Alberto Gabizon, Yasmine Amitay, Hilary Shmeeda, Samuel Zalipsky
Shaare Zedek Medical Center and Hebrew University, POB 3235, Jerusalem il-91031, Israel
Most of the currently used chemotherapeutic agents have problematic toxicities compromising efficacy, and often resulting in life-threatening events. Liposomes can provide effective control of the release rate and of the tissue distribution of many of these agents. Mitomycin-C (MMC) is a highly potent cytotoxic drug with limited clinical use due to severe subacute and cumulative toxicities that drastically reduce the tolerable dose. A mitomycin-C lipid-based prodrug (MLP) formulated in pegylated liposomes (PL-MLP) was previously reported to have significant antitumor activity and reduced toxicity in mouse tumor models 1-3. Our drug delivery strategy consists of several levels: (i) synthesis of a prodrug with avid association to the liposomal bilayer to improve retention in liposomes; (ii) choice of a pegylated liposomal vehicle with Stealth® properties to ensure stability and long circulation and to enhance tumor liposome deposition by the EPR effect; (iii) thiolytic activation of the prodrug by reducing agents in either the extracellular or intra-cellular tumor space generating MMC which rapidly dissociates from liposomes and becomes fully bioavailable. We will review here our studies examining the plasma stability, pharmacokinetics, and antitumor activity of PL-MLP in various mouse and human tumor models.