title: Biodistribution and Toxicity Studies of PRINT Hydrogel Nanoparticles in Mosquito Larvae and Cells.
abstract: Mosquito-borne diseases continue to remain major threats to human and animal health and impediments to socioeconomic development. Increasing mosquito resistance to chemical insecticides is a great public health concern, and new strategies/technologies are necessary to develop the next-generation of vector control tools. We propose to develop a novel method for mosquito control that employs nanoparticles (NPs) as a platform for delivery of mosquitocidal dsRNA molecules to silence mosquito genes and cause vector lethality. Identifying optimal NP chemistry and morphology is imperative for efficient mosquitocide delivery. Toward this end, fluorescently labeled polyethylene glycol NPs of specific sizes, shapes (80 nm x 320 nm, 80 nm x 5000 nm, 200 nm x 200 nm, and 1000 nm x 1000 nm) and charges (negative and positive) were fabricated by Particle Replication in Non-Wetting Templates (PRINT) technology. Biodistribution, persistence, and toxicity of PRINT NPs were evaluated in vitro in mosquito cell culture and in vivo in Anopheles gambiae larvae following parenteral and oral challenge. Following parenteral challenge, the biodistribution of the positively and negatively charged NPs of each size and shape was similar; intense fluorescence was observed in thoracic and abdominal regions of the larval body. Positively charged NPs were more associated with the gastric caeca in the gastrointestinal tract. Negatively charged NPs persisted through metamorphosis and were observed in head, body and ovaries of adults. Following oral challenge, NPs were detected in the larval mid- and hindgut. Positively charged NPs were more efficiently internalized in vitro than negatively charged NPs. Positively charged NPs trafficked to the cytosol, but negatively charged NPs co-localized with lysosomes. Following in vitro and in vivo challenge, none of the NPs tested induced any cytotoxic effects.
authors.affiliation: Department of Entomology, Iowa State University, Ames, Iowa, United States of America.
authors.forename: Yashdeep
authors.initials: Y
authors.lastname: Phanse
authors.affiliation: Department of Entomology, Iowa State University, Ames, Iowa, United States of America.
authors.forename: Brendan M
authors.initials: BM
authors.lastname: Dunphy
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, North Carolina, United States of America.
authors.forename: Jillian L
authors.initials: JL
authors.lastname: Perry
authors.affiliation: Department of Entomology, Iowa State University, Ames, Iowa, United States of America.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Airs
authors.affiliation: Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, Colorado, United States of America.
authors.forename: Cynthia C H
authors.initials: CC
authors.lastname: Paquette
authors.affiliation: Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, Colorado, United States of America.
authors.forename: Jonathan O
authors.initials: JO
authors.lastname: Carlson
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, North Carolina, United States of America.
authors.forename: Jing
authors.initials: J
authors.lastname: Xu
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, North Carolina, United States of America; Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: J Christopher
authors.initials: JC
authors.lastname: Luft
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, North Carolina, United States of America; Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America; Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America; Institute for Nanomedicine and Institute for Advanced Materials, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America; Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, North Carolina, United States of America; Sloan-Kettering Institute for Cancer Research, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: DeSimone
authors.affiliation: Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, Colorado, United States of America.
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Beaty
authors.affiliation: Department of Entomology, Iowa State University, Ames, Iowa, United States of America.
authors.forename: Lyric C
authors.initials: LC
authors.lastname: Bartholomay
mesh_terms: D000818:Animals; D000852:Anopheles / Q000187:drug effects* / Q000235:genetics; D001692:Biological Transport; D004337:Drug Carriers / Q000493:pharmacokinetics; D006801:Humans; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate / Q000737:chemistry / Q000493:pharmacokinetics* / Q000633:toxicity; D007306:Insecticides / Q000494:pharmacology; D007814:Larva / Q000187:drug effects*; D009032:Mosquito Control / Q000379:methods*; D053758:Nanoparticles / Q000737:chemistry / Q000633:toxicity*; D011092:Polyethylene Glycols / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology
chemical_list: D004337:Drug Carriers; D007306:Insecticides; D034741:RNA, Small Interfering; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D011092:Polyethylene Glycols