title: Folate-Binding Protein Self-Aggregation Drives Agglomeration of Folic Acid Targeted Iron Oxide Nanoparticles.
abstract: Folate-conjugated nanomaterials have been widely investigated for drug and imaging-agent delivery. In this work, two folic acid (FA) conjugated iron oxide particles (IOP), a ∼40 nm diameter FA-IOP and a ∼450 nm diameter FA-IOP(FA-SeraMag), were synthesized. Both particles aggregated in the presence of serum folate-binding protein (FBP) at physiological concentration and buffer conditions. Mixing 0.01% w/w FA-conjugated iron oxide particles with FBP-induced agglomeration generated an average hydrodynamic particle diameter of 3800 ± 1100 nm for ∼40 nm FA-IOP and 4030 ± 1100 nm for FA-SeraMag as measured by dynamic light scattering (DLS). The presence of excess human serum albumin (HSA) (600 μM) did not prevent agglomeration of the ∼40 nm FA-IOP; however, it did inhibit agglomeration of FA-SeraMag. Atomic force microscopy measurement provided additional insight into particle morphology with the detection of individual particles in the agglomerate. This behavior is an example of a triggered cascade. A protein structural change is induced by FA binding, and the structural change favors aggregation of the ∼4 nm diameter FBPs on the particle surface; this further triggers the agglomeration of both the ∼40 and ∼450 nm diameter IOPs.
authors.affiliation: Department of Chemistry, ‡Department of Biomedical Engineering, §Department of Physics, and ∥Program in Macromolecular Science and Engineering, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Junjie
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Chemistry, ‡Department of Biomedical Engineering, §Department of Physics, and ∥Program in Macromolecular Science and Engineering, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Sarah
authors.initials: S
authors.lastname: Klem
authors.affiliation: Department of Chemistry, ‡Department of Biomedical Engineering, §Department of Physics, and ∥Program in Macromolecular Science and Engineering, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Alexis K
authors.initials: AK
authors.lastname: Jones
authors.affiliation: Department of Chemistry, ‡Department of Biomedical Engineering, §Department of Physics, and ∥Program in Macromolecular Science and Engineering, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Bradford
authors.initials: B
authors.lastname: Orr
authors.affiliation: Department of Chemistry, ‡Department of Biomedical Engineering, §Department of Physics, and ∥Program in Macromolecular Science and Engineering, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Mark M
authors.identifier: 0000-0001-7759-7456
authors.initials: MM
authors.lastname: Banaszak Holl
mesh_terms: D005290:Ferric Compounds / Q000378:metabolism*; D005492:Folic Acid / Q000378:metabolism*; D058972:Folic Acid Transporters / Q000378:metabolism*; D006801:Humans; D053768:Metal Nanoparticles; D018625:Microscopy, Atomic Force; D012709:Serum Albumin / Q000378:metabolism; D013499:Surface Properties
chemical_list: D005290:Ferric Compounds; D058972:Folic Acid Transporters; D012709:Serum Albumin; C000499:ferric oxide; D005492:Folic Acid