Date of Award

Spring 2020

Document Type

Open Access Dissertation

Department

Environmental Health Sciences

First Advisor

Geoffrey Scott

Abstract

Nanomedicine is a new field of science defined by the European Science Foundation as “the science and technology of diagnosing, treating, and preventing disease and traumatic injury, of relieving pain, and of preserving and improving human health, using molecular tools and molecular knowledge of the human body” (ESF 2004). The medical community has, however, made significant steps forward in understanding the potential nanomaterials may have in medical treatment of certain diseases. Current nanoparticles being evaluated include platinum, selenium, and ceria (Pt, Se, and CeO2, respectively). While it is understood that these nanoparticles have potential medical applications, there is a significant need to better understand both their potential therapeutic uses as well as any adverse toxic effects they may have. Thus it is necessary to further examine these nanoparticles and understand the full impact they have on health, particularly at the cellular and subcellular level. Furthermore, the effectiveness of these nanoparticles in the treatment of diseases, such as cancer and metabolic disorders including fibrotic diseases, needs to be better understood to fully exploit their utility in Nanomedicine. In this study, we evaluated the effects of three nanoparticles-Selenium (Se), Platinum (Pt) and Cerium (Ce) on primary mouse embryonic fibroblast cells. NPs were synthesized in the lab. Se NPs were produced via a chemical reduction of selenium ions using ascorbic acid as a reducing agent. PVP-coated Pt NPs were prepared by dissolution of Pt salts into water which chemically induced to convert to platinum atoms by using a reducing agent such as sodium borohydride NaBH4 using the method described by Park et al.(2002); PVP-coated cerium oxide nanoparticles NPs were synthesized as described previously by Merrifield et al. (2013). The physicochemical properties of SE, Pt and Ce NPs, such as morphology, size distribution, and surface potential, were determined. Cultured primary mouse embryonic fibroblast cells (MEFs) were exposed to Se (1, 25 and 50 μg/ml), Pt (1, 25, 50 μg/ml) and cerium (1, 25 and 50 μg/ml) nanoparticles for up to 6 days and evaluated for cell viability, proliferation, necrosis, DNA damage, and TGFB-1 signaling proteins expression by Immunoblotting. Results indicated: (1) Se NP induced the intrinsic pathway of apoptosis in primary mouse MEFs, at a minimal concentration of 1 μg Se/ml, without causing necrosis to the primary cells and may provide a new therapy for some metabolic and neoplastic diseases; (2) Pt NPs did not induce any toxicity in cell viability or lead to necrosis in MEFs, but significantly reduce proliferation by > ~ 50% and induction of TGFb-1 canonical pathway, causing production of endogenous collagen and a-smooth muscle actin (a-SMA) thus indicating it might serve a big role in the TGFB-1 signaling pathway in early stage cancer therapy but it may pose a hazard to patients with fibrotic diseases such as cardiac fibrosis; and (3) Cerium oxide nanoparticles (Nanoceria) were able to inhibit TGFB-1 signaling via inhibition of smad2/3 and downstream factors expression and inflammation progression in MEF, without induction of adverse effect in in vitro studies. These findings indicated the Se NPs caused cell death and show promise as a potential for cancer therapy while Pt NPs signals tgf-b-1, which might help to limit early stage cancer development but may have adverse effects during the later stages of cancer or those suffering from fibrotic disease such cardiac fibrosis. Nanoceria, unlike Pt NPs, down regulates tgf-b-1 signaling, which makes it appropriate for patients with fibrotic diseases, such as cardiac fibrosis. In this research, these nanoparticles showed incredible potential as future therapies for cancer and cardiac fibrosis.

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