UMD Theses and Dissertations
Permanent URI for this collectionhttp://hdl.handle.net/1903/3
New submissions to the thesis/dissertation collections are added automatically as they are received from the Graduate School. Currently, the Graduate School deposits all theses and dissertations from a given semester after the official graduation date. This means that there may be up to a 4 month delay in the appearance of a given thesis/dissertation in DRUM.
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Item LIGHT ACTIVATABLE PURE PORPHYRIN NANOPARTICLES FOR THE PHOTODYNAMIC OPENING OF THE BLOOD-BRAIN BARRIER AND GLIOBLASTOMA TREATMENT(2022) Inglut, Collin Thomas; Huang, Huang Chiao; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Glioblastoma (GBM) consistently recurs due to infiltrating cancer cells that cannot be removed by surgery and chemotherapy. The diffusive nature of GBM makes complete surgical resection unsafe, and the intact blood-brain barrier (BBB) prevents the penetration and accumulation of nearly all chemotherapy in infiltrative GBM cells. Existing BBB opening strategies are often associated with increased risk of edema, hemorrhage, or neurotoxicity and thus have limited clinical success. Photodynamic therapy (PDT) is a photochemistry-based treatment modality that has shown promise in treating GBM and opening the BBB in the clinic. In fact, a single adjunctive dose of PDT has been shown to add as much as 18 months to patient survival. However, the full potential of PDT is limited by the light activation depth of the ‘gold standard’ pro-drug photosensitizer, 5-aminolevulinic acid (5-ALA). In addition, large doses of PDT can result in edema and neurotoxicity. To address these issues, our lab has developed a photodynamic priming (PDP) strategy using the verteporfin (VP) photosensitizer, which operates at low optical energy to enhance intratumoral drug accumulation without damaging the healthy brain tissues. Unfortunately, VP is hydrophobic and requires liposomal encapsulation for intravenous administration, which can alter the photosensitizers cellular pharmaceutics. Here, we develop and compare a novel carrier-free pure-photosensitizer nanoparticle to a clinically relevant liposomal formulation.This dissertation covers a complementary, four-pronged approach to enhance drug delivery to brain tumors and treat GBM: (1) Understand the photoactivation depth of clinically relevant photosensitizers in the rodent brain for the targeting of infiltrative GBM cells. (2) Explore the mechanisms of photochemistry-induced BBB opening. (3) Engineer light-activable nanotechnology that can open the BBB, improve drug delivery, and eradicate GBM cells. And (4) develop a high-throughput model to examine the BBB integrity and efflux transporter function. The central hypothesis of this dissertation is the delivery of photoactivatable pure-photosensitizer nanoparticles can eradicate GBM cells and enhance drug delivery to microscopic GBM tumors.Item Lipid-Hydrogel Nanoparticles: Synthesis Methods and Characterization(2009) Hong, Jennifer S.; Raghavan, Srinivasa R; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)This dissertation focuses on the directed self-assembly of nanoscale soft matter particles using methods based on liposome-templating. Nanoscale liposomes, nano-sized hydrogel particles ("nanogels"), and hybrids of the two have enormous potential as carriers in drug delivery and nanotoxicity studies, and as nanovials for enzyme encapsulation and single molecule studies. Our goal is to develop assembly methods that produce stable nanogels or hybrid lipid-polymer nanoparticles, using liposomes as size and shape templates. First we describe a bulk method that employs liposomes to template relatively monodisperse nanogels composed of the biopolymer, alginate, which is a favorable material for nanogel formation because it uses a gentle ionic crosslinking mechanism that is suitable for the encapsulation of cells and biomolecules. Liposomes encapsulating sodium alginate are suspended in aqueous buffer containing calcium chloride, and thermal permeabilization of the lipid membrane facilitates transmembrane diffusion of Ca2+ ions from the surrounding buffer into the intraliposomal space, ionically crosslinking the liposome core. Subsequent lipid removal results in bare calcium alginate nanogels with a size distribution consistent with that of their liposome template. The second part of our study investigates the potential for microfluidic-directed formation of lipid-alginate hybrid nanoparticles by adapting the above bulk self-assembly procedure within a microfluidic device. Specifically we investigated the size control of alginate nanogel self-assembly under different flow conditions and concentrations. Finally, we investigate the microfluidic directed self-assembly of lipid-polymer hybrid nanoparticles, using phospholipids and an N-isopropylacrylamide monomer as the liposome and hydrogel precursors, respectively. Microfluidic hydrodynamic focusing is used to control the convective-diffusive mixing of the two miscible nanoparticle precursor solutions to form nanoscale vesicles with encapsulated hydrogel precursor. The encapsulated hydrogel precursor is polymerized off-chip and the resultant hybrid nanoparticle size distributions are highly monodisperse and precisely controlled across a broad range relevant to the targeted delivery and controlled release of encapsulated therapeutic agents. Given the ability to modify liposome size and surface properties by altering the lipid components and the many polymers of current interest for nanoparticle synthesis, this approach could be adapted for a variety of hybrid nanoparticle systems.Item Controlled liposome formation and solute encapsulation with continuous-flow microfluidic hydrodynamic focusing(2008-12-11) Jahn, Andreas; DeVoe, Don L; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Liposomes enable the compartmentalization of compounds making them interesting as drug delivery systems. A drug delivery system (DDS) is a transport vehicle for a drug for in vivo drug administration. Drugs can be encapsulated, bound, or otherwise tethered to the carrier which can vary in size from tens of nanometers to a few micrometers. Liposomal DDSs have shown their capability to deliver drugs in a new fashion, allowing exclusive sales of encapsulated drugs to be extended beyond the initial compound's patent expiration date. However, existing methods to form liposomes and encapsulate drugs are based on bulk mixing techniques with limited process control and the produced liposomes frequently require post-processing steps. In this dissertation, a new method is demonstrated to control liposome formation and compound encapsulation that pushes beyond existing benchmarks in liposome size homogeneity and adjustable encapsulation. The technology utilizes microfluidics for future pharmacy-on-a-chip applications. The microfluidic system allows for precise control of mixing via molecular diffusion with reproducible and controlled physicochemical conditions compared to traditional bulk-phase preparation techniques (i.e. test tubes and beakers). The laminar flow and facile fluidic control in microchannels enables reproducible self-assembly of lipids into liposomes in a sheathed flow-field. Confining a water-soluble compound to be encapsulated to the immediate vicinity where liposome formation is expected to occur reduces sample consumption without affecting liposome loading. The ability to alter the concentration and control the amount of encapsulated compounds within liposomes in a continuous-flow mode is another interesting feature towards tailored liposomal drug delivery. The liposome formation strategy demonstrated in this dissertation offers potential for point-of-care drug encapsulation, eliminating shelf-life limitations inherent to current liposome preparation techniques.