Fischell Department of Bioengineering Theses and Dissertations
Permanent URI for this collectionhttp://hdl.handle.net/1903/6628
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Item ENGINEERING TARGETED LIGHT ACTIVATABLE NANOPLATFORMS TO MANAGE RECURRENT CANCERS(2024) Pang, Sumiao; Huang, Huang Chiao HH; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Cancer recurrence poses a significant challenge in various malignancies that adverselyaffect long-term survival and quality of life. Glioblastoma (GBM) and ovarian cancer exhibit particularly high recurrence rates. For GBM, tumor recurrence is nearly universal (90%) within 10 months post initial treatment due to its invasive characteristics, limited delivery of therapeutic agents, and persistent drug resistance, resulting in a 5-year survival rate of <10%. While standard chemotherapy and surgery can temporarily alleviate symptoms for both diseases, there has been no significant improvement in long-term disease management or survival extension over several decades. Therefore, it is critical to develop targeted therapies that integrates well with current standards of care strategies. Photomedicine is a promising treatment modality, and the two main phototherapies are photodynamic therapy (PDT) which involves photosensitizer administration followed by light activation resulting in non-thermal chemical damage and photothermal therapy (PTT) which involves exogenous or endogenous sensitizing agents followed by light activation resulting in thermal damage. Clinical applications of both modalities have shown its feasibility and safety; however, they face challenges due to (i) limited cancer selectivity, (ii) heterogenous treatment response, and (iii) low monotherapy treatment efficacy. Leveraging strategic therapeutic targets to advance the current sensitizing agents for targeted delivery is a potential solution to overcome these limitations. The overall objective of this dissertation is to advance and evaluate targeted light-activatable nanoplatforms for phototherapy delivery with considerations for the current clinical workflow of GBM and advanced ovarian cancer. This is achieved through the following goals, (1) engineering a novel Fn14 receptor-directed gold nanorods (DART-GNRs) to assess selectivity and PTT efficacy for GBM, and (2) evaluate safety and long-term efficacy of targeted light-activatable multi-agent nanoplatform (tLAMP) to deliver targeted PDT for peritoneal carcinomatosis. First, this work establishes a reproducible synthesis protocol for DART-GNRs, characterizes its photothermal properties, and demonstrate high selectivity towards the Fn14 receptor of cancer cells. Second half of this dissertation established and investigated a two-fiber tissue optical property (TOP) monitoring method for liquid phantoms and for peritoneal carcinomatosis mouse model to enable safer light dosimetry during PDT, established an irinotecan active loading method to reproducibly synthesize tLAMP, and determined tLAMP tumor nodule penetration depth for enhanced targeted PDT combination therapy with adjuvant chemotherapy to enhance long-term survival for ovarian cancer.Item DEVELOPMENT OF GLYCOSAMINOGLYCAN MIMICKING NANOGEL TECHNOLOGIES FOR CONTROLLED RELEASE OF THERAPEUTICS TO TREAT RETINAL DISEASES IN DIFFERENT AGE GROUPS(2024) Kim, Sangyoon; Lowe, Tao L.; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Retinal diseases, such as diabetic retinopathy, glaucoma, macular degeneration, and retinoblastoma, affect around 13 million people worldwide, with projections indicating a rise to 20 million by 2030. These conditions lead to irreversible vision loss and significant impairment in both adults and children, with an annual economic burden of $139 billion in the United States alone. Aging significantly increases the risk of certain retinal conditions, and with improvements in healthcare leading to increased life expectancy, these conditions are becoming more prevalent due to the natural aging process and associated physiological changes in the eye. Current treatments are either destructive or have low efficacy and are not optimized for the younger population. While therapeutics including small molecular drugs, proteins and antibodies show promise in treating these diseases by reducing inflammation and neuronal apoptosis, their effectiveness is hindered by short half-lives and inability to cross the blood-retinal barrier (BRB). Nanoparticles offer a potential solution by improving drug delivery across biological barriers, yet no nanoparticles have been developed to effectively transport intact proteins or small molecules across the BRB to the retina without toxicity, slow clearance and stability. Therefore, there is an unmet need to evaluate the physical and physiological property changes of the eye along development and develop nanoparticle systems that can control and sustain the release of therapeutics across the blood retinal barrier (BRB) to treat the retinal diseases. In this project, the thickness, rheological property, permeability and morphological property changes of ocular barriers including sclera, cornea and vitreous humor in the developing eye from preterm to adult were evaluated using porcine ex vivo model. Two glycosaminoglycan mimicking nanogel systems, poly(NIPAAm-co-DEXcaprolactoneHEMA) nanogels with and without positive or negative charges and β-cyclodextrin based poly(β-amino ester) (CD-p-AE) nanogels were developed for sustained release of intact proteins including insulin and anti-TNFα, and small hydrophobic drugs, respectively across the ex vivo porcine sclera and in vitro BRB models: human fetal retinal pigment epithelial (hfRPE), adult retinal pigment epithelial (ARPE-19) and human cerebral microvascular endothelial (hCMEC/D3) cell monolayers. Completion of this project will have a significant impact on developing novel personalized nanotherapeutics to treat retinal diseases in different age groups.Item Magnetic Drug Targeting: Developing the Basics(2013) Nacev, Aleksandar Nelson; Shapiro, Benjamin; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Focusing medicine to disease locations is a needed ability to treat a variety of pathologies. During chemotherapy, for example, typically less than 0.1% of the drugs are taken up by tumor cells, with the remaining 99.9% going into healthy tissue. Physicians often select the dosage by how much a patient can physically withstand rather than by how much is needed to kill all the tumor cells. The ability to actively position medicine, to physically direct and focus it to specific locations in the body, would allow better treatment of not only cancer but many other diseases. Magnetic drug targeting (MDT) harnesses therapeutics attached to magnetizable particles, directing them to disease locations using magnetic fields. Particles injected into the vasculature will circulate throughout the body as the applied magnetic field is used to attempt confinement at target locations. The goal is to use the reservoir of particles in the general circulation and target a specific location by pulling the nanoparticles using magnetic forces. This dissertation adds three main advancements to development of magnetic drug targeting. Chapter 2 develops a comprehensive ferrofluid transport model within any blood vessel and surrounding tissue under an applied magnetic field. Chapter 3 creates a ferrofluid mobility model to predict ferrofluid and drug concentrations within physiologically relevant tissue architectures established from human autopsy samples. Chapter 4 optimizes the applied magnetic fields within the particle mobility models to predict the best treatment scenarios for two classes of chemotherapies for treating future patients with hepatic metastatic breast cancer microtumors.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.