PLGA-Lipid Hybrid (PLH) Microparticles Enhance the Intracellular Uptake and Anti-Bacterial Activity of Rifampicin.

An urgent demand exists for the development of effective carrier systems that systematically enhance the cellular uptake and localization of antibiotic drugs for the treatment of intracellular pathogens. Commercially available antibiotics suffer from poor cellular penetration, restricting their efficacy against pathogens hosted and protected within phagocytic cells. In this study, the potency of the antibiotic, rifampicin, against intracellular small colony variants (SCV) of Staphylococcus aureus was improved through encapsulation within a strategically engineered cell-penetrant delivery system, composed of lipid nanoparticles encapsulated within a poly(lactic-co¬-glycolic) acid (PLGA) nanoparticle matrix. PLGA-lipid hybrid (PLH) microparticles were synthesized through the process of spray drying, whereby rifampicin was loaded within both the polymer and lipid phase, to create a nanoparticle-in-microparticle system capable of efficient redispersion in aqueous biorelevant media and with programmable release kinetics. The ability for PLH particles to disintegrate into nanoscale agglomerates of the precursor nanoparticles was shown to be instrumental in optimizing rifampicin uptake in RAW264.7 macrophages, with a 7.2- and 1.6- fold increase in cellular uptake, when compared to the pure drug and PLGA microparticles (of an equivalent initial particle size), respectively. The enhanced phagocytosis and extended drug release mechanism (under the acidic macrophage environment) associated with PLH particles induced a 2.5-log reduction in CFU, compared to initial colonies at 2.50 µg/mL rifampicin dose. Thus, the ability for PLH particles to reduce the intracellular viability of S. aureus, without demonstrating significant cellular toxicity, satisfies the requirements necessary for the safe and efficacious delivery of antibiotics to macrophages for the treatment of intracellular infections.