Excessive blood clotting, associated with diseases such as atherosclerosis and diabetes, leads to locally restricted blood flow and can cause fatal heart attacks or strokes in acute thromboembolic states.  The current state-of-the-art treatment for these conditions is catheter-directed delivery of enzymatic drugs to digest the fibrin network that forms the clot scaffold.  The highly localized nature of acute thrombotic events presents an opportunity for implementing reactive nanomedicine agents.  We have previously established the feasibility of nanoparticle-based radical generators as a first step towards remotely-activatable theranostics by coordinating an enediyne-dithiol ligand to gold nanoparticles.  Irradiating the nanoparticles at their surface plasmon resonant frequency photothermally triggers the radical-producing cyclization reaction, which we can monitor spectroscopically and through TEM visualization of the polymerized products.  As one extension of this work, we have coordinated an enediyne-diamine ligand to water-soluble PEGylated gold nanoparticles.  Subsequent irradiation generates analogous polymer coatings in the absence of substrate, illustrating that thermal activation is still operative at distances up to 8 nm from the particle surface.  In order to evaluate the ability of our radical generators to degrade proteinaceous biopolymers, we have used the enediyne-bearing gold nanoparticles to attack purified fibrin clots.  Upon photolysis, our nanoparticles are able to effectively degrade the protein matrix, causing damage visible in SEM images and quantifiable by SDS-PAGE.  As an alternative to laser-based heating, we have also explored in vitro magnetic hyperthermia as a means to trigger the radical generating reaction on iron oxide nanoparticles, which are well known as MRI contrast agents.  Catechol groups are used to anchor enediyne-containing ligands to the iron oxide surface to generate aqueous and organic soluble nanoparticles.  These solutions can then be thermally or magnetically activated to promote cyclization with concomitant radical polymerization.  Combined, these efforts represent viable routes to new potent nanomedicine agents for pernicious thrombotic disorders.

Photothermally- and magnetically- triggered radical generating nanoparticle agents and their degradative effect on fibrin clots

246th National Meeting (2013)

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