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¹ LiPlasome Pharma A/S and ² Department of Chemistry, Technical University of Denmark, Lyngby, Denmark and ³ Cancer Research Unit, Tom Connors Cancer Research Centre, University of Bradford, Bradford, United Kingdom

Requests for reprints: Kent Jørgensen, LiPlasome Pharma A/S, Technical University of Denmark, DK-2800 Lyngby, Denmark. Phone: 45-45252458; Fax: 45-45883136. E-mail: jorgense{at}liplasome.com

The use of many common clinically relevant chemotherapeutics is often limited due to insufficient delivery to the tumor and dose-limiting systemic toxicities. Therefore, therapeutics that specifically target tumor cells and are nontoxic to normal cells are required. Here, we report the development of a novel class of liposomes composed of lipid prodrugs, which use the increased secretory phospholipase A₂ type IIA (sPLA₂) activity of the tumor microenvironment as a trigger for the release of anticancer etherlipids (AEL). Treatment of sPLA₂-secreting tumor cells in vitro with liposomes consisting of proAELs resulted in growth inhibition comparable with addition of the AELs alone. Using a specific sPLA₂ inhibitor, we showed the low cytotoxicity of the nonhydrolyzed proAEL liposomes and have proven the sPLA₂ dependency of the activation of proAELs to cytotoxic AELs. In addition, we showed that our proAEL liposomes circumvent the inherent hemolytic toxicities associated with the use of etherlipids, thereby allowing i.v. administration of such therapeutics as nontoxic prodrug liposomes. Furthermore, using a sPLA₂-secreting human colon cancer xenograft model, we showed that the proAEL liposomes are capable of inducing a tumor growth delay in vivo. Taken together, these data support the validity of this novel tumor-selective liposomal prodrug delivery strategy. This new approach also provides a promising system for tumor-selective delivery and release of conventional chemotherapeutics encapsulated in the sPLA₂-degradable prodrug liposomes.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

⁴ S.S. Jensen, T.L. Anderson, T. Kaarsgaard, J. Davidsen, T. Fichtner, and K. Jørgensen, unpublished observations.

Received 5/11/04; revised 7/19/04; accepted 8/31/04.