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Synthesis and Characterization of Indolizine Derivatives and of Hyaluronic Acid Nanoparticles for Treatment of Cancer and Inflammation via Modulating Immune System
- Author(s)
- 이슬비
- Advisor
- 김은하
- Department
- 일반대학원 분자과학기술학과
- Publisher
- The Graduate School, Ajou University
- Publication Year
- 2021-08
- Language
- eng
- Keyword
- Cancer immunotherapy; Hyaluronic acid nanoparticles; Indolizine derivatives; Innate immunity; Sting pathway activator; Type 1 Interferon; anti-inflammation
- Alternative Abstract
- The complexity of the innate immune response has recently been demonstrated that it plays a part not just in immunity to the pathogens, but also in controlling of tissue homeostasis. Consequently, innate immunity may play a significant role in the development of human diseases including cancer, atherosclerosis, psoriasis, inflammatory bowel disease, rheumatoid, fibrosis, wound healing and chronic inflammatory lung disease. Here, I present synthesis and characterization of indolizine derivatives and of hyaluronic acid nanoparticles for treatment of cancer and inflammation via modulating immune system. In Chapter 1, synthesis and characterization of indolizine derivatives having synergistic effect on Stimulator of interferon gene signaling for cancer treatment will be delivered. To continue our endeavor for discovery of immune transmitter, based on indolizine chemical scaffold, having a synergistic effect on activation of STING pathway, we conducted structure-activity relationship (SAR) study of indolizine scaffold to improve the immune modulation activity of indolizine compounds. Based on luciferase reporter gene assay, we confirmed a new indolizine compounds have the increased effect on activating STING pathway with the presence of cGAMP. Stimulation of STING-IRF pathways by the compound were validated in THP-1 cells to confirm that the compound worked effectively with hSTING agonist. We observed that compound 12 has a better effect on activating the STING pathway than compound 8. In Chapter 2, we I present synthesis and characterization of the hyaluronic nanoparticles (HANPs) for psoriasis treatment. We designed HANPs according to degree of substitution (DS) and found size of HANPs are decrease as DS increased. Interestingly, increase of therapeutic effects for psoriasis was observed as size of HANPs decreased. We conducted stability test of compound 22c, which have highest activity, and confirmed it is stable for 2 weeks. Therapeutic effect for psoriasis in vitro was confirmed by monitoring the mRNA expression level of inflammatory cytokines and of psoriasis related genes in HaCaT cells. In addition, therapeutic effect of compound 22c in vivo was confirmed in methotrexate-induced psoriasis mouse skin. Overall, we believe HANPs the beneficial reagents for curing psoriasis.
- Fulltext
- Appears in Collections:
- Graduate School of Ajou University > Department of Molecular Science and Technology > 3. Theses(Master)
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