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Background: In neuroendocrine tumors, the norepinephrine transporter (NET) is very active and has been exploited for diagnostic imaging purposes and/or therapy with localized radiotherapy. Integrin αvβ3 is generously expressed by and/or activated on cancer cells, but not by nonmalignant cells. Purpose: In the present investigation, the anticancer efficacy of the dual targeting of norepinephrine transporter (NET), benzylguanidine (BG), and thyrointegrin αvβ3 receptors antagonist triazole tetraiodothyroacetic acid (TAT) conjugated via the non-cleavable linker polyethylene glycol (P, PEG400) in the treatment of human neuroblastoma was evaluated. Experimental approach: The synthesized dual targeting compound, a novel new chemical entity named BG-P 400 -TAT, has purity &gt; 98% and was formulated and tested in neuroblastoma models using neuroblastoma cell lines (SK-N-FI, SMS-KCN and SMS-KANR) implanted in SCID and NSG mice models. Key Results: BG-P 400 -TAT demonstrated significant ( **P&lt; 0.01, ***P&lt; 0.001) suppression of neuroblastoma tumor progression, growth, and viability in both mice models implanted with the neuroblastoma. The pharmacokinetic and biodistribution profile of BG-P 400 -TAT showed a significant increase in BG-P 400 -TAT levels in plasma and xenografts of NSG compared to SCID mice. Further our RNAseq genome-wide expression profiling experiments in neuroblastoma cell line SKNAS results showed that BG-P 400 -TAT treatment altered the signal transduction pathways, intracellular multiprotein complexes and Independent GSEA. Conclusion &amp; Implications: BG-P 400 -TAT represents a potential lead candidate for the treatment of neuroblastoma and other neuroendocrine tumors.

Anticancer Efficacy and Mechanisms of a Dual Targeting of Norepinephrine Transporter and Thyrointegrin αvβ3 Antagonist in Neuroblastoma