Global ETD Search

11	Chemical Programming of Macrophages via Direct Activating Receptor Labeling for Targeted Tumour Immunotherapy Yang, Zi Ling (Sissi) 11 1900 (has links) Antibody-recruiting molecules (ARMs) are therapeutic tools that simultaneously bind a hapten-specific serum antibody and a cancer cell surface protein, resulting in the activation and recruitment of an immune cell to the cancer surface. However, ARM efficacy is limited by the ability of ARMs to form a quaternary complex with the immune cell receptor, antibody, and cancer cell surface. The Rullo lab has previously developed and characterized a covalent ARM (cARM) that irreversibly links the ARM to the antibody and simplifies the quaternary binding equilibria. cARMs have shown a marked increase in both target immune recognition and therapeutic efficacy. However, cARM efficacy is still limited by the affinity of the antibody for the immune receptor. We aim to investigate how direct covalent engagement of the immune receptor and elimination the antibody-immune receptor binding equilibria impacts immune activation and therapeutic efficacy. This thesis focuses on the chemical programming of macrophages through direct covalent immune receptor engagement. We have developed and characterized covalent immune programmers (CIPs), which are molecules that contain a macrophage targeting domain and a tumour targeting domain. The macrophage targeting domain binds the activating receptor CD64 on the macrophage surface and contains a chemical warhead that covalently labels the receptor once bound. The tumour targeting domain can promote macrophage tumour engagement resulting in tumoricidal function. Flow cytometry experiments have shown that CIPS are able to bind Fc receptors specifically and effectively on the surface of macrophages. Further, CIPs were able to induce macrophage activation and induce target specific phagocytosis. These experiments have also shown that direct engagement of the receptor by the CIP is more effective than antibody-mediated engagement, suggesting that overall immune complex stability affects immune cell activation. Taken together, these concepts can be used to guide future immunotherapeutic design. / Thesis / Master of Science (MSc) Chemical Immunology Immunotherapy Macrophage Programming Peptide Drugs Covalent Drugs Proximity Induced Labeling Cancer
12	Transdermal Drug Delivery Enhanced by Magainin Peptide Kim, Yeu Chun 06 November 2007 (has links) The world-wide transdermal drug delivery market is quite large, but only a small number of agents have FDA approval. The primary reason for such limited development is the difficulty in permeating the stratum corneum layer of human skin. In our study, we developed a novel percutaneous delivery enhancing approach. Magainin peptide was previously shown to disrupt vesicles from stratum corneum lipid components and this ability of magainin allows us to propose that magainin can increase skin permeability. Therefore, we tested the hypothesis that magainin, a pore-forming peptide, can increase skin permeability by disrupting stratum corneum lipid structure and that magainin¡¯s enhancement requires co-administration of a surfactant chemical enhancer to increase magainin penetration into the skin. In support of these hypotheses, synergistic enhancement of transdermal permeation can be observed with magainin peptide in combination of N-lauroyl sarcosine (NLS) in 50% ethanol-PBS solution. The exposure to NLS in 50% ethanol solution increased in vitro skin permeability to fluorescein 15 fold and the addition of magainin synergistically increased skin permeability 47 fold. In contrast, skin permeability was unaffected by exposure to magainin without co-enhancement by NLS-ethanol. To elucidate the mechanism of this synergistic effect, several characterization methods such as differential scanning calorimetry, Fourier transform infrared spectroscopy, and X-ray diffraction were applied. These analyses showed that NLS-ethanol disrupted stratum corneum lipid structure and that the combination of magainin and NLS-ethanol disrupted stratum corneum lipids even further. Furthermore, confocal microscopy showed that magainin in the presence of NLS-ethanol penetrated deeply and extensively into stratum corneum, whereas magainin alone penetrated poorly into the skin. Together, these data suggest that NLS-ethanol increased magainin penetration into stratum corneum, which further increased stratum corneum lipid disruption and skin permeability. Finally, skin permeability was enhanced by changing the charge of magainin peptide via pH change. We modulated pH from 5 to 11 to change the magainin charge from positive to neutral, which decreased skin permeability to a negatively charged fluorescein and increased skin permeability to a positively charged granisetron. This suggests that an attractive interaction between the drug and magainin peptide improves transdermal flux. pH Ethanol N-lauroyl sarcosine Magainin Antimicrobial peptide Stratum corneum Chemical enhancer Transdermal drug delivery Drug delivery systems Transdermal medication Peptide drugs Skin Permeability
13	Soypeptide lunasin in cytokine immunotherapy for lymphoma Lewis, David 01 August 2014 (has links) Indiana University-Purdue University Indianapolis (IUPUI) / Immunostimulatory cytokines can enhance anti-tumor immunity and are part of the therapeutic armamentarium for cancer treatment. We previously reported that chemotherapy-treated lymphoma patients acquire a deficiency of Signal Transducer and Activator of Transcription 4 (STAT4), which results in defective IFNy production during clinical immunotherapy. With the goal of further improvement in cytokine-based immunotherapy, we examined the effects of a soybean peptide called lunasin that exhibits immunostimulatory effects on natural killer cells (NKCs). Peripheral blood mononucleated cells (PBMCs) from healthy donors and chemotherapy-treated lymphoma patients were stimulated with or without lunasin in the presence of IL-12 or IL-2. NK activation was evaluated, and its tumoricidal activity was assessed using in vitro and in vivo tumor models. Chromatin immunoprecipitation (ChIP) assay was performed to evaluate the histone modification of gene loci that are regulated by lunasin and cytokine. Adding lunasin to IL-12- or IL-2-cultuted NK cells demonstrated synergistic effects in the induction of IFNG and genes involved in cytotoxicity. The combination