(64f) Nanoparticle-Based Delivery of Drugs Dramatically Enhances Killing of Filarial Worms

Lymphatic filarial diseases represent a significant global cost and social burden, affecting up to 120 million individuals annually. Current antifilarial therapies include the use of mass dosing of multiple drugs, such as ivermectin, diethylcarbamazine, and albendazole. Extended use of these types of drugs have been shown to produce unwanted toxic side effects, which significantly impacts patient compliance. The obligatory endosymbiont bacterium, Wolbachia, helps confer enhanced pathogenicity. Therefore many recent mass drug administration efforts have included the antibiotic doxycycline to inhibit the microfilarial burden. Several delivery issues affect treatment with these drugs. Firstly, in order to reach the lymphatic tissues where macrofilariae reside, high doses are required to compensate for the short half-life of the drugs. Additionally, penetration of the soluble drugs through the outer cuticle of the worms is limited. We hypothesize that the use of amphiphilic polyanhydride nanoparticles could significantly improve the current standard of therapy by providing dose sparing, shortened killing times, and improved penetration.

Amphiphilic polyanhydride nanoparticles represent a versatile drug delivery platform. Their surface erosion mechanism results in a sustained and predictable release profile of co-encapsulated drugs that can be tailored for a quick burst release or a slower zero-order release by modifying the copolymer chemistry. This serves to lengthen the amount of time the localized drug concentration is within therapeutic limits, providing potential for a single-dose formulation and improved patient compliance. The nanoparticles stably encapsulate their payloads, conferring thermal protection to the drugs or proteins at ambient temperature. This could potentially reduce the cost of drug administration by eliminating the need for refrigeration during transportation to endemic regions. Our work has shown that polyanhydride nanoparticles are efficiently internalized by macrofilarial worms, allowing lethal co-delivery of antifilarial and antibacterial payloads at suboptimal doses. The nanoparticles can be functionalized to target specific surface receptors, allowing targeted delivery. This potential for specific targeting could provide further dose sparing and enhanced worm killing.

Current in vivo studies show that co-encapsulation of ivermectin and doxycycline provided sixteen-fold reduction in total drug dosage relative to comparative macrofilaricidal drugs. This dose sparing is further enhanced by a 50% decrease in the number of required treatments. Previous in vitro confocal laser microscopy studies showed extensive tissue penetration by the nanoparticles, compared to negligible penetration for the soluble drugs. These studies are corroborated by recent in vivo electron microscopy studies, which demonstrate extensive fragmentation of internal tissues. This observation is hypothesized to be a result of channeling of the nanoparticles, resulting in a subsequent release of concentrated drug. Together, all of these studies provide foundational information for the rational design of a nano-carrier platform that can have a transformative impact on the treatment of filarial diseases.