Dissertations, Theses, and Capstone Projects

Date of Degree

2-2023

Document Type

Dissertation

Degree Name

Ph.D.

Program

Chemistry

Advisor

Hiroshi Matsui

Committee Members

Ruth Stark

Rein Ulijn

Mande Holford

Subject Categories

Chemistry | Materials Chemistry | Oncology | Therapeutics

Keywords

superparamagnetic iron oxide nanoparticles, iron oxide nanotubes, drug delivery, exosome, Galvanic replacement reaction, peptide-self assembly, nanotherapeutics, integrins

Abstract

Nano-scale materials have gained much attention during the past few decades due to the stark differences in their properties compared to bulk material. Thus, they are being studied for a myriad of applications ranging from harnessing solar energy to diagnostics. This thesis focuses on the synthesis of hollow iron oxide nanoparticles using Galvanic replacement reactions and their application in drug delivery. Moreover, the use of a peptide precursor for the enhancement of exosomes is also discussed.

Chapter 1 discusses a simple and economical Galvanic approach used for the synthesis of hollow one-dimensional iron oxide nanotubes. In the initial reaction, the nanowire substrate (Ag) is oxidized by MnO4- ions to form an intermediate nanotube substrate (Mn3O4), which is then reduced by Fe2+ ions to form a Fe2O3 nanotube product. Mn3O4 intermediate aid to expand the scope of the reaction for various metal oxides. To test the generality of this approach, the synthesis of SnO2, CuO, and NiO2 nanotubes is also examined. Thus, this method could offer robust, economical, and scale-up engineering to generate a variety of metal oxide nanotubes based on the reduction potential hierarchy.

Chapter 2 discusses a nanoparticle-based novel drug delivery strategy, effective in targeting metastatic sites in the lung. As proof of principle, iron oxide nanoparticle with a characteristic cage shape (IO-NC) is developed to target lung metastases from breast cancer. The strategy is to coat IO-NC with lung-tropic exosomes, a membrane-bound nanoparticle released by breast cancer cells to prime the microenvironment in the lung for metastasis. Preliminary studies in pre-clinical animal models have yielded successful results in ferrying and unloading cargo to lung metastatic sites. However, since the exosomes are derived from the cancer cells, this hybrid particle cannot be directly translated to the bedside. On this end, the use of patient-derived exosomes as a novel precision medical approach or immune cell (T-cell or macrophage) derived exosomes are attractive prospects.

Chapter 3 describes the development of a targeted nanocarrier by direct conjugation of integrin a6b4 (a specific receptor protein in the exosome), the key molecule for the organ specificity of lung-tropic exosomes as discussed in chapter 2 to IO-NCs. Preliminary studies discussed here show the successful attachment of integrin a6b4 to IO-NCs and the preferential accumulation of the integrin a6b4-IO-NCs in lungs in immunodeficient mice. Devising novel strategies that successfully target metastatic sites, as discussed in chapters 2 and 3 is critical in the advancement of nanotherapeutics for the treatment of metastatic stage cancer.

Chapter 4 focuses on the enhancement of exosome secretion in cells using a self-assembling peptide NapFFK(NBD)Yp. This peptide, once taken up, undergo self-assembly triggered by alkaline phosphatase enzyme present in the cells. Such peptide self-assembly has been shown to increase the number of exosomes secreted in cancer cell line MB 231 by 4-folds and the increase in exosome number has been observed to be dependent on the peptide concentration. In addition, the packaging of the exosome, when probed using proteomics, does not change due to the peptide treatment. Thus, an effective method for the enhancement of exosome biogenesis is discussed in this chapter and it has the potential to expand the scope of exosome application which is currently being limited due to the low yield of exosomes generated from the cells.

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