A. James Clark School of Engineering
Permanent URI for this communityhttp://hdl.handle.net/1903/1654
The collections in this community comprise faculty research works, as well as graduate theses and dissertations.
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Item Leveraging Biomaterials to Direct Immune Function in Cancer and Autoimmunity(2022) Tsai, Shannon Joanne; Jewell, Christopher M; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Immune dysregulation and difficulties in directing immune function in cancer and autoimmune disease pose complex challenges for existing vaccines and immunotherapies. In cancer, tumor cells exploit processes to evade the immune system. Conversely, autoimmune diseases such as multiple sclerosis (MS) occur when immune cells incorrectly attack healthy host tissue and cells. To address the dichotomy of dysregulated immune responses that can arise, next generation vaccines and immunotherapies demand better control over the specificity and types of immune of responses generated within lymph nodes (LNs). This dissertation investigated two approaches to improve immune signal delivery for precision control over immune responses. In the first approach, self-assembling vaccine nanoparticles were engineered with tunable charge and cargo loading to efficiently deliver immune signals in specific combinations and doses without compromising function. These studies offer new insight into biomaterial design for therapeutic cancer vaccines and demonstrate that the physiochemical properties of biomaterials - particularly the interplay between charge, uptake, and affinity - play an important role in the immune signals that can promote T cell expansion against tumor antigens. In the second approach, a biomaterial-based platform is used to control immune signal delivery to LNs during autoimmunity. Direct injections of therapeutic vaccine carriers into the LNs of mice offer new insight into how the localized combination of myelin peptide (MOG) and rapamycin (Rapa) - an immunomodulatory signal, promote potent and selective immune tolerance. This body of work demonstrates that immune function is highly localized to the signals delivered to the LNs, requiring an idealized combination of both self-antigen and immunomodulatory signal to promote the proliferation, retention, and polarization of antigen specific T cells towards regulatory T cells that can selectively limit inflammatory T cell phenotypes and combat autoimmunity. Together, these two approaches offer new insight into how biomaterials can be rationally harnessed to direct immune function across cancer and autoimmune disease.Item Harnessing Degradable Materials to Study and Engineer Lymph Node Function(2017) Andorko, James; Jewell, Christopher M; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Vaccines have benefited global health by controlling or eradicating multiple previously fatal diseases. While many early vaccines were efficacious, sophisticated new vaccines and immunotherapies need to address current challenges in the field, including diseases that avoid immune detection or lack strong molecular targets for the immune system. Overcoming these hurdles requires strategies to specifically control the magnitude and type of immune response generated. Biomaterials offer attractive features to achieve this goal, including protection of encapsulated signals, controlled release of cargos, and tunable features for cell targeting. Intriguingly, recent research reveals many common biomaterials activate the immune system, even without other signals. This intrinsic activation results, at least in part, from biomaterial physicochemical features that mimic pathogens and other foreign materials. Surprisingly, although degradable materials are being intensely studied as vaccines carriers, little research has investigated how the intrinsic immunogenicity of these materials changes as polymers degrade. The work in this dissertation reveals parameters impacting material intrinsic immunogenicity and exploits this new understanding to test the influence of biomaterial-based vaccines on the function of lymph nodes (LNs), key tissues that coordinate immunity. In the first aim, the immunostimulatory properties of a library of degradable polymers, poly(beta-amino esters) (PBAEs), were investigated in cell and animal models. PBAEs in soluble forms did not activate innate immune cells (e.g., dendritic cells, DCs). When PBAEs were formulated into particles to mimic a common vaccine strategy, DC activation increased in a molecular weight-specific manner. Using intra-lymph node (i.LN.) injection, a novel technique to control the dose, kinetics, and combination of signals in LNs, PBAE intrinsic immunogenicity was confirmed in mice. In the second aim, microparticles encapsulating immune signals were introduced into mice via i.LN. injection and immune responses were quantified in treated LNs, untreated LNs, and in blood. These results elucidated the interplay between local LN rearrangement and systemic antigen-specific responses which ultimately led to prolonged survival in cancer models. By understanding how the properties and administration of biomaterial-based vaccines impact immunity, this dissertation provides information that can help create new design rules for future vaccines that actively direct the immune system toward a desired response.Item Development and Biophysical Characterization of HK Polymer for siRNA Delivery to Tumor in a Mouse Model(2014) Chou, Szu-Ting; Mixson, Archibald J; Seog, Joonil; Chemical Engineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Delivery has been the major obstacle for nucleic acid therapeutics, including the RNA interference (RNAi) approach. Mixson's lab has been focused on the development of a non-viral peptide-based delivery system, HK (histidine-lysine) polymers, which have shown promise as carriers of plasmids and small interference RNA (siRNA) in several cell lines and in tumor-bearing models. In a previous study, a four-branched peptide, denoted H3K(+H)4b, with the predominant repeating -HHHK- sequence in the branch, has been shown to be the most effective and least toxic carrier in vitro and in vivo. Building on these results, I utilized different approaches including several structure and stability molecular characterization methods to study polyplex and to develop more effective carriers for improved therapy with siRNAs targeting malignancies. To understand the role of histidine in the stability of the H3K(+H)4b/siRNA polyplex, the physicochemical properties were investigated. With the use of isothermal titration calorimetry and heteronuclear single quantum coherence NMR, histidines were shown to form hydrogen bonds with siRNA, which enhanced the stability and biological activity of the polyplexes. In addition, to enhance resistance to nucleases and to target the tumors selectively, H3K(+H)4b was chemically modified with different patterns of polyethylene glycol (PEG) and cyclic RGD (Arg-Gly-Asp, cRGD) peptide conjugates. The luciferase marker gene expressed stably by tumor xenografts in mouse models was targeted in order to evaluate the efficacy of HK carriers of siRNA that differed in location and number of cRGD-PEG attachments. The most effective carrier was (RGD-PEG)4H3K(+H) (RP-HK), which has a cRGD-PEG on each of its four terminal branches. Consistent with its prolonged stability, as observed by pharmacokinetic studies, the RP-HK polyplex down-regulated luciferase activity in tumor xenografts by nearly 70% compared with the untreated group. Subsequently, the RP-HK polyplex was used to target the Raf-1 oncogene, an important mediator of tumor cell growth and angiogenesis. As in the luciferase studies, the polyplex reduced Raf-1 mRNA by more than 75%, and more importantly, the treatment inhibited the tumor growth by 60% in a mouse model. We anticipate that further design and engineering of HK carriers will improve the predictability and therapeutic activity of siRNA polyplexes in cancer treatment.