The development of an ideal smart nano-device therapeutic for cancer requires an engineered molecular agent that can specifically target cancer cells, contain in vivo imaging capabilities, carry the therapeutic, have apoptosis detection capabilities and determine the signature of the cancer. A series of poly(amidoamine) (PAMAM) dendrimers has been synthesized incorporating three of the five components onto a single generation five dendrimer. The PAMAM dendrimer is partially acetylated to increase the solubility and specificity of targeting. Fluorescein is incorporated onto the dendrimer for the purpose of imaging the molecular therapeutic in vivo. Folic acid is then conjugated to the dendrimer as a targeting agent. The final step is to conjugate the therapeutic, either Taxol, Methotrexate or a combination of the two drugs. The effective design and development of dendrimers as molecular therapeutics requires the ability to characterize the structure and behavior of the dendrimer agents. Atomic force microscopy (AFM) is a very useful technique for this purpose. AFM has the ability to image in air and in liquid on a variety of surfaces. As a molecular therapeutic, the dendrimer will be subjected to a number of complex biological environments and interfaces. To better understand how the dendrimer therapeutic will behave as it encounters these environments and interfaces, a series of experiments to study the dendrimers with AFM were carried out. Images in air on a flat surface, such as mica, yield information about the shape and poly-dispersity of a dendrimer sample. The effect of pH, using physiological fluid, on the behavior of the dendrimer therapeutic can also be obtained with AFM. Model biological systems, such as a dimyristoylphosphatidylcholine (DMPC) lipid bilayer, have been studied using AFM. Data will be presented showing the interaction of the different dendrimer therapeutics with a lipid bilayer in real time.
Center for Nanobiotechnology, University of Michigan
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