Designer nanoparticles to detect and treat disease

Abstract

Conjugation of targeting, imaging and drug molecules to nanoparticles has been a developing area of interest over the last 10-15 years. Although great strides have been made, characterization and activity of functionalized nanoparticles is still incomplete. More work needs to be done to allow generalized predictions to be made about the impact of size, amount loading and the best synthetic approaches to utilize nanoparticles to their fullest potential. Imaging agents such as fluorophors and chelated metals have been attached to the surface of dendrimers and studied as profusion or targeted imaging agents. One important target, the translocator protein(TSPO, formerly named peripheral benzodiazepine or PBR), has not been targeted with a nanoparticle. The translocator protein is a mitochondrial membrane protein that spans the lipid bi-layer and mediates cholesterol transport across the mitochondrial membrane. Two cell lines that have high expression of TSPO are MDA-MB-231 human breast cancer and C6 rat glioma cell. The first portion of this dissertation describes the synthesis, characterization and imaging capabilities of a TSPO targeted dendrimer with fluorescence, MRI and EM capabilities. Matrix metalloproteinases (MMPs) are another target for substantiating the role of nanoparticles in biology. MMPs are a class of zinc dependant enzymes that have been found to degrade the extra cellular matrix. Several MMPs have been discovered and studied, but MMPs 2, 7 and 9 are most interesting for their high expression associated with the proliferation in certain types of tumor cells1-2. Although pharmacological inhibitors have been unsuccessful in treating MMP associated cancers, other approaches utilizing the enzymes have been successful. For example, small peptide sequences that are selectively cleaved by a specific MMP(s) have been developed and used in molecularly activated fluorescence probes and prodrug. The second portion of this dissertation describes the incorporation of dendrons to develop MMP-9 activated delivery of doxorubicin or paclitaxel to cancer cells.