Design, synthesis, and characterization of nanoscale therapeutics and nanocomposites

Nanobiotechnology involves creating nanofabricated materials to examine and engage with biological systems on cellular, subcellular and molecular levels. This field is expected to have a major impact in the area of development of novel therapeutics in the years to come. The main objective of my research is to use the principle of polyvalency---the simultaneous attachment of multiple ligands on one entity to multiple complementary receptors on another entity---to design and synthesize potent nanoscale therapeutics against pathogens/toxins. My research is focused on gaining greater insights into factors influencing the properties of these molecules and then exploring the possibility to achieve remote control over function of the biomolecules, which are interfaced with these nanoscale materials, for interesting applications.;To that end, we synthesized biocompatible polyvalent anthrax toxin inhibitors that are more than 4 orders of magnitude more potent than the corresponding monovalent inhibitors. We observed that even a small number of pendant ligands, which is close to the number of binding sites on the target, may be sufficient to synthesize a potent polyvalent inhibitor. This study also highlighted the role of kinetics in influencing the potency in polyvalent systems. Taking clues from the structure of the target---a heptameric subunit of anthrax toxin---we synthesized heptavalent inhibitors using a rational design approach. Optimal activity was seen when the effective dimensions of the inhibitor match the spatial distribution of peptide binding sites on the target anthrax toxin. These inhibitors neutralized anthrax toxin both in vitro and in vivo. In another study, using the unique property of carbon nanotubes to absorb near-infrared radiation, we were able to achieve remote control over the activity of enzymes adsorbed on the carbon nanotubes. Mechanistic studies showed that the phenomenon responsible for protein deactivation was not photothermal, but rather photochemical. We have used this effect and the unique physicochemical properties of carbon nanotubes to design polyvalent nanotube-peptide conjugates that selectively destroy the anthrax toxin heptamer and to design optically transparent coatings that self-clean following either visible or near-infrared irradiation. The strategies developed in this work may be broadly applicable for the targeted destruction of proteins, pathogens and cells, with applications ranging from antifouling coatings to proteomics and novel therapeutics.