Engineering the Protein Corona of a Synthetic Polymer Nanoparticle for Broad-Spectrum Sequestration and Neutralization of Venomous Biomacromolecules.

Biochemical diversity of venom extracts often occurs within a small number of shared protein families. Developing a sequestrant capable of broad-spectrum neutralization across various protein isoforms within these protein families is a necessary step in creating broad-spectrum antivenom. Using directed synthetic evolution to optimize a nanoparticle (NP) formulation capable of sequestering and neutralizing venomous phospholipase A2 (PLA2), we demonstrate that broad-spectrum neutralization and sequestration of venomous biomacromolecules is possible via a single optimized NP formulation. Furthermore, this optimized NP showed selectivity for venomous PLA2 over abundant serum proteins, was not cytotoxic, and showed substantially long dissociation rates from PLA2. These findings suggest that it may show efficacy as an in vivo venom sequestrant and may serve as a generalized lipid-mediated toxin sequestrant.

Amphiphilic graft copolymers from end-functionalized starches: synthesis, characterization, thin film preparation, and small molecule loading.

End-functionalized macromolecular starch reagents, prepared by reductive amination, were grafted onto a urethane-linked polyester-based backbone using copper-catalyzed azide-alkyne cycloaddition (CuAAC) chemistry to produce novel amphiphilic hybrid graft copolymers. These copolymers represent the first examples of materials where the pendant chains derived from starch biopolymers have been incorporated into a host polymer by a grafting-to approach. The graft copolymers were prepared in good yields (63-90%) with high grafting efficiencies (66-98%). Rigorous quantitative spectroscopic analyses of both the macromolecular building blocks and the final graft copolymers provide a comprehensive analytical toolbox for deciphering the reaction chemistry. Due to the modular nature of both the urethane-linked polyester synthesis and the postpolymerization modification, the starch content of these novel hybrid graft copolymers was easily tuned from 28-53% (w/w). The uptake of two low molecular weight guest molecules into the hybrid polymer thin films was also studied. It was found that binding of 1-naphthol and pterostilbene correlated linearly with amount of starch present in the hybrid polymer. The newly synthesized graft copolymers were highly processable and thermally stable, therefore, opening up significant opportunities in film and coating applications. These results represent a proof-of-concept system for not only the construction of starch-containing copolymers, but also the loading of these novel polymeric materials with active agents.

Engineered nanoparticles bind elapid snake venom toxins and inhibit venom-induced dermonecrosis.

Envenomings by snakebites constitute a serious and challenging global health issue. The mainstay in the therapy of snakebite envenomings is the parenteral administration of animal-derived antivenoms. Significantly, antivenoms are only partially effective in the control of local tissue damage. A novel approach to mitigate the progression of local tissue damage that could complement the antivenom therapy of envenomings is proposed. We describe an abiotic hydrogel nanoparticle engineered to bind to and modulate the activity of a diverse array of PLA2 and 3FTX isoforms found in Elapidae snake venoms. These two families of protein toxins share features that are associated with their common (membrane) targets, allowing for nanoparticle sequestration by a mechanism that differs from immunological (epitope) selection. The nanoparticles are non-toxic in mice and inhibit dose-dependently the dermonecrotic activity of Naja nigricollis venom.

Polymer antidotes for toxin sequestration.

Toxins delivered by envenomation, secreted by microorganisms, or unintentionally ingested can pose an immediate threat to life. Rapid intervention coupled with the appropriate antidote is required to mitigate the threat. Many antidotes are biological products and their cost, methods of production, potential for eliciting immunogenic responses, the time needed to generate them, and stability issues contribute to their limited availability and effectiveness. These factors exacerbate a world-wide challenge for providing treatment. In this review we evaluate a number of polymer constructs that may serve as alternative antidotes. The range of toxins investigated includes those from sources such as plants, animals and bacteria. The development of polymeric heavy metal sequestrants for use as antidotes to heavy metal poisoning faces similar challenges, thus recent findings in this area have also been included. Two general strategies have emerged for the development of polymeric antidotes. In one, the polymer acts as a scaffold for the presentation of ligands with a known affinity for the toxin. A second strategy is to generate polymers with an intrinsic affinity, and in some cases selectivity, to a range of toxins. Importantly, in vivo efficacy has been demonstrated for each of these strategies, which suggests that these approaches hold promise as an alternative to biological or small molecule based treatments.