Biomacromolecules, molecules and functional nanoparticles for therapeutic and diagnostic applications
Embargo Lift Date: 2018-04-01
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Cancer is one of the most important global health problem. In the last decade, researchers have focused on the development of novel sensitive diagnostic agents and potential therapeutic molecules to further contribute to the success of cancer treatment and increase survival rates of cancer patients. Magnetic resonance imaging (MRI) is a powerful diagnostic tool and used in clinics for cancer imaging. Superparamagnetic iron oxide nanoparticles (SPIONs) are used as a negative contrast agent to increase sensitivity of MRI. SPIONs can be coated with biocompatible natural or synthetic materials to maintain stability and improve their blood distribution profile. SPIONs can also be non-covalently functionalized with peptide amphiphile (PA) molecules through hydrophobic interactions to render them water soluble and biocompatible. In addition, several efforts have been made to improve specificity and sensitivity of SPIONs by attaching cancer targeting agents such as peptides. For cancer therapy, metal based drugs have attracted attention because of their biological and pharmaceutical properties over the past decades. The understanding of interactions between potential agents and biomolecules is important for designing novel anticancer drugs against tumors to overcome the toxicity of currently used chemotherapeutic drugs and achieve more precision. Herein, I investigated the potential of proline-rich PA coated SPIONs as a negative contrast agent for cancer diagnosis by MRI. To achieve water solubility and cancer targeting, positively charged K and LPPR peptide sequences were presented on the PA micelles. PA functionalization provided a water-dispersible hybrid system. Biocompatibility and efficient uptake of the SPIONs were found to be improved with PA coating. This hybrid system provided enhancement in the MR imaging of tumor tissue in chemically induced breast cancer model. In addition, in vivo experiments and histological examinations revealed the biodistribution and bioelimination profile of the nanoparticles. These SPION/PA system can potentially be used as a contrast agent in cancer diagnosis by MRI. In addition, I analyzed the interactions between metal based molecules that can be used as cancer therapeutics and calf thymus DNA or human serum albumin (HSA) by spectroscopic and calorimetric methods which showed the binding modes, affinities and the effects on the structure of these biomacromolecules. Although similar structures demonstrated similar binding characteristics, each molecule has different association with DNA or HSA. The obtained results are promising for the development of metal or half metal based anticancer agents targeting DNA and carried by HSA.