Folate receptor targeted, rare-earth oxide nanocrystals for bi-modal fluorescence and magnetic imaging of cancer cells

Targeted cancer imaging using rare-earth oxide nanocrystals, free from heavy metals (Cd, Se, Te, Hg and Pb), showing bright red-fluorescence and magnetic resonance imaging (MRI) is presented. Y2O3 nanocrystals (YO NC) doped in situ with fluorescent (Eu3+) and paramagnetic (Gd3+) impurities and conjugated with a potential cancer targeting ligand, folic acid (FA), were prepared using an all-aqueous wet-chemical process. Structural, optical and magnetic properties of these multifunctional nanocrystals were investigated by X-ray diffraction, electron microscopy, photoluminescence and magnetization studies. Highly monodisperse nanocrystals of size similar to 20 nm with cubic bixbyite crystal structure showed bright red-fluorescence when doped with Eu3+. Co-doping with Gd3+ and mild air drying resulted significantly enhanced fluorescence quantum efficiency of similar to 60% together with paramagnetic functionality, enabling T-1-weighted MR contrast with similar to 5 times higher spin-lattice relaxivity compared to the clinically used Gd3+ contrast agent. Cytotoxicity and reactive oxygen stress studies show no toxicity by YO NC in both normal and cancer cells up to higher doses of 500 mu M and longer incubation time, 48 h. Cancer targeting capability of FA conjugated NCs was demonstrated on folate receptor positive (FR+) human nasopharyngeal carcinoma cells (KB) with FR depressed KB (FRd) and FR negative (FR-) lung cancer cells A549 as controls. Fluorescence microscopy and flow-cytometry data show highly specific binding and cellular uptake of large concentration of FA conjugated NCs on FR+ve cells compared to the controls. Thus, the present study reveals, unique bi-modal contrast imaging capability, non-toxicity and cancer targeting capability of multiple impurities doped rare-earth oxide nanocrystals that can find promising application in molecular imaging. (C) 2009 Elsevier Ltd. All rights reserved.