| Diseases caused by neurodegeneration (e.g., Parkinson's Disease (PD)) afflict millions of Americans. The incidence of these age-related diseases and their associated costs will increase concomitantly with the U.S. life expectancy. Currently, therapy for PD is palliative and symptomatic. Therefore, innovative approaches for preventive therapy are needed. Because of the compelling evidence linking oxidative stress and PD, preventive therapy may be achieved with antioxidants like Coenzyme Q10 (CoQ10). CoQ10 could hinder the progression of neurodegeneration by attenuating underlying oxidative stress rather than simply alleviating symptoms, but it is extremely difficult to administer. Although antioxidant and neuronal drug delivery have been rarely studied, drug delivery platforms that integrate bioengineering, pharmacology and nanotechnology may revolutionize pharmaceutical therapies. Drug-loaded, biodegradable poly(lactide-co-glycolide) (PLGA) nanoparticles have many advantages over conventional drug therapy, and the current antioxidant (CoQ10)-loaded biodegradable nanoparticles may significantly enhance neuronal antioxidant drug therapy. This thesis investigated a nanoparticle-based drug delivery approach to attenuating the oxidative damage associated with PD.; Nanoprecipitation yielded surfactant-free, empty and loaded biodegradable PLGA nanoparticles with controllable physical and CoQ10 encapsulation properties. CoQ10 release from the nanoparticles was sustained for two weeks. A novel methodology was developed to purify surfactant-free nanoparticles, which did not alter the diameter, polydispersity, morphology, CoQ10 encapsulation or surfactant-free characteristics of the CoQ10-loaded nanoparticles. Successful purification of surfactant-free nanoparticles from unencapsulated molecules (CoQ10 or QDs) was a major contribution of this work. Biocompatible, quantum dot (QD)-loaded nanoparticles were also developed and utilized to elucidate nanoparticle-cell interactions via confocal microscopy. The synthesis of novel CoQ10-QD co-loaded nanoparticles represented a first step toward simultaneous drug delivery and cell imaging with a single, multifunctional nanoparticle platform.; Additionally, an in vitro model of long-term, oxidative stress-induced dopaminergic neurodegeneration was developed. First, time-dependent development of rotenone-induced cytotoxicity, lipid peroxidation and antioxidant alterations was established in differentiated PC12 cells. Purified, CoQ10-loaded nanoparticles were applied in this cell model and were biocompatible to 60 mug/mL. More importantly, these nanoparticles exhibited trends of attenuating cytotoxicity and oxidative stress in the rotenone-damaged PC12 cells. These novel surfactant-free, loaded nanoparticles have utility and promise in both drug delivery and cell imaging applications. |
