Self-regulating novel iron oxide nanoparticle-based magnetic hyperthermia in swine: biocompatibility, biodistribution, and safety assessments.

Studies demonstrating the successful and safe application of magnetic hyperthermia in large animals are scarce. A therapeutic approach for advanced cancer comprising multicore encapsulated iron oxide (IO) Sarah Nanoparticles (SaNPs), that uniquely self-regulate their temperature, was developed thus overcoming the safety challenges of hyperthermia. SaNPs are intravenously injected and accumulate in tumor tissue, leading to selective heating upon exposure to an external alternating magnetic field (AMF). A series of studies were conducted in healthy swine to assess SaNPs' safety, alone or combined with AMF application. Administration of single high (up to 22 mg IO/kg) or low (3.6 mg IO/kg) SaNP doses had no adverse effects, including no infusion reactions. Vital signs remained stable with no significant clinical pathology changes, and no treatment-associated toxicities. Biodistribution analysis indicated that SaNPs predominantly accumulate in the lungs and clear in a dose- and time-dependent manner. In minipigs that received a single SaNP no-observed-adverse-effect-level (NOAEL)-based dose (3.6 mg IO/kg) with AMF, the average percentage remaining in vital organs after 90 days was 13.7%. No noticeable clinical signs were noted during the 87 to 92-day observation period following irradiation, and no inflammation, necrosis, nor thermal damage were found in the histopathology evaluation. In another minipig, ~ 90 days after three recurrent high doses (14 mg IO/kg), without AMF, almost half of the injected SaNPs were cleared with no residual detrimental effects. We demonstrate that the approach is safe and well tolerated in swine, opening potential avenues as a novel therapeutic modality for cancer patients.

Novel Nanoparticle-Based Cancer Treatment, Effectively Inhibits Lung Metastases and Improves Survival in a Murine Breast Cancer Model.

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.

The self-adjusting file (SAF). Part 2: mechanical analysis.

INTRODUCTION: The study was designed to explore the mechanical properties of the self-adjusting file (SAF) and its application in the root canal using continuous irrigation. METHODS: The compressibility of the SAF file and the resulting peripheral force were measured using specially designed systems. The abrasivity of the file was tested on dentin blocks representing a flat root canal. The durability of the SAF file was tested using a functional fatigue-to-failure assay. Degradation of the file was evaluated by using files that were previously used for 10, 20, and 30 minutes and comparing their efficacy with that of new, unused files. The potential of extruding irrigant beyond the apex was explored in roots with an open apical foramen. RESULTS: The SAF file was elastically compressible from a diameter of 1.5 mm to dimensions similar to those of a #20 stainless steel K-file. This compression resulted in an evenly applied force to the root canal walls. The in-and-out vibration of the file and the peripheral force, combined with its abrasivity, allow for hard-tissue removal. Under the conditions of the experiment, no mechanical failure was observed with up to 29 minutes of operation in the root canal. The file loses its efficacy after prolonged use, with a 40% reduction after 30 minutes of operation. The operation of the file with continuous irrigation did not push the irrigant beyond an open apical foramen. CONCLUSIONS: The SAF file is an elastically compressible file that effectively removes dentin and can mechanically endure use under its recommended mode of operation with a minimal loss of efficacy.