The neurokinin-1 receptor (NK1R) plays a significant role in the progression and metastasis of several neuroendocrine tumors. Due to its upregulation in these cancers, NK1R constitutes an attractive receptor for development of ligand-targeted imaging and therapeutic agents. In this report, we present the design and synthesis of an NK1R targeting ligand conjugated to the chemotherapeutic agent, tubulysin B hydrazide (TubBH), via a self-immolative linker. We then explore the ability of this low molecular weight tubulysin conjugate to kill NK1R overexpressing cancer cells both in vitro and in vivo without killing receptor negative healthy cells. Because similar studies in mice bearing NK1-negative tumors reveal no therapeutic impact, we conclude that our NK1R targeting ligand is specific for NK1R-expressing cells. Taken together, the data suggest a possible new approach for the treatment of NK1R-positive neuroendocrine cancers.
Keywords: conjugation; drug targeting; ligand-targeted therapy; neuroendocrine cancer; neurokinin-1 receptor; receptors; substance P; tubulysin; tumor.