Intracellular uptake of poly(ethylene glycol) and folic acid modified magnetite nanoparticles
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Intracellular uptake of poly(ethylene glycol) and folic acid modified magnetite nanoparticles Yong Zhang, Nathan Kohler, and Miqin Zhang Department of Materials Science & Engineering, University of Washington Seattle, WA 98195-2120, U.S.A. ABSTRACT Superparamagnetic magnetite nanoparticles were surface-modified with poly (ethylene glycol) (PEG) or folic acid, to resist the protein adsorption and avoid their recognition by macrophage cells, and to improve their cell internalization and ability to target specific cells. The nanoparticle uptake into human osteosarcoma cells, MG63, was visualized using both fluorescence and confocal microscopy, and quantified using inductively coupled plasma emission spectroscopy (ICP) measurement. Fluorescence and confocal microscopy results showed that the nanoparticles were internalized into the cells after the cells were cultured for 48h in the medium containing the nanoparticles modified with PEG or folic acid. ICP measurements indicated that both the PEG and folic acid modification increased the amount of the nanoparticle uptake into the cells, in comparison with that of unmodified nanoparticles. INTRODUCTION Superparamagnetic nanoparticles have been studied for applications in cell separation [1], MRI contrast enhancement [2], drug delivery [3], and magnetic-field-assisted radionuclide therapy [4]. Among these applications, internalization of magnetic nanoparticle into target cells is the critical step. The nanoparticle intracellular uptake process generally involves two steps: (1) nanoparticles are selectively attached to the target cells, i.e., cell recognition; and (2) intracellular access of the nanoparticles from the cell membranes, i.e. receptor mediated endocytosis. Problems yet to be solved for the internalization process are: (a) rapid elimination of the nanoparticles from the blood stream after they have been injected intravascularly; (b) nonspecific targeting; and (c) low efficiency of internalization of endocytosed ligands grafted on the nanoparticles [5]. The rapid elimination of nanoparticles from the blood stream is due to their recognition by the macrophages of the mononuclear phagocyte system (MPS) as a consequence of the adsorption of blood proteins (opsonins) onto the nanoparticle surface [6]. It is possible to modify the nanoparticle surface with hydrophilic, flexible, and nonionic polymers, such as poly(ethylene glycol) (PEG) to minimize or eliminate the protein adsorption. Surfaces covered with polyethylene glycol (PEG) are biocompatible, i.e. nonimmunogenic, nonantigenic, and protein-resistive, because PEG has uncharged hydrophilic groups and very high surface mobility leading to high steric exclusion [7, 8]. For targeting specific cells, low molecular weight (MW) targeting agents, such as folic acid, is frequently overexpressed on the surface of human tumor cells [9]. Being absent from most normal cells, this receptor has been used as a tumor marker [10]. In addition, the folate receptor is efficiently cell internalized after binding with its ligand, i.e.
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