Drug/Gene Delivery via Dendrimers
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Thomas Lewistlewis@che.utexas.edu Office: CPE 3.402 Phone: 512-471-6754 |
Motivation for the development of commercial materials with novel functional properties is a recent theme of research in polymeric materials. One such effort in this regard is a new class of synthetic, tree-like molecules known as dendrimers, which are made via controlled, iterative reaction steps that add a layer of monomers (generation, see Figure 1) to the branch points located on the periphery of the molecule. These materials have found applications in a variety of contexts including hostguest chemistry, electrochemistry, photochemistry, nanoparticle synthesis, catalysis, drug-delivery, and gene transfection.
Figure 1. Generation number refers to the number of branch points that exist along a linear portion of the dendrimer extending from the core to the periphery. Above, a 3rd generation polyamidoamine dendrimer is shown.
My research is motivated by the applications of dendrimers in biomedical context such as drug delivery, cancer therapy, and gene transfection. Gene transfection and drug delivery via dendrimers can be broadly characterized to occur in two phases: 1) Complexation of the dendrimer with the desired host (DNA or drug) due to the electrostatic interactions between dendrimers and the host molecules: A common feature between DNA and many drug molecules is that they are both charged organic molecules, and hence dendrimers with oppositely charged functional groups can bind onto them and serve as effective vehicles; 2) Delivery of the complex to the desired target cells: This stage requires the transport of the dendrimer DNA complex to and through the cell membranes.
Despite a large number of experiments quantifying the above processes, a number of fundamental issues remain unresolved and has hindered the widespread application of dendrimers. For instance, experiments probing the condensation of DNA on dendrimers noted significant differences as a function of the generation number of the dendrimer.2 Other experiments have noted similar generation number effects in their transfection efficiencies. The physics underlying these observations have not been resolved. My research uses computer simulations, specifically coarse-grained polymer physics based theories to shed insights into three critical problems motivated by the dendrimer complexation and delivery processes: 1) The structure of DNA-dendrimer complexes; 2) Distribution of drug molecules inside the dendrimerdrug complex; and 3) Interaction of the dendrimer-drug and DNA-dendrimer complexes with a cell membrane.