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Formulation and characterization of bioactive lipid containing reconstituted high density lipoproteins
AdvisorRyan, Robert O
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Reconstituted high density lipoproteins (rHDLs) are a versatile and useful delivery vehicle that allows for the incorporation of hydrophobic, bioactive agents into their milieu. The term nanodisks (ND) is used to distinguish between rHDL, composed of only phospholipids and apolipoprotein, and rHDL that contain a third integrated component. Statin-induced myopathy is the predominant indicator of patient adherence to a statin treatment. The coenzyme Q (CoQ) deficiency hypothesis predicts that muscle myopathy is caused by a statin-induced depletion of coenzyme Q10 in muscle tissue, and administration of CoQ may alleviate such symptoms. CoQ supplementation is required for treatment of otherwise fatal primary CoQ deficiencies. A decline in lutein content in the macula of the human eye is correlated to a progression in age-related macular degeneration. With age, humans gradually incorporate less lutein in the retinal pigment epithelial cells (RPE) of the macula. The death of RPE cells eventually leads to secondary photoreceptor cell death and vision loss. Herein described in this thesis is the incorporation of three, hydrophobic, bioactive agents into a ND platform via the direct solubilization method. C2C12 mouse myotubes treated with simvastatin and CoQ10 ND produced elevated basal and maximal OCRs when compared to a simvastatin control. Spontaneously arising retinal pigment epithelial 19 cells incubated with lutein ND produced a ~50% increase in viability and a 2-fold reduction in reactive oxygen species levels compared to control cells exposed to UV irradiation. The effectiveness of ND-mediated delivery of CoQ or lutein in vivo has yet to be determined and will require future investigations in an animal model.