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

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.
AuthorsBainan Wu, Si Wang, Surya K De, Elisa Barile, Bridget A Quinn, Irina Zharkikh, Angela Purves, John L Stebbins, Robert G Oshima, Paul B Fisher, Maurizio Pellecchia
JournalChemistry & biology (Chem Biol) Vol. 22 Issue 7 Pg. 876-887 (Jul 23 2015) ISSN: 1879-1301 [Electronic] United States
PMID26165155 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
CopyrightCopyright © 2015 Elsevier Ltd. All rights reserved.
Chemical References
  • Antineoplastic Agents
  • Receptor, EphA2
  • Paclitaxel
Topics
  • Amino Acid Sequence
  • Animals
  • Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
  • Cell Line, Tumor
  • Cell Survival (drug effects)
  • Drug Delivery Systems (methods)
  • Female
  • Humans
  • Male
  • Melanoma, Experimental (drug therapy, metabolism)
  • Mice
  • Mice, Nude
  • Models, Animal
  • Molecular Targeted Therapy
  • Paclitaxel (analogs & derivatives, chemistry, pharmacology)
  • Pancreatic Neoplasms (drug therapy, metabolism)
  • Rats
  • Receptor, EphA2 (agonists, chemistry)
  • Xenograft Model Antitumor Assays

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