PURPOSE: Current treatments for osteosarcoma (OS) have a poor prognosis, particularly for patients with metastasis and recurrence, underscoring an urgent need for new targeted therapies to improve survival. Targeted alpha-particle therapy selectively delivers cytotoxic payloads to tumors with radiolabeled molecules that recognize tumor-associated antigens. We have recently demonstrated the potential of an FDA approved, humanized anti-GD2 antibody, hu3F8, as a targeted delivery vector for radiopharmaceutical imaging of OS. The current study aims to advance this system for alpha-particle therapy of OS. METHODS: The hu3F8 antibody was radiolabeled with actinium-225, and the safety and therapeutic efficacy of the [225Ac]Ac-DOTA-hu3F8 were evaluated in both orthotopic murine xenografts of OS and spontaneously occurring OS in canines. RESULTS: Significant antitumor activity was proven in both cases, leading to improved overall survival. In the murine xenograft's case, tumor growth was delayed by 16-18 days compared to the untreated cohort as demonstrated by bioluminescence imaging. The results were further validated with magnetic resonance imaging at 33 days after treatment, and microcomputed tomography and planar microradiography post-mortem. Histological evaluations revealed radiation-induced renal toxicity, manifested as epithelial cell karyomegaly and suggestive polyploidy in the kidneys, suggesting rapid recovery of renal function after radiation damage. Treatment of the two canine patients delayed the progression of metastatic spread, with an overall survival time of 211 and 437 days and survival beyond documented metastasis of 111 and 84 days, respectively. CONCLUSION: This study highlights the potential of hu3F8-based alpha-particle therapy as a promising treatment strategy for OS.
Bone Neoplasms , Osteosarcoma , Humans , Mice , Animals , Dogs , Proof of Concept Study , X-Ray Microtomography , Antibodies, Monoclonal, Humanized , Osteosarcoma/diagnostic imaging , Osteosarcoma/radiotherapy , Bone Neoplasms/diagnostic imaging , Bone Neoplasms/radiotherapy , Cell Line, Tumor
Force spectroscopy using magnetic tweezers (MTs) is a powerful method to probe the physical characteristics of single polymers. Typically, molecules are functionalized for specific attachment to a glass surface at one end and a micrometer-scale paramagnetic bead at the other end. By applying an external magnetic field, multiple molecules can be stretched and twisted simultaneously without exposure to potentially damaging radiation. The majority of MTs utilize mobile, permanent magnets to produce forces on the beads (and the molecule under test). However, translating and rotating the permanent magnets may require expensive precision actuators, limit the rate at which force can be changed, and may induce vibrations that disturb tether dynamics and bead tracking. Alternatively, the magnetic field can be produced with an electromagnet, which allows fast force modulation and eliminates motor-associated vibration. Here, we describe a low-cost quadrapolar electromagnetic tweezer design capable of manipulating DNA-tethered MyOne paramagnetic beads with forces as high as 15 pN. The solid-state nature of the generated B-field modulated along two axes is convenient for accessing the range of forces and torques relevant for studying the activity of DNA motor enzymes like polymerases and helicases. Our design specifically leverages technology available at an increasing number of university maker spaces and student-run machine shops. Thus, it is an accessible tool for undergraduate education that is applicable to a wide range of biophysical research questions.
