Degree Type

Dissertation

Date of Award

2018

Degree Name

Doctor of Philosophy

Department

Veterinary Microbiology and Preventive Medicine

Major

Microbiology

First Advisor

Bryan H. Bellaire

Abstract

This dissertation focuses on the design of novel strategies for the prevention and treatment of neglected tropical and infectious diseases using polyanhydride nanoparticles as a drug delivery platform. The overall goal of this research is to design efficacious drug delivery vehicles that are effective against the filarial nematode Brugia malayi and B. pahangi and intracellular bacteria Mycobacterium tuberculosis, M. paratuberculosis, and M. marinum. The primary goal is to use the polyanhydride nanoparticles to deliver high enough microenvironmental concentrations to cause the death of the organism, thereby reducing the mortality, morbidity, and transmission of the disease. While a wide array of vaccine delivery vehicles have been investigated the majority of the research has focused on the use of polyesters and polyanhydride. This research presented shows the benefits of biodegradable polyanhydride as an effective drug delivery platform using the polymers and copolymers of various chemistries.

We demonstrate the use of a polyanhydride nanoparticle-based platform for the co-delivery of the antibiotic doxycycline with multiple antiparasitic drugs, (ivermectin, diethylcarbamazine, and albendazole) to reduce microfilariae burden and to rapidly kill adult worms. By encapsulating two of these drugs, ivermectin, and doxycycline, into biodegradable polyanhydride nanoparticles, we report the ability to effectively kill adult B. malayi and B. pahangi worms with up to a 4,000-fold reduction in the amount of drug used. Additionally, we significantly reduced the average time to death of the macrofilaria (five-fold) when the anti-filarial drug cocktail was delivered within polyanhydride nanoparticles.

Knowledge gained from filarial studies was then applied to kill the intracellular bacteria Mycobacterium, we sought to examine the effectiveness of the first line antituberculous rifampicin, isoniazid, pyrazinamide, and ethambutol, encapsulated into various polymer and copolymer combinations in vitro. Initial experiments focused on particle internalization, co-localization, and reduced macrophage bacterial population. Subsequently, gained knowledge from the in vitro effectiveness was then applied to systemic acute M. tuberculosis in vivo infection focusing on multi-drug resistance and extensively drug-resistant strains. We observed through short course chemotherapy utilizing the nanoparticle-based drug delivery platform 20:80 CPTEG:CPH, we were able to reduce the prevalence of a persister bacterial population significantly. In summary, the studies described herein support the rational design and use of a polyanhydride nanoparticle drug delivery platform to reduce both the course of treatment and the amount of drug needed to treat neglected infectious disease effectively.

DOI

https://doi.org/10.31274/etd-180810-5948

Copyright Owner

Andrea Marie Binnebose

Language

en

File Format

application/pdf

File Size

215 pages

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