Dissertation
DESIGN AND ENGINEERING OF NANOPARTICLE-BASED DRUG DELIVERY SYSTEMS FOR IMPROVED THERAPY OF ISCHEMIC STROKE AND GLIOMA
Doctor of Philosophy (PhD), Washington State University
01/2020
Handle:
https://hdl.handle.net/2376/112191
Abstract
Nanotechnology innovates the development of medicine and pharmacy because it offers tools and approaches to design and engineer nanomaterials that can increase drug delivery efficacy and tissue targeting. Brain diseases usually cause high disability and death rates, such as ischemic stroke and glioma. While many nanoparticle-based drug delivery systems have been developed to treat brain diseases, the fundamental questions in understanding how drug delivery systems interact with diseased brain tissues have not been fully addressed. Brain vasculature plays a central role in the pathogenesis of many brain diseases. In my dissertation, I will address how nanoparticle-based drug delivery systems interact with brain vasculature to improve therapies of ischemic stroke and glioma. Specifically, I raised two questions: 1) How can we target inflamed brain endothelium to treat ischemic stroke? 2) Can we deliver therapeutics across blood brain barrier to treat glioma? Ischemic stroke is an acute and severe neurological disease. Reperfusion to an ischemic brain is used to restore blood circulation in brain after stroke; however, this causes secondary tissue damage induced by inflammation responses, so-called ischemia/reperfusion (I/R) injury. Adhesion of neutrophils to endothelial cells underlies the initiation of inflammation in I/R. Inspired by this interaction, we designed a drug delivery system comprised of neutrophil membrane-derived nanovesicles loaded with Resolvin D2 (RvD2) that can target inflamed endothelium and enhance the resolution of inflammation, thus protecting brain damage during ischemic stroke. Blood brain barrier (BBB) is formed by a tight vasculature which prevents most therapeutics to enter the brain. We asked whether nanoparticles (NPs) can target activated neutrophils in situ to deliver therapeutics across BBB for improved therapies of glioma. We have designed doxorubicin-loaded polymeric nanoparticles coated with anti-CD11b antibodies that were able to specifically bind to activated neutrophils and subsequently internalized by neutrophils. Our polymeric nanoparticles increased doxorubicin delivery and mouse survival in the mouse glioma model. In summary, our studies have provided a deeper understanding about the interactions between nanotherapeutics and brain vasculature present in the pathogenesis of brain diseases. Based on this knowledge, we will rationally design drug delivery systems to improve current treatments of brain diseases.
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Details
- Title
- DESIGN AND ENGINEERING OF NANOPARTICLE-BASED DRUG DELIVERY SYSTEMS FOR IMPROVED THERAPY OF ISCHEMIC STROKE AND GLIOMA
- Creators
- Xinyue Dong
- Contributors
- Zhenjia Wang (Advisor)Jiyue Zhu (Committee Member)Kathryn E. Meier (Committee Member)Marcos Frank (Committee Member)
- Awarding Institution
- Washington State University
- Academic Unit
- Pharmacy and Pharmaceutical Sciences, College of
- Theses and Dissertations
- Doctor of Philosophy (PhD), Washington State University
- Number of pages
- 169
- Identifiers
- 99900581413401842
- Language
- English
- Resource Type
- Dissertation