© 2000 by Oxford University Press
Journal of the National Cancer Institute, Vol. 92, No. 3, 253-261,
February 2, 2000
© 2000 Oxford University Press
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Delivery of c-myb Antisense Oligodeoxynucleotides to Human Neuroblastoma Cells Via Disialoganglioside GD2-Targeted Immunoliposomes: Antitumor Effects
Affiliations of authors: G. Pagnan, F. Pastorino, L. Raffaghello, P. G. Montaldo, M. Ponzoni, Laboratory of Oncology, G. Gaslini Children's Hospital, Genoa, Italy; D. D. Stuart, T. M. Allen, Department of Pharmacology, University of Alberta, Edmonton, Canada; B. Calabretta, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA.
Correspondence to: Mirco Ponzoni, Ph.D., Laboratory of Oncology, G. Gaslini Children's Hospital, Largo G. Gaslini 5, 16148, Genoa, Italy (e-mail: mircoponzoni{at}ospedale-gaslini.ge.it).
BACKGROUND: Advanced-stage neuroblastoma resists conventional treatment; hence, novel therapeutic approaches are required. We evaluated the use of c-myb antisense oligodeoxynucleotides (asODNs) delivered to cells via targeted immunoliposomes to inhibit c-Myb protein expression and neuroblastoma cell proliferation in vitro.METHODS: Phosphorothioate asODNs and control sequences were encapsulated in cationic lipid, and the resulting particles were coated with neutral lipids to produce coated cationic liposomes (CCLs). Monoclonal antibodies directed against the disialoganglioside GD2 were covalently coupled to the CCLs. 3H-labeled liposomes were used to measure cellular binding, and cellular uptake of asODNs was evaluated by dot-blot analysis. Growth inhibition was quantified by counting trypan blue dye-stained cells. Expression of c-Myb protein was examined by western blot analysis. RESULTS: Our methods produced GD2-targeted liposomes that stably entrapped 80%-90% of added c-myb asODNs. These liposomes showed concentration-dependent binding to GD2-positive neuroblastoma cells that could be blocked by soluble anti-GD2 monoclonal antibodies. GD2-targeted liposomes increased the uptake of asODNs by neuroblastoma cells by a factor of fourfold to 10-fold over that obtained with free asODNs. Neuroblastoma cell proliferation was inhibited to a greater extent by GD2-targeted liposomes containing c-myb asODNs than by nontargeted liposomes or free asODNs. GD2-targeted liposomes containing c-myb asODNs specifically reduced expression of c-Myb protein by neuroblastoma cells. Enhanced liposome binding and asODN uptake, as well as the antiproliferative effect, were not evident in GD2-negative cells. CONCLUSIONS: Encapsulation of asODNs into immunoliposomes appears to enhance their toxicity toward targeted cells while shielding nontargeted cells from antisense effects and may be efficacious for the delivery of drugs with broad therapeutic applications to tumor cells.
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