title: Systemic combinatorial peptide selection yields a non-canonical iron-mimicry mechanism for targeting tumors in a mouse model of human glioblastoma.
abstract: The management of CNS tumors is limited by the blood-brain barrier (BBB), a vascular interface that restricts the passage of most molecules from the blood into the brain. Here we show that phage particles targeted with certain ligand motifs selected in vivo from a combinatorial peptide library can cross the BBB under normal and pathological conditions. Specifically, we demonstrated that phage clones displaying an iron-mimic peptide were able to target a protein complex of transferrin and transferrin receptor (TfR) through a non-canonical allosteric binding mechanism and that this functional protein complex mediated transport of the corresponding viral particles into the normal mouse brain. We also showed that, in an orthotopic mouse model of human glioblastoma, a combination of TfR overexpression plus extended vascular permeability and ligand retention resulted in remarkable brain tumor targeting of chimeric adeno-associated virus/phage particles displaying the iron-mimic peptide and carrying a gene of interest. As a proof of concept, we delivered the HSV thymidine kinase gene for molecular-genetic imaging and targeted therapy of intracranial xenografted tumors. Finally, we established that these experimental findings might be clinically relevant by determining through human tissue microarrays that many primary astrocytic tumors strongly express TfR. Together, our combinatorial selection system and results may provide a translational avenue for the targeted detection and treatment of brain tumors.
authors.affiliation: David H. Koch Center, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Fernanda I
authors.initials: FI
authors.lastname: Staquicini
authors.forename: Michael G
authors.initials: MG
authors.lastname: Ozawa
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Moya
authors.forename: Wouter H P
authors.initials: WH
authors.lastname: Driessen
authors.forename: E Magda
authors.initials: EM
authors.lastname: Barbu
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nishimori
authors.forename: Suren
authors.initials: S
authors.lastname: Soghomonyan
authors.forename: Leo G
authors.initials: LG
authors.lastname: Flores
authors.forename: Xiaowen
authors.initials: X
authors.lastname: Liang
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Paolillo
authors.forename: Mian M
authors.initials: MM
authors.lastname: Alauddin
authors.forename: James P
authors.initials: JP
authors.lastname: Basilion
authors.forename: Frank B
authors.initials: FB
authors.lastname: Furnari
authors.forename: Oliver
authors.initials: O
authors.lastname: Bogler
authors.forename: Frederick F
authors.initials: FF
authors.lastname: Lang
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Aldape
authors.forename: Gregory N
authors.initials: GN
authors.lastname: Fuller
authors.forename: Magnus
authors.initials: M
authors.lastname: Höök
authors.forename: Juri G
authors.initials: JG
authors.lastname: Gelovani
authors.forename: Richard L
authors.initials: RL
authors.lastname: Sidman
authors.forename: Webster K
authors.initials: WK
authors.lastname: Cavenee
authors.forename: Renata
authors.initials: R
authors.lastname: Pasqualini
authors.forename: Wadih
authors.initials: W
authors.lastname: Arap
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001812:Blood-Brain Barrier / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007501:Iron / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008958:Models, Molecular; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D019151:Peptide Library; D011990:Receptors, Transferrin / Q000378:metabolism; D014168:Transferrin / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D002352:Carrier Proteins; D009842:Oligopeptides; D019151:Peptide Library; D011990:Receptors, Transferrin; D014168:Transferrin; D007501:Iron