1. Academic Validation
  2. Design and Characterization of Novel EphA2 Agonists for Targeted Delivery of Chemotherapy to Cancer Cells

Design and Characterization of Novel EphA2 Agonists for Targeted Delivery of Chemotherapy to Cancer Cells

  • Chem Biol. 2015 Jul 23;22(7):876-887. doi: 10.1016/j.chembiol.2015.06.011.
Bainan Wu # 1 Si Wang # 1 Surya K De # 1 Elisa Barile # 1 Bridget A Quinn 2 Irina Zharkikh 1 Angela Purves 1 John L Stebbins 1 Robert G Oshima 1 Paul B Fisher 2 Maurizio Pellecchia 1
Affiliations

Affiliations

  • 1 Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
  • 2 Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine and VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298-0033, USA.
  • # Contributed equally.
Abstract

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.

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