Nigericin-mediated liposome loading of topotecan: Is nigericin a potential drug release regulator?

Topotecan was loaded into large unilamellar vesicles using nigericin-generated pH gradient or with triethylammonium (TA) ion gradient. Despite that in both loading methods, the encapsulated counter ion was 5-sulfosalicylate (5ssa), the resultant formulations exhibited distinct properties. In NaCl-containing release buffer, vesicles prepared with nigericin/Na+ system could release topotecan at a faster rate than 5ssa–TA vesicles, whereas in the absence of Na+, there was no difference in the drug release kinetics. In plasma, both formulations could prolong the circulation halftime of topotecan, but 5ssa–TA vesicles were more able to stabilize the encapsulated topotecan, as evidenced by the increased t1/2 and decreased conversion of lactone to carboxylate form. However, the improved drug retention did not mean the elevated safety and efficacy. In L1210 ascitic tumor model, the administration of 5ssa–TA vesicles at 10 mg/kg induced the early death of ∼60% mice at 6–7 days. In contrast, the treatment with nigericin/Na+ vesicles at the same dose level resulted in a mean survival time of ∼18.0 days, ∼1.38-fold of that of free topotecan. In addition, the formulation was safer than free topotecan. The results indicated that nigericin could be used as release regulator to optimize drug release kinetics, resulting in safe and efficacious liposome-based topotecan formulation. The results were promising since no liposome topotecan formulations with reduced toxicity were reported.