title: Design, synthesis and bioevaluation of an EphA2 receptor-based targeted delivery system.
abstract: Because of its overexpression in a range of solid tumors, the EphA2 receptor is a validated target for cancer therapeutics. We recently described a new targeted delivery system based on specific EphA2-targeting peptides conjugated with the chemotherapeutic agent paclitaxel. Here, we investigate the chemical determinants responsible for the stability and degradation of these agents in plasma. Introducing modifications in both the peptide and the linker between the peptide and paclitaxel resulted in drug conjugates that are both long-lived in rat plasma and that markedly decrease tumor size in a prostate cancer xenograft model compared with paclitaxel alone treatment. These studies identify critical rate-limiting degradation sites on the peptide-drug conjugates, enabling the design of agents with increased stability and efficacy. These results provide support for our central hypothesis that peptide-drug conjugates targeting EphA2 represent an innovative and potentially effective strategy to selectively deliver cytotoxic drugs to cancer cells.
authors.affiliation: Cancer Research Center, Sanford-Burnham Medical Research Institute, 10901 N. Torrey Pines Rd., La Jolla, CA 92037 (USA).
authors.forename: Elisa
authors.initials: E
authors.lastname: Barile
authors.forename: Si
authors.initials: S
authors.lastname: Wang
authors.forename: Swadesh K
authors.initials: SK
authors.lastname: Das
authors.forename: Roberta
authors.initials: R
authors.lastname: Noberini
authors.forename: Russell
authors.initials: R
authors.lastname: Dahl
authors.forename: John L
authors.initials: JL
authors.lastname: Stebbins
authors.forename: Elena B
authors.initials: EB
authors.lastname: Pasquale
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
authors.forename: Maurizio
authors.initials: M
authors.lastname: Pellecchia
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004337:Drug Carriers / Q000138:chemical synthesis* / Q000737:chemistry; D015195:Drug Design; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D017239:Paclitaxel / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry; D011471:Prostatic Neoplasms / Q000188:drug therapy; D036104:Receptor, EphA2 / Q000737:chemistry / Q000378:metabolism*; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D010455:Peptides; D036104:Receptor, EphA2; D017239:Paclitaxel
keywords: EphA2; chemotherapy; drug discovery; ephrins; targeted delivery