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theses

Developing safe and efficacious treatments for central nervous system disorders is difficult as the brain’s physiology limits drug penetration and distribution while promoting efflux. In addition, many complex transport mechanisms within the central nervous system are not fully understood. This dissertation investigates a novel approach to improve the pharmacokinetic profiles of drugs in the central nervous system by modulating cerebrospinal fluid flow and altering drug clearance rates. This was accomplished by 1) developing fabrication methods and characterizing polymeric drug delivery systems capable of co-delivering small molecule modulators of cerebrospinal fluid production and 2) creating a pharmacokinetic model to elucidate cerebrospinal fluid flow rates and sustained drug release rates necessary to improve treatment pharmacokinetics. Within this work, we also explored parameters for developing primary cell based in vitro systems of choroid plexus tissue, an epithelial monolayer responsible for cerebrospinal fluid secretion. These results demonstrate the feasibility of fabricating localized drug delivery systems to deliver cerebrospinal fluid modulating-drugs and provide quantitative predictions of the improvements these systems have on co-delivered drug pharmacokinetics in the brain. The drug delivery, computational, and cellular tools produced within this work also provide the scientific community improved methods to develop novel treatment strategies for neurological conditions directly impacted by choroid plexus function and cerebrospinal fluid flow.

http://dissertations.umi.com/gsnb.rutgers:12340

Ph.D.

Includes bibliographical references

doi:10.7282/t3-vg2x-ny66

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