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.

Tumor Targeted Albumin Coated Bismuth Sulfide Nanoparticles (Bi2S3) as Radiosensitizers and Carriers of Curcumin for Enhanced Chemoradiation Therapy

“…The FA conjugate was used to target delivery of the synthesized nanoparticles to the tumor site. 28,29 For example, Huang et al reported FA conjugated silica-modified gold nanorods as targeted CT imaging and also radiation therapy. 30 Second, for combination chemotherapy and radio therapy the CUR was loaded on Bi 2 S 3 @BSA-FA (Bi 2 S 3 @BSA-FA-CUR).…”

“…The amount of conjugated FA was determined by UV–vis spectrophotometry analysis and calculated to be 0.9 ± 0.31 mg FA per 100 mg Bi 2 S 3 @BSA-FA. The FA conjugate was used to target delivery of the synthesized nanoparticles to the tumor site. , For example, Huang et al reported FA conjugated silica-modified gold nanorods as targeted CT imaging and also radiation therapy …”

Distributions: The Importance of the Chemist’s Molecular View for Biological Materials

“…We have demonstrated non-Gaussian distributions in collagen nanomorphology with D -spacing measured from 59 to 75 nm. 13−20 We found that, in general, there is very little variation in D -spacings within bundles (groups of aligned fibrils) but large variations between bundles. 18 Existing models of collagen structure cannot explain these D -spacing distributions, but a recent study documented changes in collagen structure at all levels of hierarchy, including D -spacing, as a function of disease.…”

“…The structure and function of serum FBP have been extensively detailed by ourselves 11−13,51,79 and others. 80−95 For the purposes of this Perspective, it is important to note that FBP is derived from membrane-bound folate receptors (FRs) and plays a critical role in the complex, multiprotein process of cellular uptake of FA and in embryonic development.…”

“…We complemented these methods with other bulk techniques, notably NMR and fluorescence spectroscopy, mass spectrometry, DLS, confocal microscopy, and fluorescence lifetime imaging microscopy (FLIM). We demonstrated that rp-HPLC can be used to separate trailing and branching defects in poly­(amidoamine) (PAMAM) dendrimers − and separate species with different numbers of hydrophobic ligands (dyes, drugs, targeting agents) attached to the hydrophilic backbone. − AFM allowed for direct, representative imaging of samples and surfaces with nanometer precision in the x and y directions and subnanometer precision vertically. − Importantly, AFM is a topographic technique, measuring the volume of imaged features along with surface morphology and material properties. Hierarchical features from the nanometer to micron scale can be characterized, and no staining is required for contrast .…”