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dc.contributor.advisorPorter, Tyrone M.en_US
dc.contributor.authorChiu, Joannaen_US
dc.date.accessioned2020-02-13T14:08:59Z
dc.date.issued2020
dc.identifier.urihttps://hdl.handle.net/2144/39368
dc.description.abstractGlioblastoma multiforme (GBM) is the most common and lethal primary brain cancer, killing approximately 17,000 patients in the US each year. Despite innovations in drugs and targeted therapies, the mortality rate has remained unchanged for over two decades, largely due to the impermeability of the blood brain barrier (BBB) and the poor response of GBM to most chemotherapeutics. Small interfering RNA (siRNA) has demonstrated clinical success in modulating the expression of oncogenic genes and is emerging as an attractive therapeutic against GBM. However, siRNA suffers from in vivo delivery issues such as sensitivity to enzymatic degradation, rapid clearance, and exclusion by the BBB. These challenges can be addressed by using nanoparticles which are gaining prominence in cancer therapy for their capacity to package a broad spectrum of drugs, extend circulation times, and modify the surface with a variety of targeting moieties. This thesis introduces a lipid-coated calcium phosphate nanoparticle (LCaP) designed for intracellular delivery of siRNA as well as transcellular transport across the BBB. The calcium phosphate core entraps the siRNA and protects it from nucleases, while the lipid coating shields charges to provide colloidal stability and an area for ligand attachment to facilitate receptor-mediated transcytosis. LCaPs were fabricated and characterized for their physiochemical properties; by altering the calcium to phosphate ratio, LCaP features such as size, surface charge, and siRNA loading could be tailored. LCaPs were then used to deliver siRNA in vitro and demonstrated successful and sustained knockdown of a reporter gene stably transfected in a cancer cell line. In addition, siRNA against the epidermal growth factor receptor variant III (EGFRvIII), a mutation specific to GBM, was delivered via LCaPs and demonstrated dose-dependent protein knockdown and a subsequent reduction in cell viability, indicating the potential of EGFRvIII as a therapeutic target. In order to improve BBB penetration, LCaPs were decorated with the targeting peptide, Angiopep-2, which binds to the low density lipid receptor related protein 1 that facilitates molecular transport across the BBB. BBB penetration was evaluated as a function of Angiopep-2 density in a BBB model incorporating human-derived induced pluripotent cells differentiated into brain endothelial cells along with immortalized human cancer cells. The BBB platform enabled more physiologically relevant evaluation of LCaP penetration and could be used as a screening platform for other nanoparticles or GBM therapeutics.en_US
dc.language.isoen_US
dc.rightsAttribution-NonCommercial 4.0 Internationalen_US
dc.rights.urihttp://creativecommons.org/licenses/by-nc/4.0/
dc.subjectBiomedical engineeringen_US
dc.titleDevelopment of a lipid-coated calcium phosphate nanoparticle for siRNA delivery to the brainen_US
dc.typeThesis/Dissertationen_US
dc.date.updated2020-01-29T02:03:11Z
dc.description.embargo2021-01-28T00:00:00Z
etd.degree.nameDoctor of Philosophyen_US
etd.degree.leveldoctoralen_US
etd.degree.disciplineBiomedical Engineeringen_US
etd.degree.grantorBoston Universityen_US
dc.identifier.orcid0000-0001-5297-8025


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Attribution-NonCommercial 4.0 International
Except where otherwise noted, this item's license is described as Attribution-NonCommercial 4.0 International