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WIREs Nanomed Nanobiotechnol
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Magnetic nanoparticle biosensors

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Abstract One of the major challenges in medicine is the rapid and accurate measurement of protein biomarkers, cells, and pathogens in biological samples. A number of new diagnostic platforms have recently been developed to measure biomolecules and cells with high sensitivity that could enable early disease detection or provide valuable insights into biology at the systems level. Most biological samples exhibit negligible magnetic susceptibility; therefore, magnetic nanoparticles have been used for diverse applications including biosensing, magnetic separation, and thermal ablation therapy. This review focuses on the use of magnetic nanoparticles for detection of biomolecules and cells based on magnetic resonance effects using a general detection platform termed diagnostic magnetic resonance (DMR). DMR technology encompasses numerous assay configurations and sensing principles, and to date magnetic nanoparticle biosensors have been designed to detect a wide range of targets including DNA/mRNA, proteins, enzymes, drugs, pathogens, and tumor cells. The core principle behind DMR is the use of magnetic nanoparticles as proximity sensors that modulate the spin‐spin relaxation time of neighboring water molecules, which can be quantified using clinical MRI scanners or benchtop nuclear magnetic resonance (NMR) relaxometers. Recently, the capabilities of DMR technology were advanced considerably with the development of miniaturized, chip‐based NMR (µNMR) detector systems that are capable of performing highly sensitive measurements on microliter sample volumes and in multiplexed format. With these and future advances in mind, DMR biosensor technology holds considerable promise to provide a high‐throughput, low‐cost, and portable platform for large scale molecular and cellular screening in clinical and point‐of‐care settings. WIREs Nanomed Nanobiotechnol 2010 2 291–304 This article is categorized under: Diagnostic Tools > Biosensing Diagnostic Tools > In Vitro Nanoparticle-Based Sensing

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Principles of DMR sensing assays using magnetic nanoparticles. (a) Magnetic relaxation switching assays involve assembly of magnetic nanoparticle clusters using a target biomarker as a cross‐linking bridge, or disassembly of preformed clusters using an enzyme or competitive binding. Clustering magnetic nanoparticles causes them to more efficiently dephase the nuclear spins of neighboring water molecules, shortening the transverse relaxation time (T2). Likewise, disassembly of clusters increases T2 relaxation time. (b) Tagging cells with magnetic nanoparticles imparts a magnetic moment that is proportional to the number of nanoparticles bound. Following washing procedures to remove unbound nanoparticles, the magnetic moment can be measured as a decrease in T2 relaxation time. (Reprinted with permission from Ref 25. Copyright 2008 Nature Publishing Group).

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Tumor cell detection and profiling using the µNMR device. (a) Her2/neu was detected on the surface of the breast cancer cell line BT474 using anti‐Her2 CLIO and Mn‐MNP nanoparticles. The change in R2 varied linearly with cell number, and detection sensitivity was greater using the more magnetic Mn‐MNP. (b) Detection threshold was approximately two cells in the 1‐µl sample volume using the Mn‐MNP nanoparticles. (c) DMR results correlated well with other molecular detection techniques (Western blot and flow cytometry), but required substantially fewer cells. (d) Profiling of fine‐needle aspirates obtained from a panel of mouse tumor xenografts for the cancer markers Her2/neu, EGFR, and EpCAM. A control particle was used as an estimate of cell concentration based on non‐specific phagocytosis. Use of the three‐marker approach increased the success rate of a correct cancer ‘diagnosis’. (Reprinted with permission from Ref 26. Copyright 2009 National Academy of Sciences, USA).

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Detection of tuberculosis (TB) bacteria using the µNMR device by tagging cells with magnetic nanoparticles. (a) Using a membrane filter mounted at the outlet of the microcoil probe, bacterial samples could be concentrated, washed of excess magnetic nanoparticles, and resuspended prior to measurement of T2 relaxation time. (b) Detection threshold was approximately 100 colony‐forming units (CFUs) using CLIO nanoparticles and 6 CFUs using the higher relaxivity cannonball nanoparticles. Sensitivity was increased to ∼1 CFU in 1 ml of sample using filtration. (Reprinted with permission from Ref 27. Copyright 2009 John Wiley and Sons, Inc.).

