Citation

Melanin is a comprehensive term referring to the dark pigment commonly present in biological entities. Acting as a significant pigment, melanin plays a crucial role in safeguarding against diverse stresses, such as radiation and radical species. Due to its special properties, melanin-based materials have been widely studied for biomedical applications. In this Ph.D. dissertation, three studies applying melanin-simulated materials for cancer, autoimmune diseases, and inflammatory diseases will be introduced, along with additional modifications to the materials. In Chapter 1, comprehensive physicochemical properties and biological roles of melanin were reviewed. Melanin has multiple roles in living organisms; it has been widely investigated for biomedical purposes. In order to apply melanin-based materials, it is essential to accumulate fundamental characteristics of melanin. In Chapter 2, it was designed that lysyl oxidase (LOX)-responsive nanoparticles to interact with the collagen matrix of the tumor microenvironment. Collagen-coated and imiquimod-loaded polydopamine nanoparticles (CPN/IQ) could form crosslinked structures with the collagen matrix via LOX. In vitro, anchoring of CPN/IQ nanoparticles was observed with LOX-secreting CT26 cells, but this was blocked by a LOX inhibitor. In CT26 tumor-bearing mice, co-administration of nanoparticles plus the LOX inhibitor did not significantly alter the anti-tumor efficacy among nanoparticles. In the absence of the LOX inhibitor, however, a single administration of CPN/IQ could provide sustained responsiveness to near- infrared irradiation and ablation of primary tumors. In the primary tumor microenvironment, CPN/IQ lowered the Treg cell population but increased the cytotoxic CD3+CD8+ T cell population. In splenic dendritic cells, CPN/IQ treatment significantly increased the CD11c+CD86+ and CD11c+CD80+ cell populations. In a CT26 distant tumor-rechallenge model, CPN/IQ treatment increased the cytotoxic CD3+CD8+ T cell population and provided 100% survival of mice until 64 days. This study indicates the feasibility of tumor immune microenvironment modulation using LOX-responsive size- transforming nanoparticles. The concept of LOX-responsive collagen matrix- anchoring nanoparticles may be broadly applied to other tumor tissues with LOX-rich tumor microenvironments. In Chapter 3, tolerogenic nanovaccine was developed and tested it an animal model of multiple sclerosis. The nanovaccine was constructed to deliver the self-antigen, MOG peptide, and dexamethasone on an abatacept- modified polydopamine core nanoparticle (AbaLDPN-MOG). AbaLDPN- MOG could target dendritic cells and undergo endocytosis followed by trafficking to lysosomes. AbaLDPN-MOG blocked the interaction between CD80/CD86 and CD28 in antigen-presenting cells and T cells, leading to decreased interferon gamma secretion. The subcutaneous administration of AbaLDPN-MOG to mice yielded significant biodistribution to lymph nodes and, in experimental-autoimmune encephalomyelitis (EAE) model mice, increased the integrity of the myelin basic sheath and minimized the infiltration of immune cells. EAE mice were treated with AbaLDPN-MOG before or after injection of the autoantigen, MOG. Pre-immunization of AbaLDPN-MOG before the injection of MOG completely blocked the development of clinical symptoms. Early treatment with AbaLDPN-MOG at 3 days after injection of MOG also completely blocked the induction of symptoms. Notably, treatment of EAE symptom-developed mice with AbaLDPN-MOG significantly alleviated the symptoms, indicating that the nanovaccine had therapeutic effects. Although AbaLDPN was used for MOG peptide delivery in the EAE model, the concept of AbaLDPN can be widely applied for the prevention and alleviation of other autoimmune diseases. In Chapter 4, application of pyomelanin was investigated. Pyomelanin is one the type of melanin synthesized from bacteria or fungi species. It protects the microorganisms from UV irradiation or oxidative stress as radical scavenger. In the context of radical elimination, it has ability to intracellular ROS, therefore, in this study, pyomelanin nanoparticles (PMNP) were synthesized and applied to the inflammatory disease, such as inflammatory bowel disease (IBD). PMNP synthesized from homogentisic acid-?-lactone (HGL) through auto-oxidation and showed radical scavenging activity likewise pyomelanin and regulated inflammatory response. Thus, it also revealed therapeutic activity in IBD and the efficacy was superior to the mesalazine (5-ASA) and eumelanin nanoparticles (EMNP). This result has been explained by pharmacokinetic profile of PMNP in gastrointestinal (GI) tract attributed its distinctive chemical structures. Keyword: melanin, eumelanin, polydopamine, photothermal therapy, anti- inflammation, autoimmune disease, pyomelanin Student Number: 2018-25394