Abstract
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Objectives: Metastatic melanoma is a very aggressive neoplasm presenting high mortality rates in a few months and resistance to therapeutic interventions. Previous studies have shown that tissue factor expression (TF), a blood coagulation initiator protein, correlates with the histological grade of malignancy and vascularity, playing a fundamental role in tumor invasion, tumor growth, angiogenesis and metastasis. Ixolaris, a non-immunogenic molecule that specifically binds to TF, has already demonstrated in vivo reduced growth of melanoma tumor metastatic nodules (B16-F10). Thus, the main objectives of this work were: I) To develop an efficient and stable labeling technique of Ixolaris with Iodine-131(131I) which could also maintain its biological activity; II) To study and compare in healthy and melanoma-induced mice, the biodistribution of 131I and 131I-Ixolaris; and III) to evaluate whether 131I-Ixolaris could serve as a metastatic melanoma agent.
Methods: Ixolaris radioiodination was done using iodogen at room temperature. Quality control was made with paper and liquid chromatography (sephadex G-75). Labeling stability was accessed for 24h and the anticoagulant activity of 131I-Ixolaris was measured using a coagulometer. Planar and SPECT imaging and biodistribution studies were performed after intravenous administration (iv) of 131I or 131I-Ixolaris in a murine melanoma model (B16-F10) divided in 3 groups: I-D0 of induction; II-D15; and III-D1 and D15 (double treatment). Animals were sacrificed at D18.
Results: In vitro studies have demonstrated that 131I-Ixolaris is stable at plasma and saline for at least 24h and maintains its inhibitory activity on blood coagulation. Biodistribution studies and lung nodules counts showed that the fractionated use of 9MBq of 131I-Ixolaris (D1/D15) reached better results showing a decrease in lung metastatic nodules. Scintigraphy 90 minutes after iv of 131I-Ixolaris demonstrated uptake in pulmonary topography.
Conclusions: These results suggest that 131I-Ixolaris has a promising future as a theranostics agent, and could serve as a new tool for the management and treatment of metastatic melanoma. This work was supported by FAPERJ and CNPq.