title: Novel phage display-derived neuroblastoma-targeting peptides potentiate the effect of drug nanocarriers in preclinical settings.
abstract: Molecular targeting of drug delivery nanocarriers is expected to improve their therapeutic index while decreasing their toxicity. Here we report the identification and characterization of novel peptide ligands specific for cells present in high-risk neuroblastoma (NB), a childhood tumor mostly refractory to current therapies. To isolate such targeting moieties, we performed combined in vitro/ex-vivo phage display screenings on NB cell lines and on tumors derived from orthotopic mouse models of human NB. By designing proper subtractive protocols, we identified phage clones specific either for the primary tumor, its metastases, or for their respective stromal components. Globally, we isolated 121 phage-displayed NB-binding peptides: 26 bound the primary tumor, 15 the metastatic mass, 57 and 23 their respective microenvironments. Of these, five phage clones were further validated for their specific binding ex-vivo to biopsies from stage IV NB patients and to NB tumors derived from mice. All five clones also targeted tumor cells and vasculature in vivo when injected into NB-bearing mice. Coupling of the corresponding targeting peptides with doxorubicin-loaded liposomes led to a significant inhibition in tumor volume and enhanced survival in preclinical NB models, thereby paving the way to their clinical development.
authors.affiliation: Experimental Therapy Unit, Laboratory of Oncology, Istituto Giannina Gaslini, Genoa, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Loi
authors.forename: Daniela
authors.initials: D
authors.lastname: Di Paolo
authors.forename: Marco
authors.initials: M
authors.lastname: Soster
authors.forename: Chiara
authors.initials: C
authors.lastname: Brignole
authors.forename: Alice
authors.initials: A
authors.lastname: Bartolini
authors.forename: Laura
authors.initials: L
authors.lastname: Emionite
authors.forename: Jessica
authors.initials: J
authors.lastname: Sun
authors.forename: Pamela
authors.initials: P
authors.lastname: Becherini
authors.forename: Flavio
authors.initials: F
authors.lastname: Curnis
authors.forename: Andrea
authors.initials: A
authors.lastname: Petretto
authors.forename: Monica
authors.initials: M
authors.lastname: Sani
authors.forename: Alessandro
authors.initials: A
authors.lastname: Gori
authors.forename: Marco
authors.initials: M
authors.lastname: Milanese
authors.forename: Claudio
authors.initials: C
authors.lastname: Gambini
authors.forename: Renato
authors.initials: R
authors.lastname: Longhi
authors.forename: Michele
authors.initials: M
authors.lastname: Cilli
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Allen
authors.forename: Federico
authors.initials: F
authors.lastname: Bussolino
authors.forename: Wadih
authors.initials: W
authors.lastname: Arap
authors.forename: Renata
authors.initials: R
authors.lastname: Pasqualini
authors.forename: Angelo
authors.initials: A
authors.lastname: Corti
authors.forename: Mirco
authors.initials: M
authors.lastname: Ponzoni
authors.forename: Serena
authors.initials: S
authors.lastname: Marchiò
authors.forename: Fabio
authors.initials: F
authors.lastname: Pastorino
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D061505:Cell Surface Display Techniques; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008081:Liposomes; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D009447:Neuroblastoma / Q000188:drug therapy* / Q000473:pathology; D010455:Peptides / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D008081:Liposomes; D010455:Peptides; D004317:Doxorubicin
keywords: Liposomes; Nanocarriers; Neuroblastoma; Peptides; Phage display screening; Targeted therapy