(635a) Liposomal Co-Encapsulation of 5-Fluorouracil and Doxorubicin for Synergistic Anticancer Activity

Combinations of chemotherapy drugs rather than single drugs are clinically used to combat late stage and metastatic cancers, due to their ability to simultaneously attack cancer cells via multiple mechanisms.  However, clinical trials show that combination chemotherapy can result in increased side effects and little change in therapeutic efficacy compared to single drug treatments.  These reactions can be attributed to both antagonistic interactions (reduction of efficacy upon combination) and separate drug pharmacokinetics, which can lead to drastically different drug concentrations at the tumor site than was originally administered.  Here, we investigated drug interactions and developed a dual-drug carrier for controlled and effective combination delivery.  Drug pairs were screened for synergistic interactions against the human breast cancer cell line BT474 in vitro utilizing the well-established Combination Index method.  Antimetabolite 5-fluorouracil and anthracycline doxorubicin were identified as highly synergistic in a specific concentration ratio.  It was also found that certain ratios of the same drug pair were antagonistic, demonstrating that poor control of drug ratios can be detrimental to therapeutic efficacy.  Multi-drug entrapment in a single vehicle can unify drug pharmacokinetics and ensure that the cancer cells are exposed to the optimal, originally administered synergistic drug ratios.  Since both 5-fluorouracil and doxorubicin are water soluble, liposomes were chosen for their encapsulation in the aqueous core.  Liposomes which co-encapsulated 5-fluorouracil and doxorubicin in the specific synergistic ratio resulted in enhanced cell death compared to liposomes singly loaded with either drug.  Thus, our system for dual-drug delivery provides a method to preserve the potency of the combination throughout blood circulation until reaching the target site, and can ultimately improve the therapeutic efficacy of chemotherapy.