Theses and Dissertations from UMD
Permanent URI for this communityhttp://hdl.handle.net/1903/2
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 give thesis/dissertation in DRUM
More information is available at Theses and Dissertations at University of Maryland Libraries.
Browse
2 results
Search Results
Item PRUSSIAN BLUE NANOIMMUNOTHERAPIES FOR NEUROBLASTOMA(2019) Cano-Mejia, Juliana; Fernandes, Rohan; Fisher, John P; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Neuroblastoma is the most common extracranial solid tumor in children, accounting for 15% of cancer-related deaths. Despite improvements in diagnosis and surgical techniques, neuroblastoma remains challenging to treat due to the heterogeneity of the tumor, low neoantigen expression, immunosuppressive tumor environment, and high recurrence rate. We have therefore engineered a nanoimmunotherapy that combines the advantages of nanotechnology and immunotherapy to combat the aforementioned challenges in treating neuroblastoma. Specifically, our ensemble comprises of Prussian blue nanoparticles (PBNPs) biofunctionalized with the immune adjuvant CpG-oligodeoxynucleotide (CpG). We utilize PBNPs for photothermal therapy (PTT), which ablates tumor cells and releases tumor antigens and adjuvants that increase tumor immunogenicity. Additionally, the PBNPs are biofunctionalized with CpG (CpG-PBNPs) to serve as a depot for local delivery of exogenous immune adjuvants that play an important role in breaking tolerance to tumor antigens and improving tumor antigen presentation. We hypothesize that this approach of targeting tumor cells, antigen presenting cells, and T cells, may hold the key in converting a non-responsive “cold” tumor such as neuroblastoma into a responsive “hot” tumor, leading to better treatments. We first describe the synthesis and characterization of CpG-PBNPs using a facile layer-by-layer coating scheme. The resultant nanoparticles exhibit monodisperse size distributions, multiday stability, and are not cytotoxic. The strong, intrinsic absorption of PBNPs in the CpG-PBNPs is leveraged to administer PTT (CpG-PBNP-PTT) that triggers immunogenic tumor cell death releasing tumor antigens, which increases tumor antigenicity. Simultaneously, the CpG coating functions as an exogenous adjuvant that complements the endogenous adjuvants released by the CpG-PBNP-PTT (e.g. ATP, calreticulin, and HMGB1), increasing adjuvanticity. When administered in a murine model of neuroblastoma, CpG-PBNP-PTT results in complete tumor regression in a significantly higher proportion (70%) of treated animals relative to controls. Further, the long-term surviving, CpG-PBNP-PTT-treated animals reject tumor rechallenge suggesting that our nanoimmunotherapy generates immunological memory. When we treat a synchronous model of neuroblastoma, 50% of nanoimmunotherapy-treated mice show complete eradication of both tumors compared to controls, which showed no survival efficacy. Our findings show the importance of simultaneous cytotoxicity, antigenicity, and adjuvanticity in generating robust and persistent antitumor immune responses. The strategies described in this dissertation encompass novel examples of nanoimmunotherapies to be applied in the clinic for the treatment of neuroblastoma.Item Biodegradable Prussian blue nanoparticles for photothermal immunotherapy of advanced cancers(2015) Cano-Mejia, Juliana; Fernandes, Rohan; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Multifunctional nanoparticles represent a class of materials with diverse therapy and imaging properties that can be exploited for the treatment of cancers that have significantly progressed or advanced, which are associated with a poor patient prognosis. Here, we describe the use of biodegradable Prussian blue nanoparticles (PBNPs) in combination with anti-CTLA-4 checkpoint blockade immunotherapy for the treatment of advanced cancers. Our nanoparticle synthesis scheme yields PBNPs that possess pH-dependent intratumoral stability and photothermal therapy (PTT) properties, and degrade under mildly alkaline conditions mimicking the blood and lymph. Studies using PBNPs for PTT in a mouse model of neuroblastoma, a hard-to-treat cancer, demonstrate that PTT causes rapid reduction of tumor burden and growth rates, but results in incomplete responses to therapy and tumor relapse. Studies to elucidate the underlying immunological responses demonstrate that PTT causes increased tumor infiltration of lymphocytes and T cells and a systemic activation of T cells against re-exposed tumor cells in a subset of treated mice. PBNP-based PTT in combination with anti-CTLA-4 immunotherapy results in complete tumor regression and long-term survival in 55.5% of neuroblastoma tumor-bearing mice compared to only 12.5% survival in mice treated with anti-CTLA-4 alone and 0% survival both in mice treated with PTT alone, or remaining untreated. Further, all of the combination therapy-treated mice exhibit protection against tumor rechallenge indicating the development of antitumor immunity as a consequence of therapy. Our studies indicate the immense potential of our combination photothermal immunotherapy in improving the prognosis and outlook for patients with advanced cancers.