Date of Award

January 2012

Document Type

Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Mark Saltzman

Subject Area(s)

Biomedical engineering, Neurosciences

Abstract

NANOPARTICLES FOR DELIVERY OF RAPAMYCIN TO GLIOBLASTOMA AND GLIOBLASTOMA-DERIVED STEM CELLS.

Kofi-Buaku Atsina1, Jiangbing Zhou1,2, Toral Patel2, Joseph Piepmeier2, and W. Mark Saltzman 1; 1 Yale University, Department of Biomedical Engineering, New Haven, CT; 2 Yale University School of Medicine, Department of Neurosurgery, New Haven, CT·

Treatment of glioblastoma remains a challenge primarily because of the difficulty of achieving effective drug delivery, and the relative resistance of cancer stem cells to conventional chemoradiotherapy· Delivery of small molecule drugs, like rapamycin that have shown some efficacy against glioblastoma in in vitro and in vivo studies, is often thwarted by short drug half-lives, systemic toxicity, first-pass metabolism, and the impenetrable blood brain barrier (BBB)· Polymeric nanoparticles have the potential to solve the afore-mentioned challenges by enabling better delivery to cells, stabilizing their contents, and achieving sustained release in a localized fashion · Particularly, ultrasmall nanoparticles improve upon the abilities of this technology by achieving better tumor distribution and cellular uptake· The purpose of this study was to investigate the effects of rapamycin delivery by ultrasmall poly (D,L-lactic-co-glycolic acid)(PLGA) nanoparticles on differentiated glioblastoma (GB) and glioblastoma-derived stem cells (GSCs) in vitro· Ultrasmall polymeric nanoparticles encapsulating rapamycin were fabricated and their effects on GB cells (U87) and GSCs (PS30, PS16, GS5) were examined and compared with free rapamycin· Viability of cells was approximated by measuring their metabolic activity using Thiazolyl Blue Tetrazolium Bromide (MTT) assay. Results demonstrate that rapamycin nanoparticles improve efficacy of delivery relative to free rapamycin as demonstrated by greater inhibition of growth in GB cells, but may also have some efficacy against GSCs·

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