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Author ORCID Identifier

N/A

AccessType

Open Access Dissertation

Document Type

dissertation

Degree Name

Doctor of Philosophy (PhD)

Degree Program

Food Science

Year Degree Awarded

2015

Month Degree Awarded

September

First Advisor

Hang Xiao

Second Advisor

David Julian McClements

Third Advisor

Eric A Decker

Fourth Advisor

Richard J Wood

Subject Categories

Food Science

Abstract

The oral bioavailability of lipophilic bioactive molecules can be greatly increased by encapsulating them within engineered lipid nanoparticles, such as micelles, microemulsions and nanoemulsions. After ingestion these engineered lipid nanoparticles are disassembled in the gastrointestinal tract (GIT), and then reassembled into biological lipid nanoparticles (mixed micelles) in the small intestine. These mixed micelles solubilize and transport lipophilic bioactive components to the epithelium cells. The mixed micelles themselves are then disassembled and reassembled into yet another form of biological lipid nanoparticle (chylomicrons, CMs) within the enterocyte cells. The CMs carry the bioactive components into the systemic (blood) circulation via the lymphatic system, thereby avoiding metabolism in the small intestine and liver. Polymethoxyflavones (PMFs) are bioactive flavonoids found in citrus fruits that have been shown to have potential health promoting properties. However, their application as nutraceuticals in functional foods and beverages is currently limited due to their low water solubility and high melting point. The oral bioavailability of lipophilic compounds can be enhanced by promoting their intestinal lymphatic transport through co-administration with digestible lipids. First, we investigated the effects of chylomicron-mediated intestinal lymphatic transport on the bioavailability of 5-hydroxy-6, 7, 8, 3', 4'-pentamethoxylflavone (5-DN), one of representative PMFs in Caco-2 cells. Our results demonstrated that oleic acid and bile acid promoted secretion of CMs in Caco-2 cells, with mean diameter ranged from 70 to 150 nm. The intracellular level of 5-DN increased 3-fold by co-incubation with the mixed micelle solution. Moreover, the basolateral level of 5-DN increased 3-fold due to enhanced chylomicron-mediated transport. Based on the above results, we then evaluate the influence of different fatty acid types on the properties of mixed micelles, cellular lipid droplets and CMs, and on the uptake of the highly lipophilic nutraceutical 5-DN. There were distinct differences in the structural properties of CMs formed depending on fatty acid unsaturation. Oleic acid (C18:1) was most effective at enhancing transport of 5-DN and led to the formation of the largest CMs. Linoleic acid (C18:2) and linolenic acid (C18:3) also promoted 5-DN incorporation into CMs, but they were less efficient than oleic acid. The metabolism of 5-DN within the epithelium cells was greatly reduced when they were incorporated into CMs, presumably because they were isolated from metabolic enzymes in the cytoplasm. These results have important implications for the design of lipid nanoparticle-based delivery systems for lipophilic drugs and nutraceuticals by targeting them to the lymphatic circulation. Fatherly, we studied the effects of triglycerides-based nanoemulsion delivery systems with different fatty acid chain lengths on the bioavailability 5-DN. 5-DN was encapsulated in medium chain triglycerides (MCT) or canola oil (long chain triglycerides, LCT) based nanoemulsion. They were subject to a simulated gastrointestinal digestion model. Finally, the mixed micelle phase was applied to Caco-2 monolayer cell model that mimics intestinal absorption. Higher bioaccessibility of 5-DN was found in MCT nanoemulsion than canola nanoemulsion, 13% vs.7% respectively. However, only 30% 5-DN crossed Caco-2 monolayer while half of them were metabolized for MCT nanoemulsion, up to 60% 5-DN and only 10% were metabolized in canola nanoemulsion. Results also demonstrated more lipid droplets and CMs were formed by canola nanoemulsion, which were responsible for transportation of 5-DN to the lymph. In conclusion, although for lipophilic components like 5-DN, relatively higher bioaccessibility can be achieved by MCT-based nanoemulsion, LCT-based emulsion was more potent in enhancing the bioavailability through increased lymphatic transport. Lipids especially the ones with polyunsaturated long chain fatty acids (PUFA) are very susceptible to oxidation. Ingestion of oxidized lipids is associated with all kinds of health risk: diabetes, tumor development and atherosclerosis. Meanwhile, the oxidation of lipids may affect the absorption of lipophilic bioactive components in foods. We compared the effect of oxidized and unoxidized PUFA, linoleic acid (LA) on the transport of the highly lipophilic compound 5-hydroxy 6,7,8,4’ tetramethoxylflavone (5-DMT) by a Caco-2 cell model. Results turned out that unoxidized LA improved bioavailability of 5-DMT by stimulating CMs. Oxidized LA also showed an effect of improving transport of 5-DMT. However, it significantly affected the morphology of Caco-2 monolayer especially the tight junction. Accordingly, the transport pathway could be altered compared to the unoxidized LA, which will ultimately influence the distribution and metabolism fate of lipophilic components in the human body. Recently, the fate of inorganic nanoparticles in foods after ingestion has been attracted highly attention. Based on the above model and experimental methods, we also investigate the transport and toxicity of inorganic nanoparticle (AuNPs) on Caco-2 cell monolayer. AuNPs with different size (15nm, 50nm and 100nm) were applied. Our results demonstrated that more amount of gold was retained in the monolayer and higher toxicity was caused for larger size of AuNPs. Besides, mixed micelles greatly improve the secretion of AuNPs. The influence may be associated with formation abundant lipid droplets and CMs in the monolayer after fatty acids were taken in.

DOI

https://doi.org/10.7275/7332475.0

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