Selective Tumor Targeting of Desacetyl Vinblastine Hydrazide and Tubulysin B via Conjugation to a Cholecystokinin 2 Receptor (CCK2R) Ligand

Charity Wayua, Jyoti Roy, Karson S. Putt, Philip S. Low

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

As the delivery of selectively targeted cytotoxic agents via antibodies or small molecule ligands to malignancies has begun to show promise in the clinic, the need to identify and validate additional cellular targets for specific therapeutic delivery is critical. Although a multitude of cancers have been targeted using the folate receptor, PSMA, bombesin receptor, somatostatin receptor, LHRH, and αvβ3, there is a notable lack of specific small molecule ligand/receptor pairs to cellular targets found within cancers of the GI tract. Because of the selective GI tract expression of the cholecystokinin 2 receptor (CCK2R), we undertook the creation of conjugates that would deliver microtubule-disrupting drugs to malignancies through the specific targeting of CCK2R via a high affinity small molecule ligand. The cytotoxic activity of these conjugates were shown to be receptor mediated in vitro and in vivo with xenograft mouse models exhibiting delayed growth or regression of tumors that expressed CCK2R. Overall, this work demonstrates that ligands to CCK2R can be used to create selectively targeted therapeutic conjugates. (Chemical Equation Presented.)

Original languageEnglish (US)
Pages (from-to)2477-2483
Number of pages7
JournalMolecular pharmaceutics
Volume12
Issue number7
DOIs
StatePublished - Jul 6 2015

Keywords

  • CCK2R
  • cholecystokinin 2 receptor
  • targeted therapy
  • tubulysin
  • vinblastine

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery

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