Partition-Optimized Single Emulsion Particles Improve Sustained Release of Amphiphilic Bumped Kinase Inhibitors to Control Malaria Transmission.

ABSTRACT

Amphiphilic molecules are challenging to be incorporated into polymeric particles for sustained release due to their significant solubility in both water and organic solvent used in the fabrication process. Here, we investigated an extensive panel of fabrication methods for the incorporation and release of amphiphilic molecules, in particular, novel amphiphilic bumped kinase inhibitors (BKIs). Previously, BKIs were shown to reduce malaria transmission by blocking of gametocyte exflagellation. Prolonged BKI bioavailability for effective transmission blocking is crucial since infectious gametocytes circulate for several weeks in the mammalian host, well beyond the half-life of BKIs. So far, delivery systems for sustained release of those BKIs have not been successfully formulated yet. Here we demonstrate that out of several delivery vehicles the partition-optimized single emulsion particles are the ideal system for incorporation and sustained release of amphiphilic BKIs. They increased the incorporation greater than 90% through optimized partitioning of amphiphilic molecules to the polymer phase and sustained release of BKIs up to several weeks with a reduction in the initial burst release. Overall this work provides a method for the incorporation and sustained release of amphiphilic BKIs, and can be adapted for other amphiphilic molecules.