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Dual MRSw sensor system to detect human telomerase (hTERT) protein and activity levels. (a) Schematic depicting the two magnetic nanoparticle sensors, which hybridize with the 30‐base pair telomeric repeat sequences (hTERT activity) or bind the hTERT protein directly using a polyclonal antibody. (b) Detection of hTERT protein in cell lysates from various cell types by MR imaging. (c) Parallel detection of hTERT protein and activity in cell lysates, demonstrating the lack of correlation between protein and activity levels. (Reprinted with permission from Ref 56. Copyright 2008 Neoplasia Press, Inc.).

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Detection of oligonucleotides, protein, and enzyme activity using MRSw sensors. (a) T2‐weighted MR image of a 384‐well plate containing varying amounts (0.5–2.7 fmol) of target or mismatched oligonucleotide and constant levels of two magnetic nanoparticle populations conjugated with different oligonucleotides complimentary to the target. Formation of nanoparticle clusters by hybridization with the target resulted in a reduction in T2 relaxation time that varied linearly with the amount of target added. (b) Magnetic nanoparticles conjugated with a polyclonal antibody specific for GFP were incubated with GFP protein or BSA as a control. T2 relaxation time decreased linearly with protein concentration, attaining a steady state within 30 min. (c) Magnetic nanoparticles were clustered using a linker containing the peptide sequence DEVD and were rapidly (∼10 min) dissociated upon addition of caspase‐3 enzyme, resulting in an increase in T2 relaxation time. (Reprinted with permission from Ref 22. Copyright 2002 Nature Publishing Group).

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Schematic diagram of the miniaturized NMR device developed for DMR. (a) The original system, consisting of an array of planar microcoils for NMR measurements, microfluidic networks for sample handling and mixing, miniaturized NMR electronics, and a small, portable magnet for polarizing magnetic field generation. Insets depict (clockwise) a planar microcoil, schematic of the NMR electronics, and a microfluidic mixing network. (b) The second‐generation µNMR with solenoidal coil embedded in a PDMS microfluidic network, which increased filling factor, reduced signal‐to‐noise ratio, and decreased the required sample volume to ∼1 μl. The probe was mounted along with all NMR electronics on a single CMOS IC chip. (c) Depiction of a membrane filter that can be mounted at the coil outlet, enabling concentration of large samples (i.e., cells) and removal of smaller impurities. (Reprinted with permission from Ref 25. Copyright 2008 Nature Publishing Group. Reprinted with permission from Ref 26. Copyright 2009 National Academy of Sciences, USA. Reprinted with permission from Ref 27 Copyright 2009 John Wiley and Sons, Inc.).

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Higher relaxivity magnetic nanoparticles developed to improve DMR detection sensitivity. (a) Transmission electron micrograph (TEM) of manganese‐doped ferrite magnetic nanoparticles (Mn‐MNP), demonstrating narrow size distribution and high crystallinity. The magnetic core was synthesized using a seed‐growth method to produce 10, 12, 16, and 22 nm crystals. (b) TEM of elemental iron (Fe) core/ferrite shell magnetic nanoparticles (‘cannonballs’) with 11 nm core diameter and 2.5 nm shell thickness. The Fe‐core was synthesized by thermal decomposition followed by controlled oxidation using oxygen gas to produce the ferrite shell, which protected the core from further oxidation. (c) For their size, the Mn‐MNP and cannonballs exhibit higher relaxivity compared to other commercially available or reported magnetic nanoparticles. (Reprinted with permission from Ref 26. Copyright 2009 National Academy of Sciences, USA. Reprinted with permission from Ref 27. Copyright 2009 John Wiley and Sons, Inc.).

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