studies in mice bearing 4T1 metastatic tumors revealed a 49.6% and 70% reduction in the number of lung metastases and their relative size, respectively, in treated vs. control mice, accompanied by a decrease in tumor cell viability in response to treatment. Moreover, SaNP treatment followed by alternating magnetic field exposure significantly improved the survival rate of treated mice compared to the controls. The median survival time was 29 ± 3.8 days in the treated group vs. 21.6 ± 4.9 days in the control, p-value 0.029. These assessments open new avenues for generating SaNPs and alternating magnetic field application as a potential novel therapeutic modality for metastatic cancer patients.

Over the last 2 decades, magnetic hyperthermia (MH) has been recognized as a promising concept for efficient cancer treatment. Recently, it has been receiving increased attention because of its procedure simplicity, noninvasive nature, and effective solid tumor heating with minimal damage to healthy surrounding normal tissues. In this paper, we report about the development of theranostic superparamagnetic iron oxide nanoclusters, demonstrating efficient heating in hyperthermia and good response under a magnetic resonance imaging (MRI) scan. Multiple cores of 25 ± 2 nm superparamagnetic iron oxide (Fe 3 O 4 ) nanoparticles and paraffin wax based on 24-hydrocarbon chains (tetracosane), used as a phase change material, were coencapsulated in an interior core of a self-assembled PEO−PPO− PEO polymer and subsequently covalently coated by 20 kDa branched poly(ethylene glycol), resulting in 135 ± 10 nm hydrodynamic diameter nanoclusters. The synthesized nanoclusters were found to have good stability in phosphate-buffered saline. The physicochemical and magnetic properties of the nanoclusters exhibit an efficient magnetic-to-thermal energy conversion with self-regulation of the hyperthermia temperature. Under irradiation to an alternating magnetic field (AMF) of 33 kA/m at a frequency of 300 kHz, the nanoclusters demonstrate a specific absorption rate (SAR) of 475 ± 17 W/g. The nanoclusters also exhibit a high transverse relaxivity of 68 (mM s) −1 at 1.5 T MRI. In preclinical studies, nanoclusters were intravenously injected to mice bearing 4T1 triple negative breast carcinoma lung metastases. Mice were irradiated by an AMF to demonstrate the antitumor efficacy, with 66% reduction in the number of metastases, which pave the route for the application of effective hyperthermia treatment for a metastatic cancer model.