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

Abstract

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 > 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< 0.01, ***P< 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 & Implications: BG-P 400 -TAT represents a potential lead candidate for the treatment of neuroblastoma and other neuroendocrine tumors.

Navigating new horizons: Prospects of NET-targeted radiopharmaceuticals in precision medicine

“…The landscape of PET imaging has greatly evolved through the ongoing quest to enhance tracer specificity and NET binding affinity, key factors for precise diagnostic imaging [39]. The narrative began with the advent of 11 C-labeled tracers such as 11 C-hydroxyephedrine (HED), an innovative tracer for delineating cardiac sympathetic nerve function [53][54][55][56]. Although 11 C-HED demonstrates high affinity for norepinephrine transport system and has been instrumental in cardiac [57] and oncological imaging [58], its clinical utility is curtailed by the short half-life of 11 C (20.4 min), which requires the proximity of a cyclotron and constrains the imaging time window.…”

“…The narrative began with the advent of 11 C-labeled tracers such as 11 C-hydroxyephedrine (HED), an innovative tracer for delineating cardiac sympathetic nerve function [53][54][55][56]. Although 11 C-HED demonstrates high affinity for norepinephrine transport system and has been instrumental in cardiac [57] and oncological imaging [58], its clinical utility is curtailed by the short half-life of 11 C (20.4 min), which requires the proximity of a cyclotron and constrains the imaging time window. Despite the achievements with 11 C-labeled tracers, the shift toward 18 F-labeling over the past two decades is driven by several advantages: cost-effectiveness due to centralized distribution, the feasibility of delayed and prolonged scans owing to a longer half-life (110 min), enhanced avaliablity of PET imaging, and the design flexibility that accommodates improved metabolic stability.…”

“…This Ivyspring International Publisher phenomenon not only contributes to the diverse autonomic symptoms experienced by patients but also serves as a potential marker for early diagnosis [9]. Furthermore, NET is a key player in the growth and progression of certain tumors [10], including neuroblastoma [11], pheochromocytoma [12], and paraganglioma [13]. The expression of NET in these malignancies provides a unique target for both diagnostic imaging and radiotherapeutic interventions [14], allowing for the precise localization and treatment of these tumors.…”