NO Mechanisms on Host Cells – A Concentration Driven Response

1. S-nitrosation of Poly(propylene sulfide) Nanoparticles for Nitric Oxide Delivery Alex Schudel1,2 and Susan N. Thomas2,3 1School of Materials Science and Engineering, 2Parker H. Petit Institute for Bioengineering and Biosciences, 3George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA Introduction and Background Lymphatic Filariasis Treatment Transnitrosation &Thermal Degradation Emulsion Polymerization Synthesis of Poly(propylene sulfide) Nanoparticles and S-nitrosation of Free Thiols Via Acidified Nitrite Lymphatic filariasis is caused by the parasite, B. malayi, which resides in the lymphatics where it eventually causes elephantiasis. There are an estimated 120M people, mostly in the developing world, who harbor the parasites. While there are several treatment options available to remove the microfilaria progeny that spread the disease, there is no current therapy that targets both the adult worms and the lymphatics leaving people currently infected with little treatment recourse. NO Mechanisms on Host Cells – A Concentration Driven Response S-nitrosation is highly efficient and directly proportional to thiol concentration Polymerization is controllable by changing parameters Core free thiol concentration is controllable Imaging set-up High-throughput real-time acquisition of worm motility movement Schematic diagram of NO mechanisms of action on host cells [Fukumara et al., 2011]. The effects of NO on host cells is highly dependent on its con-centration. Low systemic concentrations promote homeostatic mechanisms, whereas high local concentrations of NO promote cytotoxic effects and apoptosis. NO Chemical Interactions Can Be Exploited To Create NO-Vehicle Adducts S-nitrosation, the interaction of NO with free thiols, is a rapid and highly stable conjugation chemistry [Kovacs et al., 2013]. One of the most important reaction pathways for NO mechanisms is through the reaction with free thiols, called S-nitrosation. Many of the reactive intermediates formed from NO can react with free thiols, including Metal-nitrosylComplexes (M-NO), Peroxynitrite (OONO-), Nitroxyl anions (NO-), Nitrosonium ions (NO+), Nitric Oxide Radicals (NO●), Reactive Nitrogen Species (N2O3/NOx), and other S-nitrosothiols (RS-NO). Functions of SNO-NP: Transnitrosationand Thermal Degradation SNO-NP can transnitrosate to low molecular weight thiols NO released from SNO-NP undergoes oxidation to pro-drug NO2- Video data is processed and metrics to determine worm health are extracted SNO-NP are able to mediate effective worm killing due to release of NO Conclusions and Future Work • This work demonstrates: • SNO-NP adducts were successfully created by utilizing the reaction between NO2- and the free thiols of poly(propylene sulfide) nanoparticles. • SNO-NP can transnitrosate NO to low molecular weight physiological thiols or release NO, which becomes oxidized to NO2- • SNO-NP are able to effectively kill B. malayiadult female lymphatic filarial worms References Can we improve NO therapy by exploiting the drug delivery benefits of micelles? • Fukumara, D. et al. Nat. Rev. 2006; 6; 521-534 • Kovacs, I. et al. Front. Plant. Sci. 2013; 4; 1-10