Design and characterization of peptide decorated nanocarriers as chemotherapeutic agents in breast cancer

Project (M.A., Biological Sciences (Stem Cell)) -- California State University, Sacramento, 2011.Breast cancer is the most common malignant tumor among women, accounting for an estimated 24% of all cancer cases. Current therapies are clinically efficacious, but side effects linked with these therapies are serious and can cause further harm not associated with the tumor itself. It has been hypothesized that cancer stem cells allow for resistance to chemo- and radiation therapy, and contribute to tumor spread (metastasis) and disease relapse. Therefore, the development of a novel treatment method including the targeted delivery of cytotoxic agents to the tumor mass for the treatment of advanced breast cancer is vital to improving the therapeutic index and efficacy/toxicity balance. \ud Taking all of this into consideration, the goals of this project were to develop novel strategies for discovering and using treatments against breast cancer. The use of a combination therapy system for drug delivery should increase the therapeutic index, and help prevent the relapse and metastasis of resistant/stem-like cancer cells. To accomplish these goals we used several unique methodologies to discover and test new therapeutics. These methodologies include: the One Bead One Compound (OBOC) screen for drug discovery, 3D culture tumor modeling for drug screening, and nanoparticle systems for optimal drug-delivery.\ud The use of the One Bead One Compound (OBOC) combinatorial chemistry founded by Dr. Lam and colleagues has allowed for the discovery of LMS peptides that bind specifically to breast cancer cells. These peptide ligands bind to high-mannose glycans specifically found on breast adenocarcinomas. Screening these peptides using a 3D cell culture system has been shown as an effective way to model the in vivo tumor response. The 3D culture system we use is an efficient way to screen potential therapeutics, and has provided us data that suggests growth inhibitory effects of the LMS peptides. This data suggests that the LMS peptides can be used as both a targeting agent and therapeutic agent in our nanoparticle drug-delivery system. Our studies show that functionalized super paramagnetic iron-oxide (SPIO) nanoparticles are a highly efficient vehicle to use for this nanocarrier drug-delivery system. The LMS peptides, nanoparticles, and chemotherapeutic drug, can all be used alone as therapeutic agents, but the combined use of each of these agents will provide a treatment system that is much safer and efficacious than conventional therapies. \ud Assessing the combined use of the LMS peptides and the nanocarrier system is the next step in evaluating the ability of our combination therapeutic approach to increase therapeutic efficacy. The results attained from this project have provided useful data that can contribute to future discoveries in breast cancer treatment.Biological Sciences (Stem Cell