Shielded α-Nucleophile Nanoreactor for Topical Decontamination of Reactive Organophosphate
| Autor: | Jayme Cannon, Shengzhuang Tang, Jessica J. O’Konek, Pamela T. Wong, Racquel Harrison, Seok-Ki Choi, Kelly Yang, Matthew J. Ruge |
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| Rok vydání: | 2020 |
| Předmět: |
Dendrimers
Materials science Cell Survival Swine Biocompatible Materials 02 engineering and technology Nanoreactor Hydroxamic Acids 010402 general chemistry 01 natural sciences Permeability Polyethylene Glycols chemistry.chemical_compound Malaoxon Dendrimer Oximes PEG ratio Polyamines Animals Humans Moiety General Materials Science Decontamination Skin Hydroxamic acid Hydrolysis Hydrogen-Ion Concentration 021001 nanoscience & nanotechnology Oxime Combinatorial chemistry Organophosphates Nanostructures 0104 chemical sciences chemistry Acetylcholinesterase Adsorption 0210 nano-technology Linker |
| Zdroj: | ACS Applied Materials & Interfaces. 12:33500-33515 |
| ISSN: | 1944-8252 1944-8244 |
| DOI: | 10.1021/acsami.0c08946 |
| Popis: | Here, we describe a nanoscale reactor strategy with a topical application in the therapeutic decontamination of reactive organophosphates (OPs) as chemical threat agents. It involves functionalization of poly(amidoamine) dendrimer through a combination of its partial PEG shielding and exhaustive conjugation with an OP-reactive α-nucleophile moiety at its peripheral branches. We prepared a 16-member library composed of two α-nucleophile classes (oxime, hydroxamic acid), each varying in its reactor valency (43-176 reactive units per nanoparticle), and linker framework for α-nucleophile tethering. Their mechanism for OP inactivation occurred via nucleophilic catalysis as verified against P-O and P-S bonded OPs including paraoxon-ethyl (POX), malaoxon, and omethoate by 1H NMR spectroscopy. Screening their reactivity for POX inactivation was performed under pH- and temperature-controlled conditions, which resulted in identifying 13 conjugates, each showing shorter POX half-life up to 2 times as compared to a reference Dekon 139 at pH 10.5, 37 °C. Of these, 10 conjugates were further confirmed for greater efficacy in POX decontamination experiments performed in two skin models, porcine skin and an artificial human microtissue. Finally, a few lead conjugates were selected and demonstrated for their biocompatibility in vitro as evident with lack of skin absorption, no inhibition of acetylcholinesterase (AChE), and no cytotoxicity in human neuroblastoma cells. In summary, this study presents a novel nanoreactor library, its screening methods, and identification of potent lead conjugates with potential for therapeutic OP decontamination. |
| Databáze: | OpenAIRE |
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