Bimodal Magnetic–Fluorescent Probes for Bioimaging DOMINIK JAN ´ CZEWSKI, 1 YAN ZHANG, 2 GAUTOM KUMAR DAS, 2 DONG KEE YI, 3 PARASURAMAN PADMANABHAN, 4 KISHORE K. BHAKOO, 4 TIMOTHY THATT YANG TAN, 2 * AND SUBRAMANIAN TAMIL SELVAN 1 * 1 Institute of Materials Research and Engineering, 3 Research Link, Singapore 117602 2 Division of Chemical and Biomolecular Engineering, School of Chemical and Biomedical Engineering, Nanyang Technological University, Singapore 637459 3 Division of Bionanotechnology, Kyungwon University, Seong Nam City, Republic of Korea 4 Translational Molecular Imaging Group, Singapore Bioimaging Consortium, Singapore 138667 KEY WORDS quantum dots; magnetic nanoparticles; rare-earth nanoparticles; bimodal fluorescent probes; bioimaging ABSTRACT Fluorescent optical probes have been intensively used in the area of bio-imaging. In this review article, we describe the recent advancements in the synthesis and application of bi- modal magnetic–fluorescent probes for bioimaging. The bimodal probes consist of fluorescent [semiconducting quantum dots (e.g., CdSe/ZnS) or rare-earth doped (e.g., NaYF 4 :Yb,Er)] nano- particles (NPs) and magnetic (iron oxide or gadolinium based) NPs for optical and magnetic resonance (MR) imaging. Microsc. Res. Tech. 74:563–576, 2011. V V C 2010 Wiley-Liss, Inc. INTRODUCTION Recently, inorganic nanoparticles (NPs), such as, metal, semiconductor, magnetic and rare-earth (RE), have attracted immense interest in the area of bio- imaging. This review focuses mainly on the synthesis and application of bimodal magnetic–fluorescent probes for bioimaging. The review is organized as follows: First, we review recent advances in inorganic NPs with an emphasis on fluorescent and magnetic probes. Second, we describe the recent advances in the assemblies of (i) superparamagnetic iron oxide (SPIO)– quantum dot (QD) based magnetic–fluorescent probes, (ii) SPIO–RE based magnetic–fluorescent probes, (iii) Gd 31 -based magnetic contrast agent covalently attached to fluorescent (QDs or organic dyes) probes, and (iv) Gd 31 -based MRI agents and fluorescent probes in one nanomaterial domain. Finally, we end the article with concluding remarks. Advances in Quantum Dots and Magnetic NPs Quantum Dots (QDs) are semiconducting NPs and the typical examples of II-VI QDs are CdSe, CdS, and CdTe. By varying the size in the inorganic synthesis, the emission colors can be tuned. Because of quantum confinement effect, QDs can exhibit remarkable size- dependent optical properties. For example, ZnS-capped CdSe QDs can emit across the entire visible spectrum when the size of the crystal is varied from 2 to 6 nm. These QDs can also be excited with a single excitation source and they remain photostable over a longer period of time. These properties render the QDs more advantageous over organic dyes in the area of imaging. There are some excellent reviews on QDs for imaging applications (Koole et al., 2009; Medintz et al., 2005; Singhal et al., 2010). SPIO particles are another interesting class of NPs that have generated considerable interest because of superparamagnetic properties and small dimensions. Iron oxide (either c-Fe 2 O 3 or Fe 3 O 4 ) NPs are generally employed as T 2 (negative) contrast agents in magnetic resonance imaging (MRI) applications. Recently, mag- netic NPs (Fe 2 O 3 , Fe 3 O 4 , MFe 2 O 4 , where M 5 Ni, Co, Mn, or Fe) have been used as negative T 2 contrast agents for MRI (Lee et al., 2007b). NP clusters contain- ing a few NPs exhibited much higher magnetization values and improved contrast in MRI application (Berret et al., 2006; Ge et al., 2007; Happy et al., 2010). Additionally, magnetic particles have been investigated in MRI and MR force microscopy (MRFM) (Degen et al., 2009) and in biosensing (Osterfeld et al., 2008). Paramagnetic NPs (2–4 nm) were used to detect the very small area of angiogenesis in a noninvasive way (Schmieder et al., 2005). SPIO NPs were used either to probe lymph node metastases for early breast cancer diagnosis (Harisinghani et al., 2003) or used as a drug carrier (Shkilnyy et al., 2010), and also used for RF hyperthermia of cancer cells (Xu et al., 2010). Advances in Rare-Earth NPs The application of lanthanides (or in other words, REs) has attracted substantial interest in biomedical field, especially in bio-imaging (Swadeshmukul et al., 2004; Yuan and Wang, 2006). Gadolinium-diethylen- triaminopentacetate (Gd-DTPA) chelates have been widely used as T 1 MRI contrast agent, since Gd 31 ion has seven unpaired electron, symmetric S states, and high relaxivities (Kim et al., 2009). These Gd-based contrast agents are normally used in the enhancement of vessels for MR angiography or brain tumor enhance- ment resulting from the blood–brain barrier (Shen *Correspondence to: Subramanian Tamil Selvan, Institute of Materials Research and Engineering, 3 Research Link, Singapore 117602. E-mail: subramaniant@ imre.a-star.edu.sg or Timothy Thatt Yang Tan, Division of Chemical and Biomolec- ular Engineering, School of Chemical and Biomedical Engineering, Nanyang Technological University, 62 Nanyang Drive, Singapore 637459. E-mail: tytan@ ntu.edu.sg Received 11 May 2010; accepted in revised form 24 June 2010 DOI 10.1002/jemt.20912 Published online 23 August 2010 in Wiley Online Library (wileyonlinelibrary.com). V V C 2010 WILEY-LISS, INC. MICROSCOPY RESEARCH AND TECHNIQUE 74:563–576 (2011)