Several
liposome products have been approved for the treatment of
cancer. In all of them, the active agents are encapsulated in the
liposome water phase passively or by transmembrane ion gradients. An alternative approach in liposomal drug delivery consists of chemically modifying drugs to form lipophilic
prodrugs with strong association to the liposomal bilayer. Based on this approach, we synthesized a
mitomycin c-derived lipidic
prodrug (MLP) which is entrapped in the bilayer of PEGylated
liposomes (PL-MLP, Promitil®), and activated by thiolytic cleavage. PL-MLP is stable in plasma with thiolytic activation of MLP occurring exclusively in tissues and is more effective and less toxic than conventional
chemotherapy in various
tumor models. PL-MLP has completed phase I clinical development where it has shown a favorable safety profile and a 3-fold reduction in toxicity as compared to free
mitomycin c. Clinical and pharmacokinetic studies in patients with advanced colo-rectal
carcinoma have indicated a significant rate of disease stabilization (39%) in this chemo-refractory population and significant prolongation of median survival in patients attaining stable disease (13.9 months) versus progressive disease patients (6.35 months). The pharmacokinetics of MLP was typically stealth with long T½ (~1 day), slow clearance and small volume of distribution. Interestingly, a longer T½, and slower clearance were both correlated with disease stabilization and longer survival. This association of pharmacokinetic parameters with patient outcome suggests that arrest of
tumor growth is related to the enhanced
tumor localization of long-circulating
liposomes and highlights the importance of personalized pharmacokinetic evaluation in the clinical use of nanomedicines. Another important area where PL-MLP may have an added value is in
chemoradiotherapy, where it has shown a strong
radiosensitizing effect in animal models based on a unique mechanism of enhanced
prodrug activation and encouraging results in early human testing.