Liposomal Coencapsulated Fludarabine and Mitoxantrone for Lymphoproliferative Disorder Treatment*

Fludarabine (FLU)‐based combination therapies are commonly used to treat low‐grade lymphoma and chronic lymphocytic leukemia (CLL) patients. In vitro and clinical studies have indicated advantages when FLU and mitoxantrone (MTO) are applied in combination. To further enhance this effect, these two agents were coencapsulated in liposomes. FLU was passively encapsulated during liposome formation, and MTO was loaded with a transmembrane pH gradient. Entrapment efficiency, particle size, stability, and drug release kinetics were characterized. In vitro cytotoxicity study was carried out in two representative B‐cell lines: Wac3CD5 and Raji. Synergism as measured by combination index (CI) was observed in cells treated with liposomes coencapsulating FLU and MTO. Annexin V/propidium iodide (PI) analysis further confirmed that coencapsulated FLU and MTO improved the percentage of apoptosis among primary CLL cells. These data suggest that adopting liposomes containing coencapsulated drug combinations constitutes a potential strategy to promote drug synergism and may have utility in the treatment of leukemia and lymphoma. © 2007 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:1508-1518, 2008