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WIREs Nanomed Nanobiotechnol
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Monodisperse magnetic nanoparticles for biodetection, imaging, and drug delivery: a versatile and evolving technology

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Advances in nanotechnology have pushed forward the synthesis of a variety of functional nanoparticles (NPs) such as semiconductor quantum dots (QDs), magnetic and metallic NPs. The unique electronic, magnetic, and optical properties exhibited by these nanometer‐sized materials have enabled a broad spectrum of biomedical applications. In particular, iron‐oxide‐based magnetic NPs have proved to be highly versatile deep‐tissue imaging agents, having been incorporated into clinical applications due to their biocompatibility. This Interdisciplinary Review will focus on the recent advances in strategies for the synthesis and surface modification of highly monodisperse magnetic NPs and their use in imaging, drug delivery, and innovative ultrasensitive bioassays. Copyright © 2009 John Wiley & Sons, Inc.

Figure 1.

Magnetization behavior of ferromagnetic and superparamagnetic NPs under an external magnetic field. (a) Under an external magnetic field, domains of a ferromagnetic NP align with the applied field. The magnetic moment of single‐domain superparamagnetic NPs aligns with the applied field. In the absence of an external field, ferromagnetic NPs will maintain a net magnetization, whereas superparamagnetic NPs will exhibit no net magnetization due to rapid reversal of magnetic moment. (b) Relationship between NP size and the magnetic domain structures. Ds and Dc are the ‘superparamagnetism’ and ‘critical’ size thresholds.

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Figure 2.

TEM micrographs of iron oxide NPs with diameters of (a) 6 nm, (b) 7 nm, (c) 8 nm, (d) 9 nm, (e) 10 nm, (f) 11 nm, (g) 12 nm, (h) 13 nm. The organic phase high‐temperature synthetic route enables precise control of NP size.29 (Reprinted with permission from Wiley‐VCH Verlag GmbH & Co. KGaA).

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Figure 3.

General surface modification schemes for magnetic NPs. (a) Inorganic surface coating with tetraethoxysilane produces an amorphous silica shell. Polymer coating encapsulates the magnetic NP and native surface ligands (b), whereas the ligand exchange is to replace native surface ligands (c). These routes present polar or charged functional groups onto the outer surface of the NP for water solubility.

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Figure 4.

Magnetic relaxation switching technology. (a) Schematic of the transition of dispersed magnetic NPs to nanoclusters with enhanced T2 relaxivity in the presence of ligands such as oligonucleotides. The linker‐ or ligand‐mediated aggregation of nanoclusters can be enzymatically cleaved to yield disperse NPs. (b) AFM image of discrete magnetic NPs. (c) AFM image of nanoclustered magnetic NPs in the presence of target molecule. (d) Nucleic acid detection with MRS. A T2‐weighted color‐coded MR image of wells of a 384‐well plate. Each well contains similar amounts of probes. The concentration of matching and mis‐matching target sequence is varied. (e) Decrease in T2 as a function of target sequence concentration, demonstrating detection sensitivity as low as 500 attomoles.114 (Reprinted with permission from Ref 114. Copyright 2002 Macmillan Publishers Ltd.).

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Figure 5.

Ultrasensitive detection schemes for assays developed by Mirkin and Groves. (a) Fluorophore‐based bio‐barcode amplification assay to detect proteins developed by Mirkin.126 (Reproduced with permission from Wiley‐VCH Verlag GmbH & Co. KGaA.) (b) Colorimetric bio‐barcode amplification assay to detect cytokines developed by Groves.127 (Reprinted with permission from Ref 127. Copyright 2007 Macmillan Publishers Ltd). Both assays employ the magnetic NP‐loaded microbeads for the separation of positive binding events from the false‐positive background in order to increase signal‐to‐noise ratio. The high sensitivity of these assays is attributed to the high copy‐number of dye‐labeled barcode DNA and strong optical properties associated with gold NPs, respectively.

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Figure 6.

In vivo MR detection of cancer using magnetic NP‐Herceptin bioconjugates. (A) Color maps of T2‐weighted MR images of a mouse implanted with the cancer cell line NIH3T6.7 at different time points after injection of MnFe2O4–Herceptin conjugates or CLIO–Herceptin conjugates [pre‐injection (a,d), 1 h (b,e), or 2 h (c,f) after injection]. In (a–c), gradual color changes at the tumor site, from red (low R2) to blue (high R2), indicate progressive targeting by MnFe2O4–Herceptin conjugates. In contrast, almost no change was seen in the mouse treated with CLIO–Herceptin conjugates (d–f).130 (Reprinted with permission from Macmillan Publishers Ltd. Copyright 2006). (B) T2*‐weighted in vivo MR images of NIH3T6.7 cancer cells implanted in mouse model imaged at 9.4 T. Top panel: Tumor area is circled with white dotted lines, and red dotted lines indicate the hypointense contrast provided by Fe3O4 SPIOs. Bottom panel: color‐coded MR images to further delineate MR signal changes. The temporal changes in the color maps indicate progressive diffusion and targeting events of the probes (low T2* signal).143 (Reprinted with permission from Ref 143. Copyright 2005 American Chemical Society.).

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Figure 7.

Confocal laser scanning microscopy of DOXO fluorescence and optical images of multifunctional PLGA NPs developed by Hyeon et al. in KB cells treated with: (a) naked PLGA(SPIO/DOXO), (b) PLGA(SPIO/DOXO)‐PEG, (c) PLGA(SPIO/DOXO)‐Folate NPs and (d) PLGA(SPIO/DOXO)‐Folate NPs exposed to an external magnetic field.178 The fluorescence increase indicates the increase in multifunctional NP uptake mediated by the folate ligand and further uptake enhancement by the presence of an external magnetic field. (Reprinted with permission from Wiley‐VCH Verlag GmbH & Co KGaA).

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Figure 8.

In vivo near‐infrared optical imaging of SPIO‐siGFP constructs and effects on gene silencing in tumors. Mice with bilateral 9L‐GFP and 9L‐RFP tumors are imaged before and 48 h after intravenous probe injection. Substantial decrease in 9L‐GFP‐associated fluorescence was observed, in contrast to 9L‐RFP (no change). GFP and RFP images were acquired individually and later merged.190 (Reprinted with permission from Ref 190. Copyright 2007 Macmillan Publishers Ltd.).

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Robert Langer

Robert Langer

works at the interface of biotechnology and materials science. His lab is researching many topics, such as investigating the mechanism of release from polymeric delivery systems with concomitant microstructural analysis and mathematical modeling; studying applications of these systems including the development of effective long-term delivery systems for insulin, anti-cancer drugs, growth factors, gene therapy agents and vaccines; developing controlled release systems that can be magnetically, ultrasonically, or enzymatically triggered to increase release rates; synthesizing new biodegradable polymeric delivery systems which will ultimately be absorbed by the body; creating new approaches for delivering drugs such as proteins and genes across complex barriers such as the blood-brain barrier, the intestine, the lung and the skin; stem cell research including controlling growth and differentiation; and creating new biomaterials with shape memory or surface switching properties.

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