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WIREs Nanomed Nanobiotechnol
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Using the magnetosome to model effective gene‐based contrast for magnetic resonance imaging

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Abstract Formation of iron biominerals is a naturally occurring phenomenon, particularly among magnetotactic bacteria which produce magnetite (Fe3O4) in a subcellular compartment termed the magnetosome. Under the control of numerous genes, the magnetosome serves as a model upon which to (1) develop gene‐based contrast in mammalian cells and (2) provide a mechanism for reporter gene expression in magnetic resonance imaging (MRI). There are two main components to the magnetosome: the biomineral and the lipid bilayer that surrounds it. Both are essential for magnetotaxis in a variety of magnetotactic bacteria, but nonessential for cell survival. Through comparative genome analysis, a subset of genes characteristic of the magnetotactic phenotype has been found both within and outside a magnetosome genomic island. The functions of magnetosome‐associated proteins reflect the complex nature of this intracellular structure and include vesicle formation, cytoskeletal attachment, iron transport, and crystallization. Examination of magnetosome genes and structure indicates a protein‐directed and stepwise assembly of the magnetosome compartment. Attachment of magnetosomes along a cytoskeletal filament aligns the magnetic particles such that the cell may be propelled along an external magnetic field. Interest in this form of magnetotaxis has prompted research in several areas of medicine, including magnetotactic bacterial targeting of tumors, MR‐guided movement of magnetosome‐bearing cells through vessels and molecular imaging of mammalian cells using MRI, and its hybrid modalities. The potential adaptation of magnetosome genes for noninvasive medical imaging provides new opportunities for development of reporter gene expression for MRI. WIREs Nanomed Nanobiotechnol 2012, 4:378–388. doi: 10.1002/wnan.1165 This article is categorized under: Diagnostic Tools > Diagnostic Nanodevices Diagnostic Tools > In Vivo Nanodiagnostics and Imaging

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Model of magnetosome synthesis. The magnetosome is formed through a protein‐directed process by invagination of the inner plasma membrane of magnetotactic bacteria. The newly formed vesicle is attached to a cytoskeletal structure termed the magnetosome filament by virtue of the interaction between MamJ and MamK. Iron is actively imported into the magnetosome and incorporated into the magnetite crystal. The latter shape and size are determined by a number of proteins, including Mms6 (see Ref 18, Figure 4, p. 983). (Reprinted with permission from Ref 18. Copyright 2008 the Royal Society)

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Effect of MagA and Mms6 expression on transverse relaxation rate (R2) in mammalian cells. MagA‐expressing (a) and Mms6‐expressing cells (b) were cultured in various concentrations of iron‐supplemented media. R2 relaxation rate of MagA‐expressing cells increased to approximately 9 s−1 as the iron concentration was increased to 200 µM (a) (see Ref 40, Figure 1, p. 1227). (Reprinted with permission from Ref 40. Copyright 2008 Magnetic Resonance in Medicine). R2 relaxation rate of Mms6‐expressing cells was also measured in the range of 0–200 µM ferric nitrate [indicated by a blue line in (a)]. Mms6 expression produced less variability in the transverse relaxation rate compared to MagA expression (b) (see Ref 54, Figure 3). (Reprinted with permission from Ref 54. Copyright 2011 International Society for Magnetic Resonance in Medicine)

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Imaging cancer growth from MagA‐expressing tumor cells. (a and b) Axial cross sections of an anesthetized mouse show the tumor growth from MagA‐expressing cells (L) and parental controls (R) at day 14 post‐injection. The spine of the animal is down and the head is toward the viewer; arrows point to tumors. A large region of signal loss (inset, arrowhead) was observed in the MagA‐expressing tumor (c). In contrast, a smaller region of signal loss was observed in the parental tumor (d). Scanning was performed using a 3D balanced‐steady‐state free precession (b‐SSFP) pulse sequence with a custom‐built radio frequency (RF) coil and gradient insert. Scanning parameters were as follows: FOV = 3 cm, flip angle = 20°, TR/TE = 10/5 ms, phase cycling = 10, and resolution = 200 × 200 × 200 µm3. Scan time was 32 min.

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Reporter gene expression. (a) Intracellular transcription factors regulate reporter gene expression through protein–protein and protein–DNA interactions with activating sequences found in the promoter (P). Choice of reporter gene expression for medical imaging varies with the detection modality. (b) Dual modality reporter gene expression may be designed such that recognition of a given sequence [minimal sodium iodide symporter (NIS) promoter] stimulates the expression of two reporter genes (MagA and NIS). In this way, both MR contrast and radioiodide can be detected in the same cell.

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