title: Subtumoral analysis of PRINT nanoparticle distribution reveals targeting variation based on cellular and particle properties.
abstract: The biological activity of nanoparticle-directed therapies critically depends on cellular targeting. We examined the subtumoral fate of Particle Replication in Non-Wetting Templates (PRINT) nanoparticles in a xenografted melanoma tumor model by multi-color flow cytometry and in vivo confocal tumor imaging. These approaches were compared with the typical method of whole-organ quantification by radiolabeling. In contrast to radioactivity based detection which demonstrated a linear dose-dependent accumulation in the organ, flow cytometry revealed that particle association with cancer cells became dose-independent with increased particle doses and that the majority of the nanoparticles in the tumor were associated with cancer cells despite a low fractional association. In vivo imaging demonstrated an inverse relationship between tumor cell association and other immune cells, likely macrophages. Finally, variation in particle size nonuniformly affected subtumoral association. This study demonstrates the importance of subtumoral targeting when assessing nanoparticle activity within tumors.
  
  
  BACKGROUND
  Particle Replication in Non-Wetting Templates (PRINT) technology allows the production of nanoparticles with uniform size. The authors in the study utilized PRINT-produced nanoparticles to investigate specific tumor uptake by multi-color flow cytometry and in vivo confocal tumor imaging. This approach allowed further in-depth correlation between nanoparticle properties and tumor cells and should improve future design.
authors.affiliation: Department of Pharmaceutical Sciences, Eshelman School of Pharmacy, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Luke E
authors.initials: LE
authors.lastname: Roode
authors.affiliation: Department of Cell Biology and Physiology, School of Medicine, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Hailey
authors.initials: H
authors.lastname: Brighton
authors.affiliation: Carolina Center for Nanotechnology Excellence, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Bo
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Jillian L
authors.initials: JL
authors.lastname: Perry
authors.affiliation: Carolina Center for Nanotechnology Excellence, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA; Lineberger Comprehensive Cancer Center, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA; Department of Radiology, School of Medicine, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA; Biomedical Research Imaging Center, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Parrott
authors.affiliation: Department of Radiology, School of Medicine, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Farrell
authors.initials: F
authors.lastname: Kersey
authors.affiliation: Department of Pharmaceutical Sciences, Eshelman School of Pharmacy, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA.
authors.forename: J Chris
authors.initials: JC
authors.lastname: Luft
authors.affiliation: Carolina Center for Nanotechnology Excellence, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA; Lineberger Comprehensive Cancer Center, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA; Department of Cell Biology and Physiology, School of Medicine, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA; Howard Hughes Medical Institute, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Bear
authors.affiliation: Department of Pharmaceutical Sciences, Eshelman School of Pharmacy, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA; Carolina Center for Nanotechnology Excellence, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA; Lineberger Comprehensive Cancer Center, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA; Department of Chemistry, College of Arts and Sciences, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: DeSimone
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA; Departments of Genetics and Pediatrics, School of Medicine, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA. Electronic address: ian_davis@med.unc.edu.
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Davis
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005434:Flow Cytometry; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D008545:Melanoma / Q000000981:diagnostic imaging* / Q000473:pathology; D050997:Nanomedicine; D053758:Nanoparticles / Q000008:administration & dosage / Q000009:adverse effects*; D010316:Particle Size; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
keywords: Cancer; Flow cytometry; Nanomedicine; Nanoparticle; PRINT