(168c) Liposome-Encapsulated Synergistic Drug Combinations for Low Dose Chemotherapy

PEGylated liposomes revolutionized drug delivery for toxic chemotherapy drug doxorubicin, tokened as "red death", by reducing cardiotoxicity in patients. However, it remains unclear whether liposomal doxorubicin is therapeutically superior to free doxorubicin. We developed a novel PEGylated liposomal system, named DAFODIL (Doxorubicin And 5-Fluorouracil Optimally Delivered In a Liposome) which surpasses therapeutic effects of free drug administrations. DAFODIL delivers synergistic ratios of doxorubicin and 5-fluorouracil to tumors, and, with remarkably low doses, achieves greater than 90% reduction in tumor growth of a murine 4T1 mammary carcinoma model. Co-delivery of optimal, synergistic ratios ensured therapeutic effects at drug concentrations far below their maximum tolerable drug doses. Therefore, our approach improves both the therapeutic efficacy and toxicity of liposomal drug delivery systems, and provides a safe and effective means to deliver combination chemotherapies. This methodology is made feasible by extending the well-established ammonium-sulfate gradient encapsulation method to nucleobase analogues, a liposomal entrapment method initially only useful for anthracyclines. Therefore, our strategy can be utilized to efficiently evaluate various chemotherapy combinations in an effort to translate more effective combinations clinically.