Design and Characterization of Novel EphA2 Agonists for Targeted Delivery of Chemotherapy to Cancer Cells. Issue 7 (23rd July 2015)

• Record Type: Journal Article
• Authors: Wu, Bainan; Wang, Si; De, Surya K.; Barile, Elisa; Quinn, Bridget A.; Zharkikh, Irina; Purves, Angela; Stebbins, John L.; Oshima, Robert G.; Fisher, Paul B.; Pellecchia, Maurizio
• Is Part Of: Chemistry & biology. Volume 22:Issue 7(2015)
• Page Start: 876
• Page End: 887
• Publication Date: 2015-07-23
• Subjects: Biochemistry -- Periodicals; 540
• DOI: 10.1016/j.chembiol.2015.06.011
• Languages: English
• ISSNs: 1074-5521

Abstract

Summary: The development of novel, targeted delivery agents for anti-cancer therapies requires the design and optimization of potent and selective tumor-targeting agents that are stable and amenable to conjugation with chemotherapeutic drugs. While short peptides represent potentially an excellent platform for these purposes, they often get degraded and are eliminated too rapidly in vivo. In this study, we used a combination of nuclear magnetic resonance-guided structure-activity relationships along with biochemical and cellular studies to derive a novel tumor-homing agent, named 123B9, targeting the EphA2 tyrosine kinase receptor ligand-binding domain. Conjugating 123B9 to the chemotherapeutic drug paclitaxel (PTX) via a stable linker results in an agent that is significantly more effective than the unconjugated drug in both a pancreatic cancer xenograft model and a melanoma lung colonization and metastases model. Hence, 123B9 could represent a promising strategy for the development of novel targeted therapies for cancer. Graphical Abstract: Highlights: 123B9 is a potent and selective EphA2 agonist targeting its ligand-binding domain 123B9 is long lived in plasma and in vivo In 123B9-L2-PTX, 123B9 is conjugated to paclitaxel (PTX) via a linker (L2) 123B9-L2-PTX is significantly more effective than PTX in targeting tumor growth Abstract : Wu et al. derived a novel tumor-homing agent, 123B9, targeting the EphA2 receptor. Conjugating 123B9 to paclitaxel results in an agent that is significantly more effective than the unconjugated drug in in vivo models of pancreatic cancer and melanoma.