title: 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.
authors.affiliation: Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Bainan
authors.initials: B
authors.lastname: Wu
authors.affiliation: Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Si
authors.initials: S
authors.lastname: Wang
authors.affiliation: Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Surya K
authors.initials: SK
authors.lastname: De
authors.affiliation: Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Elisa
authors.initials: E
authors.lastname: Barile
authors.affiliation: 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.
authors.forename: Bridget A
authors.initials: BA
authors.lastname: Quinn
authors.affiliation: Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Irina
authors.initials: I
authors.lastname: Zharkikh
authors.affiliation: Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Angela
authors.initials: A
authors.lastname: Purves
authors.affiliation: Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: John L
authors.initials: JL
authors.lastname: Stebbins
authors.affiliation: Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Oshima
authors.affiliation: 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.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
authors.affiliation: Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Pellecchia
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016503:Drug Delivery Systems / Q000379:methods; D005260:Female; D006801:Humans; D008297:Male; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D023421:Models, Animal; D058990:Molecular Targeted Therapy; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism; D051381:Rats; D036104:Receptor, EphA2 / Q000819:agonists* / Q000737:chemistry; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D036104:Receptor, EphA2; D017239:Paclitaxel