title: Neuroblastoma-targeted nanoparticles entrapping siRNA specifically knockdown ALK.
abstract: RNA interference molecules have some advantages as cancer therapeutics, including a proved efficacy on both wild-type (WT) and mutated transcripts and an extremely high sequence-specificity. The most significant hurdle to be overcome if exogenous small interfering RNAs (siRNA) is to be used therapeutically is the specific, effective, nontoxic delivery of siRNA to its intracellular site of action. At present, human applications are confined almost exclusively to targets within the liver, where the delivery systems naturally accumulate, and extra-hepatic targets remain a challenge. Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that has recently been shown to contribute to the cell growth and progression of human neuroblastoma (NB). We investigated its potential as a therapeutic target in NB by generating anti-GD₂-targeted nanoparticles that carry ALK-directed siRNA, which are specifically and efficiently delivered to GD₂-expressing NB cells. Relative to free ALK-siRNA, anti-GD₂-targeted liposomal formulations of ALK-siRNA had low plasma clearance, increased siRNA stability, and improved binding, uptake, silencing and induction of cell death, and specificity for NB cells. In NB xenografts, intravenous (i.v.) injection of the targeted ALK-siRNA liposomes showed gene-specific antitumor activity with no side effects. ALK-selective siRNA entrapped in anti-GD₂-targeted nanoparticles is a promising new modality for NB treatment.
authors.affiliation: Department of Experimental Medicine, Experimental Therapy Unit, Laboratory of Oncology, Istituto G. Gaslini, Genoa, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Di Paolo
authors.forename: Chiara
authors.initials: C
authors.lastname: Brignole
authors.forename: Fabio
authors.initials: F
authors.lastname: Pastorino
authors.forename: Roberta
authors.initials: R
authors.lastname: Carosio
authors.forename: Alessia
authors.initials: A
authors.lastname: Zorzoli
authors.forename: Marzia
authors.initials: M
authors.lastname: Rossi
authors.forename: Monica
authors.initials: M
authors.lastname: Loi
authors.forename: Gabriella
authors.initials: G
authors.lastname: Pagnan
authors.forename: Laura
authors.initials: L
authors.lastname: Emionite
authors.forename: Michele
authors.initials: M
authors.lastname: Cilli
authors.forename: Silvia
authors.initials: S
authors.lastname: Bruno
authors.forename: Roberto
authors.initials: R
authors.lastname: Chiarle
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Allen
authors.forename: Mirco
authors.initials: M
authors.lastname: Ponzoni
authors.forename: Patrizia
authors.initials: P
authors.lastname: Perri
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D020868:Gene Silencing / Q000502:physiology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles / Q000737:chemistry; D009447:Neuroblastoma / Q000201:enzymology* / Q000235:genetics / Q000628:therapy*; D034741:RNA, Small Interfering / Q000235:genetics / Q000502:physiology*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: D034741:RNA, Small Interfering; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases