Polyanhydride Nanoparticle Delivery Platform Dramatically Enhances Killing of Filarial Worms

Abstract

Filarial diseases represent a significant social and economic burden to over 120 million people worldwide and are caused by endoparasites that require the presence of symbiotic bacteria of the genus Wolbachia for fertility and viability of the host parasite. Targeting Wolbachia for elimination is a therapeutic approach that shows promise in the treatment of onchocerciasis and lymphatic filariasis. Here we demonstrate the use of a biodegradable polyanhydride nanoparticle-based platform for the co-delivery of the antibiotic doxycycline with the antiparasitic drug, ivermectin, to reduce microfilarial burden and rapidly kill adult worms. When doxycycline and ivermectin were co-delivered within polyanhydride nanoparticles, effective killing of adult female Brugia malayi filarial worms was achieved with approximately 4,000-fold reduction in the amount of drug used. Additionally the time to death of the macrofilaria was also significantly reduced (five-fold) when the anti-filarial drug cocktail was delivered within polyanhydride nanoparticles. We hypothesize that the mechanism behind this dramatically enhanced killing of the macrofilaria is the ability of the polyanhydride nanoparticles to behave as a Trojan horse and penetrate the cuticle, bypassing excretory pumps of B. malayi, and effectively deliver drug directly to both the worm and Wolbachia at high enough microenvironmental concentrations to cause death. These provocative findings may have significant consequences for the reduction in the amount of drug and the length of treatment required for filarial infections in terms of patient compliance and reduced cost of treatment.

Neuronal protection against oxidative insult by polyanhydride nanoparticle-based mitochondria-targeted antioxidant therapy

“…This may explain why M:(FA-NP) is more efficacious in neuroprotection over Mito-Apo alone. The encapsulation efficiency coupled with the equivalent protection as compared to Mito-Apo alone also indicates that the nano-formulations provide dose-sparing, which has been observed previously (19, 66). …”

“…A significant advantage provided by the polyanhydride nanoparticles is the slow and controlled erosion of the particles, enabling a sustained release of the encapsulated cargo (19). The FA functionalization of Mito-Apo-containing nano-formulations lowered the encapsulation efficiency as expected because of exposure to aqueous conditions.…”

Nano-enabled delivery of diverse payloads across complex biological barriers

“…In addition, PLGA nanoparticles have been used to encapsulate ivermectin and demonstrated elimination of filarial worm parasites from circulation with dose sparing effects [186]. Recent studies from our laboratories have demonstrated success in using polyanhydride nanoparticles encapsulating anti-filarial drugs and antibiotics to kill parasites with several thousand fold dose-sparing [187]. Imaging of filarial worms incubated in vitro with drug-loaded polyanhydride nanoparticles indicated that these nanoparticles penetrated the worm cuticle and persist, in contrast to soluble drugs [187].…”

“…Recent studies from our laboratories have demonstrated success in using polyanhydride nanoparticles encapsulating anti-filarial drugs and antibiotics to kill parasites with several thousand fold dose-sparing [187]. Imaging of filarial worms incubated in vitro with drug-loaded polyanhydride nanoparticles indicated that these nanoparticles penetrated the worm cuticle and persist, in contrast to soluble drugs [187]. It has been speculated that encapsulation of drugs into particles may reduce the ability of filarial worms to regulate mechanisms (i.e., changes in glutamate-gated chloride channels or ABC transporter expression) that enable recovery of the worm via the expulsion of soluble drugs [11, 55, 56].…”

“…It has been speculated that encapsulation of drugs into particles may reduce the ability of filarial worms to regulate mechanisms (i.e., changes in glutamate-gated chloride channels or ABC transporter expression) that enable recovery of the worm via the expulsion of soluble drugs [11, 55, 56]. The polyanhydride nanoparticle-based delivery system successfully penetrated the cuticle and provided sustained release of anti-filarial drugs and antibiotics in nematode parasites, resulting in enhanced and rapid killing of these worms with a significantly reduced dose [187]. …”