Design of biodegradable nanoparticles for enzyme-controlled long-acting drug release

The aim of this study was the development of biodegradable polyphosphate nanoparticles as parenteral delivery systems for long-acting drug release by utilizing ubiquitarian alkaline phosphatase. Therefore, nanoparticles were prepared via ionic gelation of the polycationic drug amikacin and the polyphosphate Graham's salt. They were characterized regarding encapsulation efficiency, size, zeta potential and stability under physiological conditions. Toxicological harmlessness was assessed via cell viability studies on HEK-293 cells and hemolysis tests with erythrocytes. Release characteristics were evaluated by applying increasing alkaline phosphatase (AP) concentrations. In summary, nanoparticles displayed a mean size of 228 nm with a polydispersity index of 0.19 and a slightly negative zeta potential of -8.7 mV. After 11 days of incubation, no significant increase in particle size and PDI was observed, and 9-10 % of amikacin were released in total. The nanoparticles were found to be non-toxic on HEK-293 cells as well as on erythrocytes at concentrations >= 500 mu g/ml. Overall, an AP dependent, long-acting drug release and a congruent to monophosphate release following an almost zero order kinetic were shown at physiological relevant enzyme concentrations over at least 11 days. Concludingly, alkaline phosphatase responsive nanoparticles were developed applying by polyphosphates as alternative biodegradable excipient that show a linear, long-acting drug release as a function of enzyme activity opening new opportunities in parenteral drug delivery.