The Design and Study of Lanthanide-Chelating Macromolecular Diagnostic and Delivery Agents
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The contrast enhancing polymers we developed are new macromolecular beacons that allow the delivery of nucleic acids to be visualized at different biological scales. They contain repeated oligoethyleneamines, for binding and compacting nucleic acids into nanoparticles, and Gd(III)/Eu(III) chelates. The chelated lanthanides allow the visualization of the delivery vehicle via microscopy and via magnetic resonance imaging (MRI). We demonstrate that these new delivery beacons effectively bind plasmid DNA(pDNA) and protect their cargo nucleic acids from nuclease damage. The lanthanide-chelate materials have been found to efficiently deliver pDNA into cultured cells and do not exhibit toxicity. Micrographs of cultured cells exposed to the nanoparticle complexes formed with fluorescein-labeled pDNA and the europium-chelated polymers reveal effective intracellular imaging of the delivery process. MRI of bulk cells exposed to the complexes formulated with pDNA and the gadolinium-chelated structures show bright image contrast, allowing visualization of effective intracellular delivery on the tissue-scale. Because of their versatility as imaging probes, these delivery beacons posses remarkable potential for tracking and understanding nucleic acid transfer in vitro and have promise for in vivo imaging applications. In later studies the Ln-chelating polymers were co-polymerized with dimethylgalacterate which definitively increases luciferase gene expression (up 50x enhancement) and cellular uptake (up to 2x enhancement).
- Doctoral Dissertations