title: Rapid determination of plasmonic nanoparticle agglomeration status in blood.
abstract: Plasmonic nanomaterials as drug delivery or bio-imaging agents are typically introduced to biological systems through intravenous administration. However, the potential for agglomeration of nanoparticles in biological systems could dramatically affect their pharmacokinetic profile and toxic potential. Development of rapid screening methods to evaluate agglomeration is urgently needed to monitor the physical nature of nanoparticles as they are introduced into blood. Here, we establish novel methods using darkfield microscopy with hyperspectral detection (hsDFM), single particle inductively-coupled plasma mass spectrometry (spICP-MS), and confocal Raman microscopy (cRM) to discriminate gold nanoparticles (AuNPs) and their agglomerates in blood. Rich information about nanoparticle agglomeration in situ is provided by hsDFM monitoring of the plasmon resonance of primary nanoparticles and their agglomerates in whole blood; cRM is an effective complement to hsDFM to detect AuNP agglomerates in minimally manipulated samples. The AuNPs and the particle agglomerates were further distinguished in blood for the first time by quantification of particle mass using spICP-MS with excellent sensitivity and specificity. Furthermore, the agglomeration status of synthesized and commercial NPs incubated in blood was successfully assessed using the developed methods. Together, these complementary methods enable rapid determination of the agglomeration status of plasmonic nanomaterials in biological systems, specifically blood.
authors.affiliation: NCTR/ORA Nanotechnology Core Facility, U.S. Food and Drug Administration, Jefferson, AR 72079, United States; Department of Chemistry and Biochemistry, University of Arkansas, Fayetteville, AR 72701, United States.
authors.forename: Samir V
authors.initials: SV
authors.lastname: Jenkins
authors.affiliation: NCTR/ORA Nanotechnology Core Facility, U.S. Food and Drug Administration, Jefferson, AR 72079, United States; Arkansas Regional Laboratory, Office of Regulatory Affairs, U.S. Food and Drug Administration, Jefferson, AR 72079, United States.
authors.forename: Haiou
authors.initials: H
authors.lastname: Qu
authors.affiliation: NCTR/ORA Nanotechnology Core Facility, U.S. Food and Drug Administration, Jefferson, AR 72079, United States; Arkansas Regional Laboratory, Office of Regulatory Affairs, U.S. Food and Drug Administration, Jefferson, AR 72079, United States.
authors.forename: Thilak
authors.initials: T
authors.lastname: Mudalige
authors.affiliation: NCTR/ORA Nanotechnology Core Facility, U.S. Food and Drug Administration, Jefferson, AR 72079, United States; Office of Scientific Coordination, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, United States.
authors.forename: Taylor M
authors.initials: TM
authors.lastname: Ingle
authors.affiliation: NCTR/ORA Nanotechnology Core Facility, U.S. Food and Drug Administration, Jefferson, AR 72079, United States; Office of Scientific Coordination, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, United States; Hunan Province of Food and Drug Control, Changsha, Hunan 410001, China.
authors.forename: Rongrong
authors.initials: R
authors.lastname: Wang
authors.affiliation: Department of Chemistry and Biochemistry, University of Arkansas, Fayetteville, AR 72701, United States.
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.affiliation: NCTR/ORA Nanotechnology Core Facility, U.S. Food and Drug Administration, Jefferson, AR 72079, United States; Office of Scientific Coordination, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, United States.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Howard
authors.affiliation: Department of Chemistry and Biochemistry, University of Arkansas, Fayetteville, AR 72701, United States.
authors.forename: Jingyi
authors.initials: J
authors.lastname: Chen
authors.affiliation: NCTR/ORA Nanotechnology Core Facility, U.S. Food and Drug Administration, Jefferson, AR 72079, United States; Office of Scientific Coordination, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, United States. Electronic address: Yongbin.Zhang@fda.hhs.gov.
authors.forename: Yongbin
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001769:Blood / Q000378:metabolism*; D002951:Citrates / Q000737:chemistry; D053768:Metal Nanoparticles / Q000032:analysis* / Q000737:chemistry* / Q000648:ultrastructure; D008853:Microscopy; D011916:Rats, Inbred F344; D012542:Scattering, Radiation; D013054:Spectrophotometry, Atomic; D013059:Spectrum Analysis, Raman
chemical_list: D002951:Citrates
keywords: Blood; Darkfield microscopy; Gold; Nanoparticles; Silver; Single particle ICP-MS