Lactoferrin-conjugated poly(ethylene glycol)-coated FeO nanoparticles

The lactoferrin (Lf)-conjugated poly(ethylene glycol) (PEG)-coated FeO nanoparticles, abbreviated as FeO-Lf, was synthesized by Qiao et al. for use as a contrast agent for magnetic resonance imaging (MRI) of the brain (1). As a ligand, Lf acts to enhance the blood–brain barrier (BBB) penetration and Lf receptor-targeting of FeO-Lf. BBB is composed of tight junction-sealed brain capillary endothelial cells (BCECs) and supporting pericytes and astrocytic endfeet (2). Exogenous compounds are prevented by the BBB from reaching the brain by passive transport or through the paracellular route (3). Because many proteins including Lf could effectively cross the BBB through transcytosis, an active transport mechanism of BCECs, this mechanism has been actively used to design brain-targeted delivery systems for targeted imaging and therapy of neurological diseases (4, 5). Mammalian Lf is a cationic iron-binding glycoprotein (80 kDa), and its receptor expresses on the endothelial cells of BBB (6). Upon binding with its receptor, Lf could cross the BBB through receptor-mediated transcytosis (5). The transport of Lf across the BBB is unidirectional, from the apical side to the basolateral side, with no apparent intraendothelial degradation (1, 7). Studies with membrane preparations of mouse brains have shown that the Lf receptor in the BCECs has two classes of binding sites: a high-affinity site that has a dissociation constant (K) of 10.61 nM and a of 410 fmol bound/µg protein; and a low-affinity site that has a K of 2,228 nM and a of 51,641 fmol bound/µg protein (5). The plasma concentration of endogenous Lf (~5 nM) is lower than the K of Lf receptors in the BBB, which avoids the competitive inhibition of endogenous Lf to exogenous Lf-conjugated agents (1). Lf receptor has also been shown to be overexpressed in various tumors including brain glioma (8). Because of these features, Lf has been applied as a ligand in designing brain-targeted delivery systems. Xie et al. conjugated Lf to superparamagnetic iron oxide nanoparticles (SPIONs) to develop the contrast agent Lf-SPION (8), while Qiao et al. developed the agent FeO-Lf by conjugating Lf to FeO nanoparticles through PEG (1). For the former agent, Lf was designed to target Lf-SPIONs to tumors expressing the Lf receptor. For the latter agent, Lf served to enhance the BBB-penetrating ability of FeO-Lf by targeting Lf receptors expressed in the BCECs. Studies with the two agents showed that Lf-SPIONs were able to effectively enhance the glioma contrast, and FeO-Lf could effectively penetrate the BBB in healthy rats because of the conjugation of Lf (1, 8). This chapter summarizes the data obtained by Qiao et al. with FeO-Lf.