PROMIDOX: A dual drug liposomal formulation for improved chemotherapy of cancer

The clinical trend toward drug combinations in the treatment of cancer attempts to address the challenge of tumor diversity. Co-encapsulation of anticancer agents in pegylated liposomes may provide an effective tool to maximize multidrug efficacy by taking advantage of the long circulation time, passive targeting and reduced toxicity of these formulations.

We have developed a pegylated liposomal formulation of a mitomycin-C (MMC) lipidic prodrug (abbreviated as MLP), coined Promitil®, which has been shown to significantly reduce the toxicity of MMC and is currently undergoing clinical testing. In preclinical studies, we observed potent antitumor activity when Promitil, is co-administered with pegylated liposomal doxorubicin (PLD, Doxil). In light of the non-overlapping toxicities and non-overlapping cross resistance of MMC with DOX, we decided to explore a co-encapsulated formulation of these highly potent anticancer agents where MLP is localized in the liposome lipid bilayer, and doxorubicin (DOX) is localized in the liposome water phase via remote loading as in PLD. The resulting formulation (PLMD, Promidox) displays high loading efficiency of DOX and MLP, comparable to PLD and Promitil, respectively. PLMD has a DOX:MLP ratio (mol/mol) in the range of ~1.20 to 1.82, a mean diameter of 100 to 120 nm, and a classical DOX sulfate precipitate in cryoTEM images. The formulation and its components are chemically and physically stable for at least 1 year at 4^oC. The formulation is stable upon in vitro incubation in human plasma with nearly 100% retention of both drugs. Cytotoxicity tests indicate greater potency for the dual drug formulation when compared to co-administered Promitil and PLD, suggesting synergy. Surprisingly, this formulation extended MLP half-life in circulation when compared to the MLP of Promitil. The half-life of DOX in PLMD was similar to that of PLD. In the mouse C-26 colon carcinoma tumor model, Promidox was superior to co-administration of Promitil and PLD. Approximately 80% of the MTD of single agent Doxil and 50% of the MTD of single agent Promitil can be co-administered safely as PLMD in mice.

This dual-drug liposome formulation with attractive pharmacological properties and powerful antitumor activity is a promising therapeutic tool for cancer therapy.