of lunasin and cytokines (IL-12 plus IL-2) was capable of restoring IFNy production by NK cells from post-transplant lymphoma patients. In addition, NK cells stimulated with lunasin plus cytokines have higher tumoricidal activity than those stimulated with cytokines alone using in vitro tumor models. The underlying mechanism responsible for the effects of lunasin on NK cells is likely due to epigenetic modulation at target gene loci. Lunasin represents a different class of immune modulating agent that may augment the therapeutic responses mediated by cytokine-based immunotherapy. lunasin cancer immunotherapy lymphoma NK cell natural killer Cytokines -- Therapeutic use -- Research Soybean -- Therapeutic use -- Research Tumors -- Immunological aspects Peptide drugs -- Immunological aspects Killer cells -- Immunology Chromatin -- Analysis Cellular signal transduction Cell receptors -- Research Cell-mediated cytotoxicity Cancer -- Treatment Tumor antigens Biochemistry -- Research Apoptosis -- Research
14	TARGETED DELIVERY OF BONE ANABOLICS TO BONE FRACTURES FOR ACCELERATED HEALING Jeffery J H Nielsen (8787002) 21 June 2022 (has links) <div>Delayed fracture healing is a major health issue involved with aging. Therefore, strategies to improve the pace of repair and prevent non-union are needed in order to improve patient outcomes and lower healthcare costs. In order to accelerate bone fracture healing noninvasively, we sought to develop a drug delivery system that could safely and effectively be used to deliver therapeutics to the site of a bone fracture. We elected to pursue the promising strategy of using small-molecule drug conjugates that deliver therapeutics to bone in an attempt to increase the efficacy and safety of drugs for treating bone-related diseases.</div><div>This strategy also opened the door for new methods of administering drugs. Traditionally, administering bone anabolic agents to treat bone fractures has relied entirely on local surgical application. However, because it is so invasive, this method’s use and development has been limited. By conjugating bone anabolic agents to bone-homing molecules, bone fracture treatment can be performed through minimally invasive subcutaneous administration. The exposure of raw hydroxyapatite that occurs with a bone fracture allows these high-affinity molecules to chelate the calcium component of hydroxyapatite and localize primarily to the fracture site.</div><div>Many bone-homing molecules (such as bisphosphonates and tetracycline targeting) have been developed to treat osteoporosis. However, many of these molecules have toxicity associated with them. We have found that short oligopeptides of acidic amino acids can localize to bone fractures with high selectivity and with very low toxicity compared to bisphosphonates and tetracyclines.</div><div>We have also demonstrated that these molecules can be used to target peptides of all chemical classes: hydrophobic, neutral, cationic, anionic, short, and long. This ability is particularly useful because many bone anabolics are peptidic in nature. We have found that acidic oligopeptides have better persistence at the site of the fracture than bisphosphonate-targeted therapeutics. This method allows for a systemic administration of bone anabolics to treat bone fractures, which it achieves by accumulating the bone anabolic at the fracture site. It also opens the door for a new way of treating the prevalent afflictions of broken bones and the deaths associated with them.</div><div>We further developed this technology by using it to deliver anabolic peptides derived from growth factors, angiogenic agents, neuropeptides, and extracellular matrix fragments. We found several promising therapeutics that accelerated the healing of bone fractures by improving the mineralization of the callus and improving the overall strength. We optimized the performance of these molecules by improving their stability, targeting ligands, linkers, dose, and dosing frequency.</div><div>We also found that these therapeutics could be used to accelerate bone fracture repair even in the presence of severe comorbidities (such as diabetes and osteoporosis) that typically slow the repair process. We found that, unlike the currently approved therapeutic for fracture healing (BMP2), our therapeutics improved functionality and reduced pain in addition to strengthening the bone. These optimized targeted bone anabolics were not only effective at healing bone fractures but they also demonstrated that they could be used to speed up spinal fusion. Additionally, we demonstrated that acidic oligopeptides have potential to be used to treat other bone diseases with damaged bone.</div><div>With these targeted therapeutics, we no longer have to limit bone fracture healing to casts or invasive surgeries. Rather, we can apply these promising therapeutics that can be administered non-invasively to augment existing orthopedic practices. As these therapeutics move into clinical development, we anticipate that they will be able to reduce the immobilization time that is the source of so many of the deadly complications associated with bone fracture healing, particularly in the elderly.</div> Genetics not elsewhere classified Nanobiotechnology Animal behaviour Clinical microbiology Endocrinology Nanomedicine Regenerative medicine (incl. stem cells) Solid state chemistry Molecular medicine Proteins and peptides Solution chemistry Radiation and matter Biomaterials Biomechanical engineering bone fracture healing Anabolic Agents/pharmacology Targeted Drug DeliveryDesign Bone fracture targeted drugs Bone theapeutics targeted therapies Growth factors Neuropepetides Extracellular matrix Extracellular matrix fragments spinal fusion Angiogensis Acidic oligopeptides osteoporosic fractures diabetic bone fractures Integrin alpha 5 Acelerated Bone fracture healing Hydroxyapatite Hydroxyapatite targeting Targeting peptides Peptide drugs osteomyelitis (OM) Rheumatoid arthritis Bone fractures osteogenic therapies osteotropic osteotropic nanomedicines osteoinductive capacity Molecular Medicine Organic Chemistry Proteins and Peptides Radiochemistry Solid State Chemistry Solution Chemistry Biochemistry Animal Behaviour Biological Engineering Biotechnology Genetics Medicine Pharmacology Biomaterials Biomechanical Engineering Biomechanics Endocrinology Nanobiotechnology Nanomedicine

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