All ETDs from UAB

Advisory Committee Chair

Huang-Ge Zhang

Advisory Committee Members

Etty Benveniste

Charles Elson

William Grizzle

Hongwei Qin

Document Type

Dissertation

Date of Award

2010

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Curcumin, a pleiotropic polyphenol derived from turmeric plants Curcuma Longa with rhizome, exhibits strong evidence as an anti-inflammation, anti-oxidant and anti-cancer reagent both in vitro and in vivo. Due to its low stability and systemic bioavailability, a large amount of curcumin has to be administrated to achieve therapeutic effects both in animal and in human. The major effort to overcome this barrier is making by encapsulation of curcumin into nanoparticles such as polymers and liposomes; some promising data have demonstrated the effectiveness of such method. Exosomes are vesicle-like nanoparticles secreted by living cells. Exosomes contain both cell surface molecules and cytoplasmic molecules due to endo- and exocytosis formation pathways. These properties may make exosomes a well-armed nanoparticles drug carrier when formulated with curcumin. In this study, we showed evidence that curcumin can be encapsulated into exosomes and this encapsulation didn't disrupt the structure of exosomes. Exosomal curcumin may combine exosomes, curcumin and nanoparticles functions together to be a powerful triple threat. To test this hypothesis, we evaluate the anti-inflammatory activity of exosomal curcumin in comparison with free curcumin alone. Our in vitro studies showed that encapsulation curcumin into exosomes can increase stability and solubility of curcumin, and when RAW cells were treated with LPS, exosomal curcumin dramatically inhibited cytokines IL6 and TNF-α secretion. Meanwhile, we adapted the LPS septic shock model to evaluate the anti-inflammatory activity in vivo. Exosomes encapsulation significantly increased bioavailability of curcumin in mice plasma when 100mg/kg exosomal curcumin and free curcumin were injected (i.p) into C57BL/6j mice. Interestingly, 4mg/kg of exosomal curcumin fully protected mice from LPS induced septic shock. Meanwhile, 4mg/kg of free curcumin didn't show any protection to the mice since this dosage was far away from its effective dosage. Significant decreased MDSCs numbers were found in the lungs of exosomal curcumin treated mice but not other organs. Our previous and others data indicate that exosomes can be preferentially uptaken by circulating MDSCs. When exosomal curcumin was co-incubated with MDSCs, the cellular concentration of curcumin was much higher than free curcumin, and exosomal curcumin induced more MDSCs apoptosis. Taken together, exosomal curcumin can target and kill circulating MDSCs during acute inflammation, thereby protects mice from LPS induced life threaten.

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