Calibrated liposomal release of the anti-mitotic agent BI-2536 increases the targeting of mitotic tumor cells.

Cancer drugs which are specifically targeted at mitosis have generally under-delivered as a class. One likely reason is that only a small percentage of cancer cells in a tumor are actually dividing at any moment. If this is the case, then prolonged bioavailability in the tumor should significantly increase the efficacy of antimitotic agents. Here, we show that if the Plk1 inhibitor BI 2536 is co-encapsulated in a liposome with a pair of anions, its release rate is dependent on both the identity and stoichiometry of the anions. We created a library of liposomes with varying release rates using this approach and found that liposomal drug release rates correlated inversely with in vitro cancer cell killing. Xenografted mice treated with a single dose of slow-releasing liposomal BI 2536 experienced tumor volume decreases lasting 12 days and complete responses in 20% of mice. Treatment with two doses a week apart increased the response rate to 75%. This approach, which we termed Paired Anion Calibrated Release (PACeR), has the potential to revive the clinical utility of antimitotic cancer drugs which have failed clinical trials.