| The development of novel therapeutics is an important area in which the application of nanotechnology is expected to have a major impact in years to come. Biologically active nanostructures will allow the targeting of specific molecular interactions for increased drug potency and sensitivity. The objective of my research is to develop functional nanostructures based on the self-assembly of polymers, that have application in the development of multivalent therapeutics.; We propose to use functionalized block copolymer nanoparticles as a scaffold for the multivalent display of biologically active ligands. As a first step in this direction, we have created nanoparticles of controlled sizes by the self-assembly of amphiphilic block copolymers synthesized using ring-opening metathesis polymerization (ROMP). We synthesized a novel hydrophobic derivative of norbornene, and polymerized it using Grubbs' catalyst forming polymers of controlled molecular weight. We synthesized amphiphilic block copolymers of controlled composition and showed that they assemble into nanoparticles of controlled size. Tuning the composition of the block copolymer enables the tuning of the diameters of the nanoparticles in the 5--80 nm range.; We have also developed a novel approach for the synthesis of multivalent ligands, which allows biofunctionalization with proteins or peptides in a controlled orientation. This approach consists of the synthesis of water-soluble, activated polymer scaffolds of controlled molecular weight, which can be biofunctionalized with various thiolated ligands in aqueous media. These polymers were synthesized by ROMP and further modified to make them water-soluble. The attachment of chloride groups activated the polymers to react with thiol-containing peptides and proteins, and the formation of multivalent ligands in aqueous media was demonstrated.; Using the lessons learned in the first part of this work, we synthesized multivalent ligands based on block copolymer nanoparticles. These nanoparticles are composed of amphiphilic block copolymers that have an activated hydrophilic block to enable nanoparticle functionalization with biological ligands such as peptides in aqueous media. Nanoparticle size was varied in the 35--86 nm range, depending on block copolymer composition, and nanoparticle biofunctionalization was demonstrated by the attachment of a thiolated peptide that may enable this nanostructure to be used as an inhibitor of anthrax toxin. |
