Graduation Year

2019

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Chemistry

Major Professor

Mark McLaughlin, Ph.D.

Co-Major Professor

Jianfeng Cai, Ph.D.

Committee Member

Edward Turos, Ph.D.

Committee Member

David Morse, Ph.D.

Keywords

Myelodysplastic Syndromes, Oligonucleotides, Positional Scanning Libraries, DOTA Chelators, Internal Radiation

Abstract

Cancer remains one of the most feared diseases affecting the modern world. Second to heart disease, it is the largest cause of deaths, affecting one in three persons. Cancer cells are formed when normal, healthy cells become damage, losing their normal regulatory mechanism that control cell growth. There are many different types and progression of these cancer cells that determine the type of treatment a patient receives. The primary focus of this dissertation is to propose three studies of anticancer agents. In Chapter one, a CpG-lytic peptide conjugate was designed to target receptors on the cell membrane to concentrate the lytic peptide around the cells to cause triggered cell death, in the treatment of Myelodysplastic Syndromes (MDS). This conjugate act like monoclonal antibodies in that the molecular size is too large to enter the cell, therefore it targets the TLR9 receptors expressed extracellularly in precancer cells in MDS. Chapter two, focuses on the screening of anticancer agents used in targeted therapy. It provides a general scheme applied to the synthesis of a combinatorial library of primary amines used as small-molecule drugs coupled unto a solid support bead (Positional Scanning Library Method) to screen for biological effects on various types of cancers. Chapter three address the issue of radiotherapy treatments, one of the most widely used treatment of cancer. To improve the efficacy of conventional radiation therapy and reduce the cytotoxicity of healthy tissue, High-Dose Rate brachytherapy (HDR) may be used as a stand-alone treatment or after surgery to prevent the recurrence of cancer cells. To design and provide studies of these brachytherapy beads, a model was developed by coupling a chelating agent DOTA onto the surface of macrobeads that coordinated to Europium (III) in efforts to mimic the radiolabeling with a radioactive metal. These brachytherapy beads will be used to conduct in vitro studies in the treatment of local cancers with massive concentrations of radiation without damaging surrounding healthy tissue.

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