Anti-tumor activity of liposome encapsulated fluoroorotic acid as a single agent and in combination with liposome irinotecan

Abstract

To test the hypothesis that co-delivery of synergistic drug combinations in the same liposome provides a better anti-tumor effect than the drugs administered in separate liposomes, fluoroorotic acid (FOA) alone and in combination with irinotecan (IRN) were encapsulated in liposomes and evaluated for their anti-tumor activity in the C26 colon carcinoma mouse model. Fluoroorotic acid was dissolved in 7 M urea to increase its solubility so it could be passively loaded into liposomes at a high concentration. IRN was remote loaded into liposomes that contained the ammonium salt of the multi-valent 1,2,3,4-butanetetratcarboxylic acid with a greater than 90% efficiency and at a drug to lipid ratio of 0.2/1. When the two molecules were loaded into the same liposome, FOA was used to remote load IRN. Modulation of the drug/lipid ratio, temperature, and loading time allowed for consistent co-encapsulation of FOA + IRN at various molar ratios. The anti-tumor activity of L-FOA, L-IRN, L-FOA-IRN (5:1), and the L-FOA + L-IRN mixture (5:1) were examined in the C26 mouse model. The maximum tolerated dose of L-FOA was 10 mg/kg given weekly as compared to 100 mg/kg of the non-encapsulated FOA. Delivering two drugs in the same liposome provided a statistically better antitumor effect than delivering the drugs in separate liposomes at the same drug ratio. However, the synergistic activity of the 5:1 ratio of free drugs measured on C26 cells in vitro was not observed in the C26 tumor mouse model. These findings point out the challenges to the design of synergistic treatment protocols based upon results from in vitro cytotoxicity studies. L-FOA at 10 mg/kg as a single agent provided the best anti-tumor efficacy which supports previous suggestions that L-FOA has useful properties as a liposome dependent drug.

UDP-galactose 4′-epimerase from the liver fluke,Fasciola hepatica: biochemical characterization of the enzyme and identification of inhibitors

“…This compound is widely used in yeast molecular biology to select for transformants (Boeke et al 1984). It has also been tested as a potential anti-cancer and anti-malarial agent (Heath et al 1985; Heidelberger et al 1958; Muregi et al 2009; Rathod et al 1989; Riviere et al 2011). In these applications, the target is not GALE: 5FOA can be converted to 5-fluorouracil which then inhibits thymidylate synthase – an enzyme required for the synthesis of thymidine monophosphate (dTMP) (Boeke et al 1984; Chaudhuri et al 1958; Heidelberger et al 1958).…”

Nanomedicine-Mediated Combination Drug Therapy in Tumor

“…For example, Riviereet et al [34] compared the antitumor effect of co-delivery of the synergistic drugs fluoroorotic acid (FOA) and irinotecan (IRN) in the same liposome versus delivery of the same drugs in separate liposomes. The codelivery system was more successful in inhibiting the proliferation of C26 cells in vitro; however, the drugs did not have synergistic effects in the C26 tumor mouse model [34]. These results demonstrate the challenges associated with developing synergistic treatment protocols in vivo based on in vitro studies.…”

Liposome and Their Applications in Cancer Therapy

“…Celator Pharmaceuticals Inc developed CPX-351, a liposomal formulation of cytarabine and daunorubicin. The CPX-351 showed promising results in phase III clinical trial on the patients with secondary acute myeloid leukemia (AML) by improving the induction response over 40% (Riviere et al 2011;Cortes et al 2015).…”