Thesis (Ph. D.)--University of Wisconsin--Madison, 1969. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

Thesis (Ph. D.)--University of Texas at Austin, 2007. / Vita. Includes bibliographical references.

Thesis (Ph. D.)--University of Washington, 2006. / Vita. Includes bibliographical references (leaves 213-235).

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The growing epidemic of antimicrobial resistance has caused significant morbidity rates worldwide as well as increasing probabilities of cancer recurrence. Efforts to address this epidemic have turned to immunomodulators, a class of molecules which modify the immune system in order to fight off infection. Muramyl dipeptide (MDP) is an immunomodulator of interest due to its specificity for NOD2, a primary receptor involved in immunoregulation. However, use of MDP in vivo causes an overly strong immunostimulatory effect; furthermore, MDP is rapidly cleared from the body due to high solubility and low molecular weight. In order to improve the clinical outlook of MDP, multiple analogues and delivery methods have been explored, with mixed success. MDP analogues have found the most success as adjuvants, although strict FDA approval guidelines limit this approach. Delivery methods for MDP are costly and also induce cytotoxicity, thereby emphasizing the clinical challenges of MDP. Introduced in 1996, Spherical Nucleic Acids (SNAs) are radially oriented oligonucleotides on a nanoparticle surface. SNAs have been shown to readily enter cells with little to no cytotoxicity and in fact, they have found clinical success in a variety of gene delivery and vaccine applications, making them a versatile platform for drug delivery. Herein, we demonstrate that SNAs can be applied as cellular delivery vehicles for MDP. To achieve this, we synthesized dual-layer SNAs whereby two unique oligonucleotides were functionalized onto a gold nanoparticle core. We show that by modulating the surface charge of the SNAs, faster cellular uptake can be achieved, which presents promise for increasing drug delivery and reaching cell compartments of interest. Additionally, we show early evidence that conjugation of MDP to the SNA corona retains MDP activity. Taken together, this work proposes effective SNA designs to deliver muramyl-based immunostimulants, which show promise in the expansion of SNA utility into immunomodulation. / Thesis / Master of Science (MSc) / The growing epidemic of antimicrobial resistance has been linked to deaths, weakened immune systems, and even cancer recurrence. To address this, immunomodulators have become an area of interest. Immunomodulators are capable of modifying the immune system to restore its normal function and fight off infection. Muramyl dipeptide (MDP) is a well-known immunomodulator, however, free MDP is too potent for clinical use. Attempts to modify or deliver MDP have had mixed success. Spherical Nucleic Acids (SNAs) are a 3D orientation of short DNA strands, SNAs are able to readily enter cells with little harmful effects on the cell. Herein, we demonstrate the development of SNAs for MDP delivery. We incorporate two unique DNA strands onto the SNA and leverage charge to enhance cellular uptake. Furthermore, we show early efforts in using the modified SNA as a delivery vehicle for MDP.

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Thesis advisor: Larry W. McLaughlin / Thesis advisor: Mary F. Roberts / Nucleic acids are the only biopolymers capable of encoding and transferring information, this property has placed them at the fundamental core of all living organisms, and made them a topic of intense research for over a century. The former studies in our laboratory on simplified nucleic acid backbones provided insight into how we might rationally alter nucleic acid structure into one that possesses properties not observed in natural DNA and RNA. Here the work began as an investigation into rigidified nucleic acid systems capable of functioning as DNA. The first rigidified nucleic acid system we designed, the cyclo-2'-deoxynucleic acids, has a linkage between the C5' of the ribose sugar and base to lock the ӽ angle into the similar angle as the native nucleoside. These rigidified bases show great impact towards the DNA structure, destabilizing double helix formation. This in fact can also be found in nature to inhibit the TATA binding protein associating with its target region. The next generation of rigidified nucleosides has an extended 7-membered ring instead of the 6-membered ring that was present in the first generation to push the base closer to the helical center. Both diastereomers of the ring-expanded-cyclo-2'-deoxyadenosine have been successfully synthesized and characterized and are ready to perform further studies. The third system is the hydroxymethyl-cyclo-nucleosides. The modified nucleosides in this project not only have the same linkage as the cyclo-nucleosides in the first system to restrict the base rotation, but also have an extra carbon (C6') to give the backbone more flexibility which might better stabilize a double helix than the first generation. / Thesis (PhD) — Boston College, 2012. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.