title: Size- and charge-dependent non-specific uptake of PEGylated nanoparticles by macrophages.
abstract: The assessment of macrophage response to nanoparticles is a central component in the evaluation of new nanoparticle designs for future in vivo application. This work investigates which feature, nanoparticle size or charge, is more predictive of non-specific uptake of nanoparticles by macrophages. This was investigated by synthesizing a library of polymer-coated iron oxide micelles, spanning a range of 30-100 nm in diameter and -23 mV to +9 mV, and measuring internalization into macrophages in vitro. Nanoparticle size and charge both contributed towards non-specific uptake, but within the ranges investigated, size appears to be a more dominant predictor of uptake. Based on these results, a protease-responsive nanoparticle was synthesized, displaying a matrix metalloproteinase-9 (MMP-9)-cleavable polymeric corona. These nanoparticles are able to respond to MMP-9 activity through the shedding of 10-20 nm of hydrodynamic diameter. This MMP-9-triggered decrease in nanoparticle size also led to up to a six-fold decrease in nanoparticle internalization by macrophages and is observable by T(2)-weighted magnetic resonance imaging. These findings guide the design of imaging or therapeutic nanoparticles for in vivo targeting of macrophage activity in pathologic states.
authors.affiliation: Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235, USA.
authors.forename: Shann S
authors.initials: SS
authors.lastname: Yu
authors.forename: Cheryl M
authors.initials: CM
authors.lastname: Lau
authors.forename: Susan N
authors.initials: SN
authors.lastname: Thomas
authors.forename: W Gray
authors.initials: WG
authors.lastname: Jerome
authors.forename: David J
authors.initials: DJ
authors.lastname: Maron
authors.forename: James H
authors.initials: JH
authors.lastname: Dickerson
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Hubbell
authors.forename: Todd D
authors.initials: TD
authors.lastname: Giorgio
mesh_terms: D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005290:Ferric Compounds / Q000737:chemistry / Q000493:pharmacokinetics; D006801:Humans; D008264:Macrophages / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000737:chemistry / Q000378:metabolism; D008823:Micelles; D053758:Nanoparticles / Q000737:chemistry*; D010316:Particle Size; D011092:Polyethylene Glycols / Q000737:chemistry / Q000493:pharmacokinetics*; D011134:Polysaccharides / Q000378:metabolism; D013440:Sulfides / Q000737:chemistry / Q000493:pharmacokinetics*; D013499:Surface Properties
chemical_list: D005290:Ferric Compounds; D008823:Micelles; D011134:Polysaccharides; D013440:Sulfides; C515871:poly(ethylene glycol)-stabilized poly(propylene sulfide); C000499:ferric oxide; D011092:Polyethylene Glycols; C007789:fucoidan; D020780:Matrix Metalloproteinase 9