| The structural and functional behavior of a novel molecular imaging nanoparticle (MIN), for early detection of pancreatic cancer, is investigated. The MIN consists of a peptide nucleic acid (PNA) that binds to a known mutation of the KRAS gene, an insulin-like growth factor 1 (IGF-1) peptide analog to enter the cancerous cell, and a dendritic polymer moiety to carry MRI contrast agent. Molecular dynamics simulations were used to determine the solution structure of the MIN, which predicts that the different groups do not interfere with each other and that PNA and peptide are solvent accessible.; The in vitro functional behavior of the MIN was studied using confocal microscopy, as well as using variants with a peptide mismatch, a PNA mismatch and only the IGF-1 ligand without the PNA. A novel uptake protocol was established to study the uptake and release behavior of a fluorescently labeled poly(amido amine) (PAMAM) dendrimer. Using the uptake protocol a mass transfer coefficient of 11.8*10-3 micrometers/hour +/- 9.2*10 -3 micrometers/hour was determined for the MIN into AsPC-1 pancreatic cancer cells.; The uptake experiments showed that the peptide mismatched MIN was not taken up by the cells, yet the efficacy of the PNA was not proven conclusively due to nonspecific binding of the fluorescent dye. The fluorescently labeled IGF-1 peptide exhibited an induction time, along with a higher mass transfer coefficient of 18.*10-3 micrometers/hour +/- 6.4*10 -3 micrometers/hour.; The in vivo behavior was described using a two-compartment model, which showed a fast elimination rate constant for the MIN from the body. A more thorough analysis was done using a physiologically based pharmacokinetic model that was adapted from the literature. This model was able to capture the behavior of the MIN in the body, assuming 10-20% of the injected dose is available, due to the MIN being filtered out of the blood by the kidney and the remaining MIN existing bound to insulin-like growth factor binding proteins (IGFBPs). Being able to describe the distribution of the MIN in the mouse holds great promise to allow the accurate prediction of the in vivo behavior of the MIN in humans. |
